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MANUAL OF OPERATIONS
Secondary Prevention of
Manual of Operations Small Subcortical Strokes
Table of Contents
Topic . Section number
Introduction .I
Key SPS3 Contacts . II
Study Overview . III
Screening and Recruitment . IV
Eligibility . V
MRI in SPS3 . VI
Intracranial Arterial Imaging . VII
Measuring Blood Pressure . VIII
Characterization of Hypertension . IX
Study Entry/Randomization . X
Management of Blood Pressures . XI
Study Follow-Up . XII
Event Documentation and Processing . XIII
Premature Study Termination . XIV
Common Antihypertensive Medications . XV
Management Guidelines for Other Cerebrovascular Risk Factors . XVI
Sample Consent Form and Participant Materials . XVII
SPS3 Study Medications . XVIII
Completing SPS3 Forms . XIX
SPS3 Data Forms and Line-by-lines . XX
Data Transfer and Monitoring . XXI
Site Visits . XXII
Site payments . XXIII
Additional Training Materials .
A. How-to-get started . XXIV B. Neuropsych Examiners: Cognitive Battery Administration/Instructions . XXV C. Randomization and Data Transfer System . XXVI D. Use of Colin Automated BP Device . XXVII E. Use of Ambulatory BP Device . XXVIII F. Sending Imaging files on CD . XXIX G. Substudies . XXX Table of Contents- 03/17/11 Secondary Prevention of
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Current Date of Each Section

Section Number
Section Date
II. Key SPS3 Contacts III. Study Overview IV. Screening and Recruitment VII. Intracranial Arterial Imaging VIII. Measuring Blood Pressure IX. Characterization of Hypertension X. Study Entry/Randomization XI. Management of Blood Pressures XII. Study Follow-up XIII. Event Documentation and Processing XIV. Premature Study Termination XV. Common Antihypertensive Medications XVI. Management Guidelines for Cerebrovascular Risk Factors XVII. Sample Consent Form and Participant Materials XVIII. SPS3 Study Medications XIX. Completing SPS3 Forms See Table in Section 20 for Form/Line-by- XX. SPS3 Data Forms and Instructions Line dates and versions XXI. Data Transfer and Monitoring XXII. Site Visits XXIII. Site Payments XXIV. Getting Started XXV. Cognitive Battery/Administration XXVI. Randomization and Data Transfer System XXVII. Use of Colin Electronic BP Device XXVIII. Use of Ambulatory BP Device XXIX. Sending Imaging Files in CD XXXI. End of Study Section Dates- 03/17/11 Secondary Prevention of
Manual of Operations Small Subcortical Strokes
I. INTRODUCTION
This is the Secondary Prevention of Small Subcortical Strokes (SPS3) Manual of
Operations. It contains detailed "how-to-do-it" information, including where to look for
eligible patients, how to determine eligibility, what laboratory and other data are needed for enrollment and at each follow-up, how to randomize patients, when and how to fill out the data forms, and how to screen for stroke and study events. It is intended for use as a handbook of how-to advice on the routine (and sometimes not so routine) aspects of study operation. If the answers to your questions are not clear in this manual or the protocol, call or email us (email inquires will be answered on the same working day). Don't guess about how to do it, contact us. It is important to do it right, and if you have an unanswered question, probably others have the same question and will need the answer too. SPS3 MANUAL OF OPERATIONS MOTTO:
Don't Guess - - Ask
Get it right!
ManOp section I - 04/15/03 Secondary Prevention of
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II. KEY SPS3 CONTACTS
SPS3 Coordinating Center
SPS3 Statistical Center
S169 2211 Wesbrook Mall 1530 3rd Avenue South Vancouver, BC, V6T 2B5 Phone: (604) 822-1789 Birmingham, AL 35294-0022 Toll free: (877) 633-3612 Phone: Toll free: (866) 304-5010 WEB site: www.sps3.org
Events Coordinator:
Medical Safety Monitor:
Barney Stern, MD Axio Research Corporation University of Maryland 2601 - 4th Avenue, Ste 200 Seattle WA 98121 Phone: (410) 328-3372 Phone: (206) 577-0215 E-mail: bstern@som.umaryland.edu E-mail: elainen@axioresearch.com Fax: (410) 328-5899 For questions about patient eligibility, follow-up, events, data form completion,
patient management issues, drug supplies, etc
:
Marie-France Benavente, RN, BScN, North American SPS3 Sites Study Coordinator (UBC) Voice: (604) 822-1789 or (877) 633-3612 FAX: (604) 822-6698 Ana Roldan, MD, Latin American SPS3 Sites Study Coordinator (UBC) Voice: (604) 822-1789 or (877) 633-3612 ana.roldan@ubc.ca FAX: (604) 822-6698 Oscar Benavente, MD (UBC) Voice: (604) 822-1789 or (877) 633-3612 oscar.benavente@ubc.ca Robert Hart, MD (UTHSCSA) Voice: (210) 450-0530 or (877) 633-3612 hartr@uthscsa.edu
For questions about budget, IRB issues, administrative matters:
Camelia Robu, SPS3 Administrator (UBC) Voice: (604) 822-1789 or (877) 633-3612 camelia.robu@ubc.ca
For questions about payment invoices, SPS3 equipment (Colin electronic BP
monitor, Spaclebs ambulatory monitor),

Eduardo Martinez, SPS3 Data Manager (UTHSCSA)
Voice: (210) 450-0528 or (877) 633-3612 ManOp section II – 02/01/10 Secondary Prevention of
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For physician consultation about hypertension management:
Pablo Pergola, MD, Coordinating Center Hypertension Expert
Voice:
pergola@sbcglobal.net
For questions about drugs, drug interactions, side-effects:
Robert Talbert, PharmD
Voice: (210) 567-8318 talbert@uthscsa.edu
For questions about drug shipments:
Dave Hunt, Robert Ringer, VA Cooperative Studies Central Pharmacy
Voice:

For questions about sending neuroimaging files, CDs or MRI reprints:
Ana Roldan (UBC) Voice: (604) 822-1789 or (877) 633-3612 ana.roldan@ubc.ca
For questions about event materials:
Elaine Nasco, SPS3 Events Coordinator
Voice:

For technical questions about entering data forms and the database:
Lisa Irby, Assistant Data Manager (UAB)
Voice:
lirby@ms.soph.uab.edu; sps3@uab.edu
For patient unblinding: (contact Benavente, 778-938-0093/Hart 210-235-0972 first, -> DDC)
Dave Hunt or Robert Ringer /DDC: (505) 248-3203/ after hours follow the instructions in the message.
For questions about neuropsych testing:
Lesly
Voice: (604) 822-1789 or (877) 633-3612 sps3-psych@uthscsa.edu
For any other problem which is not satisfactorily resolved:
Oscar Benavente, MD (UBC) or Robert Hart, MD (UTHSCSA)
Voice: (604) 822-1789 or (877) 633-3612 oscar.benavente@ubc.ca; hartr@uthscsa.edu ManOp section II – 02/01/10 Secondary Prevention of
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III. STUDY OVERVIEW
Small subcortical (a.k.a. lacunar) strokes comprise about 25% of brain infarcts, occur at a younger mean age than other common stroke types, and are harbingers of vascular dementia. Most are due to intrinsic disease of the small, penetrating cerebral arteries. Despite their frequency and importance, little is known about the natural history and secondary prevention relative to other stroke subtypes (see background, SPS3 Study Protocol for more information). The overall aim of the Secondary Prevention of Small Subcortical Strokes (SPS3) project is to learn how to reduce recurrent stroke, other major vascular events and cognitive decline among survivors of S3/subcortical stroke. Randomized comparisons of two antiplatelet regimens (clopidogrel plus aspirin vs. aspirin alone) and of "usual" vs. "intensive" blood pressure lowering will be combined with efforts to identify high-risk groups. This project also focuses on subcortical vascular dementia and ethnic The main objectives of SPS3 are: 1. To compare the value of clopidogrel plus aspirin vs. aspirin alone for prevention of recurrent stroke and cognitive decline. 2. To compare the effects of "usual" vs. "intensive" blood pressure lowering in patients with recent S3 on recurrent stroke, cognitive decline, and quality of life. 3. To identify and characterize risk factors for stroke recurrence and cognitive decline in patients with recent S3, including ethnicity, and nocturnal/diurnal blood pressure To be eligible for SPS3, patients must be at least 30 years of age and have a clinical diagnosis of a small subcortical infarct or subcortical TIA with corresponding lesion on DWI occurring within 6 months of randomization. Clinical diagnosis must be confirmed by MRI, demonstrating a corresponding small subcortical stroke (see section VI), or ManOp section III – 08/15/09 Secondary Prevention of
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multiple hemispheric S3 in the absence of a cortical infarct, and absence of large cortical and subcortical stroke. Patients whose clinical presentation is a sub-cortical TIA must have a corresponding lesion on DWI. In order to collect participants likely to have cerebral small artery disease as the underlying cerebrovascular disorder, in addition to these MRI features, patients with cervical carotid atherosclerosis causing >50% stenosis or with a major cardioembolic risk source are not eligible. The rationale for including those with TIA with a corresponding lesion on DWI is that this group is felt to have risk of stroke that is similar to that of patients with minor stroke. A population-based prospective cohort study found the early risk of stroke after TIA at 30 and 90 days was 12% and 17% respectively. For patients with minor stroke, the risk during of the corresponding time intervals was 15% and 18%. In addition, the presence of abnormalities on DWI for TIA patients was found to be an independent predictor of The study consists of two randomized trials: All participants will be randomized to receive antiplatelet therapy and all participants will be randomized to a target level of blood pressure control. Participants will be randomized using a computer-generated sequence that is blocked from previewing, with participants having an equal chance to receive each antiplatelet therapy and to be assigned to each target level of blood pressure control. The study will be carried out at approximately 70 clinical sites across the US, Canada, Spain, Mexico, and South America. Following completion of the enrollment phase of SPS3 (no later than April, 2011), all patients will be followed for an additional one year to a common end-study date (no later than April, 2012). Those participants who reach the originally planned 4.5 years of follow-up (this was the original projected follow-up and was stated as such on most clinical site consent forms) will be invited to re-consent to be followed to the common end-study date. ManOp section III – 08/15/09 Secondary Prevention of
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An MRI and intracranial arterial imaging are required at study entry, and reprints/image files on CD sent to the Coordinating Center (CC). If an MRI or imaging is not done as part of routine care and the individual meets all other entry criteria, contact the CC to discuss an SPS3-funded MRI and MRA. Other MRIs will be performed if a participant suffers a stroke or TIA or meets the criteria for major cognitive decline. Neuropsychological testing will be performed at study entry and annual follow-ups. Participants will be seen in-clinic at least monthly for the first 3 months and then every three months during the course of the trial to encourage compliance, to assess for side- effects, to measure blood pressure, and to detect events. Patients will be seen for additional in-clinic visits as needed to achieve and maintain blood pressure targets. Randomization of eligible patients into SPS3 and entry of SPS3 data forms from each clinical site will be via a web-based data management system developed by the Statistical Center at the University of Alabama (Birmingham). Reprints/image files on CD of MRI imaging will be sent to the Coordinating Center. Medications for SPS3 participants – the antiplatelet agents and antihypertensive meds - will be SPS3 Organizational Overview
distributed by the VA Cooperative Clinical Sites (CS)
Studies Pharmacy (Albuquerque). Center (CC)
The SPS3 Coordinating Center will take a very hands-on role in day-to- Statistical
Center (SC)
day management and is located at the University of British Columbia in Vancouver, Canada. In addition to all D SM B Committee
Medical Safety
Steer ing Com mittee
Publications Com mittee
protocol matters and participant- related issues, administrative, contractual, and budgetary aspects are handled at the Coordinating Center. As we begin to recruit and enroll patients, you should keep in mind three key points about the design of the study: ManOp section III – 08/15/09 Secondary Prevention of
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1. Once a patient has been randomized, he or she should be kept on the assigned therapy if at all possible, considering patient safety. 2. Every living randomized patient, whether they are receiving active therapy or not, must be followed for the duration of the study. 3. It is worse to enter a patient who drops out or who is non-compliant than never to have entered the patient at all. A general outline of activities is diagrammed on the next page. The remainder of this manual describes "how to do it" in detail. ManOp section III – 08/15/09 Secondary Prevention of
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ManOp section III – 08/15/09 Secondary Prevention of
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IV. SCREENING AND RECRUITMENT
A. Where to Find Patients
Recruitment is always much harder than expected. What works best will be different at each clinical center. Based on estimated numbers of stroke patients at SPS3 clinical sites, there should be at least 50 eligible patients per year at most SPS3 sites (average is 80). You must set up a system to find them, and this will vary from site-to-site. Further, remember that SPS3 is targeting recruitment of Hispanic Americans, and this should be kept in mind as you search for participants. Potential sources of patients include: • Regular review of hospital admissions with stroke. • Screening of CT/MRIs for S3/subcortical TIA of recent onset (not asymptomatic • Screening of outpatient consultations of large neurology groups. • Soliciting referrals from non-study affiliated physicians, especially neurologists. • Media From experience in the SPS3 pilot study, identifying patients admitted to the hospital for acute stroke was by far the best source of participants. You cannot simply put up a sign and wait to be called (physician referrals are notoriously poor source of patients), but rather you need to take an active role in screening. At some hospitals, patients with non-disabling S3/subcortical TIA, particularly if sensory, may not be routinely admitted to the hospital, and so screening emergency center logbooks may be important. Because SPS3 participants will be followed closely with good blood pressure management, non-SPS3 affiliated neurologists may be quite willing to refer their patients to the study, but you can't count on them to call you: after obtaining permission, go to their offices and screen their recent consultations, then get permission to approach possible candidates. Given the large numbers of patients with S3, you should be able to achieve the recruitment goal with sufficient organization and effort and with the support of local ManOp section IV - 07/01/07 Secondary Prevention of
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neurologists. This latter aspect may require the SPS3 physicians to present the study to colleagues, to convince them to be supportive. The Health Insurance Portability and Accountability Act (HIPAA) may impact on the process by which American sites recruit patients to participate in SPS3. In preparation for screening patients for SPS3, it is important that you inform yourself of the HIPAA regulations and any implications these regulations have on screening and recruiting procedures at your individual site. Sites in Canada, Mexico, South America, and Spain should similarly ensure that they are compliant with both federal legislation and where applicable, provincial legislation. The governing act in Canada is the Personal Information Protection and Electronic Documents Act – PIPEDA. B. Efficient Screening
Screening begins at the time of initial identification of the potential subject and ends as soon as an exclusion criterion is identified or the patient is deemed eligible for the study. It makes sense, therefore, to examine the most readily available criteria first and, if the patient is still eligible, to then move on to assess for the other exclusion criteria. If a physician or nurse refers a potential patient, he/she may be able to provide information immediately that will indicate an excluding condition. For example, the patient may be known to have had a recent subcortical stroke and have atrial fibrillation. In such a circumstance, you should simply complete the Screening - 01 Form, checking "major cardioembolic source of stroke" and any other known medical exclusion, and go on to the next potential patient. Record all medical reasons for exclusion known to you at the time of the first medical exclusion – but don't waste energy tracking down more reasons for exclusion once you are aware of at least one. All patients excluded from SPS3 require only the completion of the Screening Form. Again, record whatever you know at the time when it is clear that the patient will be ManOp section IV - 07/01/07 Secondary Prevention of
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C. Who to Screen
All patients with a clinical diagnosis of a subcortical stroke within the past 6 months with neuroimaging data (CT or MRI) available should be screened systematically and a screening form completed. Additionally all patients with sub-cortical TIA in the past 6 months and corresponding lesion on DWI should also be screened for eligibility. As part of usual clinical care (i.e., not paid by the SPS3 study), transthoracic or transesophageal echocardiogram, cervical carotid imaging, EKG, CBC, BUN, creatinine, INR, lipids, glucose, and HbA1C (if diabetic) should have been done. Based on patient's history, neurological examination and supplementary tests, eligibility will initially be assessed. If the patient fulfills all inclusion criteria with no apparent exclusion criteria, he/she will be invited to participate in the study. If the individual agrees to participation, the CT does not show exclusion criteria, and an MRI was not done as part of routine stroke care, contact the CC to discuss an SPS3-funded MRI. If the clinical syndrome is compatible with a subcortical stroke but the neuroimaging does not show subcortical strokes compatible with SPS3 entry, still complete the screening form and D. General Principles of Recruitment
Patients who are initially considered to be eligible will be interviewed by a study investigator and the nature and purpose of the study explained. A patient information booklet will be provided to supplement the verbal explanation. Patients will be required to grant informed consent for further participation. The patient information booklet is designed to explain the study and potential adverse reactions to study medications in Informed consent should be obtained only when study investigator is reasonably sure that there are no medical exclusions and that the patient is likely to be compliant with study procedures. There is a major difference between obtaining informed consent and randomization: all randomized patients will be followed and counted in our results. A
patient is not in the study until the point of randomization, which will occur some time ManOp section IV - 07/01/07 Secondary Prevention of
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after informed consent is obtained. A minority of participants will not have had a clinical MRI prior to SPS3. In these patients, informed consent will be obtained and after approval from the principal investigator at the CC, an SPS3-funded MRI will be obtained. If the SPS3-funded MRI reveals an unexpected cortical infarct (an exclusion criteria) or other reason for exclusion, then the patient will not be randomized (please send images to CC for payment). Never stop or change any therapy in a patient who is about to enter the SPS3 study without first seeking permission of the patient's personal physician (typically for poorly controlled blood pressure). When a potential participant has been given aspirin, clopidogrel, dipyridamole, or other antiplatelet agent for secondary stroke prevention, your SPS3 neurology PI will discuss the situation with the patient and primary care physician. Documentation that the patient's personal physician agrees should appear in the medical record. Education of non-study physicians at your medical institution and in the community about the SPS3 study is of paramount importance for recruiting. The literature indicates that non-study physicians are a notoriously poor source of patient referrals for research studies; furthermore, these physicians can block your recruiting efforts if they are not supportive of the study. There is no substitute for the time and energy of the research nurse and the commitment of physician investigators. E. Approaching a Patient about Joining SPS3 and Obtaining Informed Consent
Once you have established that a patient had a clinical S3 or sub-cortical TIA with corresponding lesion on DWI within 6 months, screen to make sure that the patient does not have any of the medical exclusions. As described above, at any point in the screening process, if you find that the patient is medically ineligible, you need only check that exclusion criteria on the Screening Form, enter the form, and you are finished with this particular patient. The exclusion criteria are not prioritized. Use any readily available information to complete this form, but record all reasons for exclusion ManOp section IV - 07/01/07 Secondary Prevention of
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that you know. This screening form will be periodically analyzed to help us consider protocol modifications and to monitor the vigor of screening activity at your center. If there are no obvious medical exclusions, the next step is to contact the patient. Patients may be contacted directly at the hospital before they are discharged. You can give them information about the SPS3 study (verbal information, brochure, etc,) and make an appointment for subsequent outpatient evaluation and blood pressure measurement. A brief interview with the patient may be enough to determine the patient's eligibility. At this point, you are actively seeking medical reasons for exclusion. The more personal (and personable) the initial contact, the more likely you are to enroll eligible patients. Be sure to identify yourself and why you are there (or calling) clearly and immediately. As you explain the study and its goals to the patient, encourage him or her to ask questions and express concerns (and then make sure you answer them). Many patients or their families will have notions about the legitimacy of medical research. If they feel that your primary focus is simply to get patients into the study rather than genuine concern about that particular patient's health and well-being, even if you manage to enroll the patient, he or she is not likely to stay in the study. Be prepared to answer questions such as "Why should I be in your study?" and "If it was your mother/father, what would you do?" If you are not too pushy, don't overwhelm the patient with too much information at first, and allow the patient and family time and opportunity to resolve doubts and concerns, you will establish relationships which will strengthen the patient's commitment to the study. If a family member or friend is important in the decision to join SPS3, identify this person early. Face to face contact with patients is the most desirable setting for recruitment, even if it is just a quick visit to the hospital room or clinic to introduce yourself. Ask them if they would like to hear more about the study, and drop off a patient manual. If a visit or phone contact is not possible, you may write to patients inquiring about their potential interest. In these cases a prompt reply to their response is essential. ManOp section IV - 07/01/07 Secondary Prevention of
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At the same time that we are encouraging patients to join the study, we must avoid entering patients who may initially be enthusiastic but who will later withdraw for nonmedical reasons. Things that are helpful in this regard include: 1. Education and generation of enthusiasm in the patient's family or friends who are influential in health advice. 2. Permission and support of the patient's personal physician is crucial. 3. Having the patient and spouse/family come to at least two clinic visits before randomization, to demonstrate their sustained interest and commitment. It is critical to choose our patients carefully, walking the fine line between successful recruitment and avoidance of withdrawals. Remember to choose your patients wisely… It is worse to enter a patient who
drops out or who is non-compliant than never to have entered the patient at all.
F. Informed Consent
The process of obtaining informed consent begins the moment you start explaining the study to the patient. Before a patient ever sees the consent form he or she should be thoroughly familiar with the study goals, what will be expected, and what risks are involved. If you are open and straightforward from the start, the consent form should hold no surprises. While it may be only the patient who ultimately signs the form, remember that in many ways "consent" also comes from the patient's family members and caregivers. Take the time to discuss the study with them and encourage them to be present when the patient signs the form. The informed consent document is
intimidating: You should review it carefully with your patients and explain it using
language that you have already used in discussing the study. Once the consent form is signed, don't assume that you no longer need to be concerned with informed consent. "Informed Consent" is really "informed consenting" and is an ongoing process throughout the course of the study. Your patients may ManOp section IV - 07/01/07 Secondary Prevention of
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withdraw consent at any time and you MUST honor their request. Establishing good rapport with your patients from the outset and working to maintain positive relationships can head off many of these withdrawals. If your patients trust you, they will be much more willing to come to you with new or old concerns which may surface and give you a chance to talk with them. An SPS3 physician must be present and participate in
obtaining informed consent.
ManOp section IV - 07/01/07 Secondary Prevention of
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V. ELIGIBILITY
A. Inclusion Criteria - based on TOAST criteria supplemented by required MRI data.
All of the following criteria must be met, and the patient must be randomized within 6 months of the qualifying stroke/TIA with corresponding lesion on DWI. 1. One of the following lacunar clinical syndromes (adapted from Fisher): a. Pure motor hemiparesis (PMH) g. PMH with facial sparing b. Pure sensory stroke h. PMH with horizontal gaze palsy i. PMH with contralateral III palsy j. PMH with contralateral VI palsy e. Dysarthria-clumsy hand syndrome k. Cerebellar ataxia with contralateral III palsy 2. Absence of signs or symptoms of cortical dysfunction such as aphasia, apraxia, agnosia, agraphia, homonymous visual field defect, etc. 3. No ipsilateral cervical carotid stenosis (≥50%) by a reliable imaging modality done in an approved laboratory within 6 mo of qualifying event, if hemispheric. 4. No major-risk cardioembolic sources requiring anticoagulation or other specific therapy. Minor-risk cardioembolic sources will be permitted if anticoagulation is not prescribed by the patient's primary care physician. Major risk sourcesa: Minor risk sourcesc: Š Mitral valve prolapse + myxomatous changes Š Mitral annular calcification Š Prosthetic cardiac valves Š Patent foramen ovaled
Š Recent (< 3 mos transmural MI Š LV thrombus, especially if mobile or protruding Š LV wall abnormalities (without thrombus) Š Atrial Š Calcific aortic stenosis Š Non-ischemic dilating cardiomyopathiesb
Š Marantic
aAssociated with a substantial absolute risk of stroke, firmly linked to an embolic mechanism bRisk varies with the type and severity cAssociated with a low or uncertain absolute risk of initial or recurrent stroke or are incompletely established as direct embolic source dMajor risk if associated with pulmonary HTN with sustained right-to-left shunting and venous source of emboli ManOp section V - 07/01/07 Secondary Prevention of
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5. MRI evidence of S3, specifically both A and B: A. S3 on MRI: at least one of the following four specific criteria i. Diffusion-weighted imaging lesion < 2.0 cm in size at largest dimension (including rostro-caudal extent), confirmed by the ADC image, and corresponding to the clinical syndrome. This criterion must be met when the qualifying event is a TIA. ii. Well delineated focal hyperintensity < 2.0 cm in size at largest dimension (including rostro-caudal extent) on FLAIR or T2 and clearly corresponding to the clinical syndrome. If other focal hyperintensities are present, contact the Coordinating Center prior to randomization to discuss the case. The date of imaging must be within 2 months of date of qualifying stroke. If diffusion- weighted imaging is negative, this criterion alone is not sufficient for study iii. Multiple (at least 2) hypointense lesions of size 0.3-1.5 cm at largest dimension (including rostro-caudal extent) only in the cerebral hemispheres on FLAIR or T1 in patients whose qualifying event is clinically hemispheric. If qualifying event is clinically brainstem or cerebellar, this criterion alone is not sufficient for study entry. iv. Well delineated hypointense lesion < 1.5 cm in size at largest dimension (including rostro-caudal extent) on FLAIR or T1 corresponding to the clinical syndrome. MRI must be done at least 1 month after the qualifying stroke. B. Absence of cortical stroke and large (> 1.5 cm) subcortical stroke, recent or Note: "Microbleeds" < 2 mm in diameter detected by diffusion tensor imaging or other special sequences do not exclude the patient. ManOp section V - 07/01/07 Secondary Prevention of
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B. Exclusion Criteria
To be eligible for entry into the study, the patient must not meet any of the criteria listed 1. Disabling stroke (Modified Rankin Scale ≥4) 2. Previous intracranial hemorrhage (excluding traumatic) or hemorrhagic stroke 3. Age under 30 years 4. High risk of bleeding (e.g. recurrent GI or GU bleeding, active peptic ulcer disease, etc) 5. Anticipated requirement for long-term use of anticoagulants (e.g. recurrent DVT) or other antiplatelets 6. Prior cortical or retinal stroke (diagnosed either clinically or by neuroimaging), or prior cortical or retinal TIA 7. Prior ipsilateral carotid endarterectomy or ipsilateral carotid stent 8. Impaired renal function: estimated GFR < 40 9. Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR) 10. Score on the Folstein MMSE < 24, adjusted for age and education 11. Medical contraindication to MRI 12. Pregnancy or women of child-bearing potential who are not following an effective method of contraception 13. Geographic or social factors making study participation impractical 14. Unable or unwilling to provide informed consent 15. Unlikely to be compliant with therapy / unwilling to return for frequent clinic visits 16. Concurrent participation in another study with an investigational drug or device that is likely to interfere with SPS3 participation and/or outcomes. 17. Other likely specific cause of stroke (e.g. dissection, vasculitis, prothrombotic diathesis, drug abuse) ManOp section V - 07/01/07 Secondary Prevention of
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C. Pre-Randomization Procedures: 5 Requirements
1. Brain MRI - SPS3 MRI criteria for study inclusion are two-fold: ∗ Absence of recent or remote evidence of cortical or large subcortical stroke ∗ Presence of an S3 likely corresponding to the qualifying event in the judgment of the local neurology principal investigator (required for brainstem qualifying events and when the qualifying event is a subcortical TIA) or multiple hemispheric S3 on T-1 or FLAIR images 2. Imaging of the cervical carotid arteries (duplex ultrasonography, MRA, spiral CT, catheter arteriography) - all patients, not just those with hemispheric S3 3. Electrocardiography and either transthoracic or transesophageal echocardiography - Either a transthoracic or transesophageal echocardiogram, along with an electrocardiogram is required to exclude candidates with major-risk cardiogenic embolic sources. If a patient has a completely normal ECG and no history suggestive of a cardiac source of stroke, and neither a TTE nor TEE has been done as part of clinical care, contact Benavente/Hart to discuss eligibility. 4. Laboratory blood work - to assess for potential bleeding diathesis, neutropenia, and/or thrombocytopenia; to assess baseline renal function and changes influenced by lowering of BP and antihypertensive medications; and to assess vascular risk profile. Specific tests include: CBC, electrolytes, glucose, creatinine, BUN, and INR, fasting lipid profile, and HbA1C (diabetics only). 5. SPS3 Measured Blood Pressures - The SPS3 BP at entry will be the average reading from two consecutive outpatient visits, the first at least one week after stroke and at least one week prior to the second. Blood pressure will be measured 3X at each clinic visit in a standardized manner using the automated Colin electronic BP D. Intracranial Arterial Imaging
Intracranial arterial imaging is required for all SPS3 participants, but it may be done up to 1 mo post-randomization (or within 3 mo pre-randomization). If not done as part of routine clinical care (MRA, spiral CT, or angiogram), SPS3 will fund a non-contrast MRA ManOp section V - 07/01/07 Secondary Prevention of
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of the intracranial arteries (with pre-approval by the CC). Visualization of intracranial arterial circulation is important to understand and stratify prognosis and response to treatment. Identification of intracranial atherosclerotic stenosis does not exclude SPS3 participation. ManOp section V - 07/01/07 Secondary Prevention of
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VI. MRI IN SPS3
A brain MRI is required in the following three situations: • Prior to randomization to assess eligibility criteria • After a stroke or TIA during the course of the trial • Following a major cognitive decline event during the course of the trial Most MRIs will be those obtained as part of routine clinical evaluation done for acute stroke and not paid-for by the SPS3 study. Consequently, the types of available MRI images will vary between sites, depending on those used for routine clinical imaging. The "ideal" MRI sequence for SPS3 includes T1, T2, FLAIR, and diffusion-weighted images. While eligibility will be based on demonstration of S3, the presence, extent and distribution of white matter abnormalities on FLAIR images (or T2, if FLAIR is not available) will be assessed centrally as potentially important prognostic variables. The availability of diffusion-weighted images will be important for meeting MRI eligibility criteria in some patients (see below). If required to assess eligibility, the SPS3 study will pay for an MRI that is not justified by routine clinical care. Discussion with and pre-approval by the Coordinating Center are required: The SPS3 Neurologist should contact Dr. Benavente or Dr. Hart to discuss the case. SPS3 can only afford to pay $500 for such studies, well below market rates. Thus, it will be necessary for you to negotiate a special rate for SPS3-sponsored MRIs. These MRIs do not need to be interpreted by your local radiologist (saving the cost of interpretation) and need only consist of T1, T2 and FLAIR sequences (but diffusion- weighted sequences would be great!). Private, free-standing MRI units sometimes offer discount rates if done after hours. Image files on CD (preferable and less costly) or reprints of the essential films (T1, T2, FLAIR and diffusion-weighted images if available) should be sent by traceable mail to the Coordinating Center. CDs/reprints need to be sent at least monthly as receipt is ManOp section VI- 07/01/07 Secondary Prevention of
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part of the criteria for site reimbursement (see section XXIII). In most centers, it will be much less costly to send image files on a CD, and this is the preferred method. If this is not possible, it is worthwhile making an arrangement with your imaging center to obtain high-quality MRI copies for SPS3 participants. A. SPS3 MRI Criteria for an S3
Criteria for an S3 on MRI are: A black "hole" between 3-15 mm in its greatest dimension on either T1 or FLAIR images or an area of brightness < 20 mm in greatest dimension on diffusion-weighted images located in the subcortical white matter, basal ganglia, internal capsule, thalamus, brainstem or subcortical cerebellar hemispheres. Black holes on the lamina cribrosa cut(s), where Virchow-Robin spaces are typically prominent in elderly, hypertensive patients, do not count as S3. Consider the rostral-caudal dimension and make sure it does not exceed the maximal dimension based on number of sequential slices and skip Focal hyperintensities on T2/proton-weighted images by themselves qualify as S3 if all of the following criteria are met: • Corresponds to the clinical event • DWI does not conflict (i.e. not done) • Well-delineated and not one of multiple hyperdense patches For participants with brainstem/cerebellar S3, a new lesion corresponding to the qualifying clinical event must be visible on MRI. In this situation, MRI criteria for a new lesion include any of the following: • Positive diffusion-weighted image • Enhancement of a lesion on T1/FLAIR imaging • New black hole on T1/FLAIR since prior MRI • Bright lesion on T2/FLAIR that is well-delineated and clearly corresponds to ManOp section VI- 07/01/07 Secondary Prevention of
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the clinical deficit if diffusion imaging is not available • Evolution of the lesion on serial MRIs in the weeks after the clinical event. For participants entering with a subcortical TIA as the qualifying event, a new lesion corresponding to the qualifying clinical event must be visible on diffusion weighted
B. Entry MRI
Interpretation by the local SPS3-affiliated Neurologist will be used to determine SPS3 eligibility. MRIs will be re-interpreted centrally at the Coordinating Center for secondary analyses and to give feedback to the local neurologists, but the original interpretation by the on-site SPS3 Neurologist will stand for the purpose of eligibility. So it's crucial to get A special problem: size of the MRI lesion is 16 - 20 mm when imaged acutely - Based on pathological studies, lacunes are traditionally defined as cavitated areas of infarction of ≤ 1.5 cm in size. It is well known to all who interpret MRIs in acute stroke that the size of the lesion on diffusion-images, enhanced T1 images, and T1/FLAIR may not reflect its ultimate size months later. It is felt that the size usually diminishes. There is, however, limited data to support this hypothesis. SPS3 participants with acute lesions on MRI measuring between 1.5 and 2.0 cm in maximum diameter have been undergoing a repeat MRI in 3 to 6 months. The rationale for having a second MRI was to assess if the acute lesions change in size over time into smaller cavitated lesions. We performed an analysis on the first 42 repeat MRIs. In 81% of the repeat MRIs the lesion was reduced to ≤1.5 cm and in the remainder, all were ≤2.0 cm. Based on the results of this analysis, the protocol has been modified to include participants with lesions up to 2.0 cm in maximum dimensions on MRIs ManOp section VI- 07/01/07 Secondary Prevention of
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performed during the acute phase without the need for a repeat MRI in 3 to 6 months after study entry. For participants with brainstem/cerebellar S3, the protocol states that a new lesion corresponding to the qualifying clinical event must be visible on MRI. In this situation, MRI criteria for a new lesion include any of the following: ∗ Positive diffusion-weighted image ∗ Enhancement on T1/FLAIR imaging ∗ New black hole on T1/FLAIR since prior MRI ∗ Bright lesion on T2/FLAIR that is well-delineated and clearly corresponds to the clinical deficit if diffusion-weighted imaging is not available ∗ Evolution of the lesion on serial MRIs in the weeks after the clinical event. If you have a potential participant who doesn't fulfill these criteria, call the Coordinating Center to discuss the case and options for documenting MRI entry criteria. Particularly during the initial months of SPS3 screening and recruitment, there is concern that varying interpretation of MRIs by 70+ SPS3 Neurologists may result in the inclusion of participants who may not meet MRI inclusion criteria when centrally reinterpreted by neuroradiologists at the Coordinating Center. To minimize this problem, sites are required to undergo central review of the MRIs of their initial 5 patients prior to enrolling the patient. If all 5 MRIs meet criteria, this step is discontinued. Secondly, active sites where minor protocol deviations have been detected on the MRI are also required to send all MRIs for review prior to patient entry until they have demonstrated knowledge of the criteria (i.e., they have delivered 5 MRIs that meet criteria). Irrespective of these steps, please contact the Coordinating
Center regarding any "if-y" MRIs before randomizing the patient.
C. T2 Gradient Imaging Sequences
There is much current interest in detecting old "microbleeds" using special T2 gradient ManOp section VI- 07/01/07 Secondary Prevention of
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imaging. SPS3 offers the opportunity to correlate their presence with prognosis (particularly symptomatic intracerebral hemorrhage during antiplatelet therapy) and response to therapy. However, these pulse sequences are not widely available at present and not done as part of routine clinical evaluation. If such sequences are available or can be obtained, it would be great to collect these data in a subset of SPS3 participants. Consideration will be given to a supplement grant proposal is there is general interest by the SPS3 Investigators. ManOp section VI- 07/01/07 Secondary Prevention of
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VII. INTRACRANIAL ARTERIAL IMAGING IN SPS3
Visualization of intracranial arterial circulation proximate to study entry is required for SPS3 participants; however identification of intracranial atherosclerotic stenosis will not exclude SPS3 participation. SPS3 seeks to include a broad spectrum of patients with lacunar stroke, for whom there are no established therapies for secondary prevention beyond antiplatelet agents. Despite the recognized limitations of intracranial MRA, it is crucial to obtain intracranial imaging on SPS3 participants in order to understand and stratify prognosis and response to treatment. Acceptable types of imaging include spiral CT, MRA, and catheter-based contrast arteriography. Imaging should include the carotid siphon, Circle of Willis, proximal middle cerebral arteries, and basilar artery. If the SPS3 qualifying stroke involves the posterior circulation, imaging of vertebral arteries is also required. Note that intracranial imaging is in addition to cervical carotid imaging to exclude surgically amenable At most centers, intracranial imaging will be carried-out as part of routine clinical evaluation of acute ischemic stroke. In some instances when imaging is not justified for routine clinical care, SPS3 will provide $500 for a noncontrast MRA of the intracranial arteries (and cervical vertebral arteries if the qualifying stroke involves the posterior circulation). As with SPS3-funded MRIs, MRAs that are paid for by SPS3 must be pre- approved by having your SPS3 Neurologist contact the Coordinating Center to discuss the case. In order to negotiate an MRA for the reduced rate of $500, make it clear that local interpretation by a radiologist is not required. Reprints or image files on a CD of all intracranial imaging studies must to be sent to the Coordinating Center. Receipt is part of the criteria for site reimbursement (see section ManOp section VII- 06/01/2003 Secondary Prevention of
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VIII. MEASURING BLOOD PRESSURE
The technique is adapted from JNC-VII recommendations.
SPS3 BP MEASUREMENT 1. Measure BP in the morning with morning BP medications held 2. No caffeine or tobacco within prior 60 minutes 3. Sitting position: "Selected" arm relaxed and supported at level of the heart after 15 minutes of sitting quietly 4. Record the reading using the Colin electronic device 5. The length of bladder of the cuff > 80% of upper arm circumference; the width 40% of the circumference (recording cuff size) 6. Minimize physical contact during measurement 7. Three readings separated by > 2 minutes 8. Orthostatic (standing) measurements obtained after sitting BPs are measured 9. If the measured BP is unexpectedly high or low, re-check with a recently calibrated (preferably mercury) sphygmomanometer • The temporal effects of anti-HTN meds on BP in relationship to dose vary greatly between agents (for example, little intra-dose variability for thiazides, a large dose effect for direct acting vasodilators). As a general rule, SPS3 BP measurements should be taken at a time reflecting trough activity relative to the dosing of long- acting antiHTN medication. It is also optimal to measure BP at about the same time (within 2 hrs) of day for individual participants, to minimize fluctuations in BP. To achieve this end, we recommend that SPS3 clinics be held in the morning, and that patients hold all morning doses of antiHTN medications, whether it is an OD, BID, or TID dosing. You may need to contact patients the day before clinic to remind them to hold and bring the morning dose. (If morning visits are not possible for a patient, measure BP at approximately the same time of day and avoid measurement within 3 hrs of taking BP lowering meds. A patient seen in the afternoon needs to take morning doses of antiHTN meds, but hold any noon- afternoon doses.) ManOp section VIII - 07/01/07 Secondary Prevention of
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In morning clinics, after the BP measurement, ask the patient to take all held OD medication doses. Also, advise the patient to take the held morning dose of a BID/TID medication if the next dose is a bedtime dose, the BP is quite elevated, or the appointment was early morning. Alternatively, have the patient skip the held morning dose of a BID/TID medication if the appointment is in late morning and the next dose taken in the afternoon, or if the patient's BP is not too high. (We want to avoid taking two doses of the BID/TID drug close together and precipitating hypotension.) Be sure patients bring their antiHTN medications with them to clinic so that you can supervise taking/skipping the held medications. • A set of three SPS3 BP measurements for each arm is done at the initial SPS3 measurement and recorded on the Baseline form. All subsequent BP measurements are done in the "Selected" arm. The right arm is the "Selected" arm unless the left arm mean systolic BP measures > 10 mmHg than the right arm at the initial measurement. • Cuffs that are too short or too narrow may give falsely high readings, so be sure to use the correct size cuff. Four cuff sizes are available for the Colin BP measurement device: regular, large, short-wide, and thigh. It is important to use the same cuff size when repeating BP measurements over time in an individual Colin cuff size Bladder Fits arm circumference regular blue-black short-wide blue-red Each site will receive both the regular and large cuffs with the Colin automated BP machine. If you find that neither of these cuffs is the correct size for a patient and ManOp section VIII - 07/01/07 Secondary Prevention of
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that you need to use either a short-wide cuff or a thigh cuff, measure the BP using an available non-SPS3 manual or electronic instrument for which a proper sized cuff is available for the short term. Contact the Coordinating Center, and the proper sized Colin cuff will be forwarded to you for subsequent BP measurements. • To avoid elevating BP in some individuals, minimize physical contact when measuring the official SPS3 sitting BPs. Rest the patient's arm comfortably on a table. For standing BPs done later, supporting the patient's arm at heart level often requires contact - use a supporting adjustable table if possible. • The Colin automated BP machine is used in SPS3. Review of data from the literature concerning the Colin devise as well as our preliminary observations in the SPS3 pilot study support the use of automated electronic BP measurement. Electronic BP measurement is widely used in clinical practice, and several large randomized clinical trials (such as HOT) have used high-quality, validated electronic BP measurements. The inherent day-to-day variability in BP as well as the intrinsic variability in manual measurement of BP is likely to exceed small, largely random, differences between carefully measured manual vs. electronic Electronically measured BPs have the advantage of avoiding any bias in BP measurement by investigators, seeking to achieve targets. Additionally, it is likely that inter-observer variability in manual BP measurement in a multicenter trial involving 100 or more investigators would be comparable to or more than that achieved with high-quality electronic measurements. Finally, use of electronic BP measurements is in-line with trends in clinical practice at many large hospitals and In SPS3, a single type of electronic BP device is used at all sites, to minimize variability and simplify quality control. For "routine" SPS3 BP determinations, three ManOp section VIII - 07/01/07 Secondary Prevention of
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recordings taken at least 2 minutes apart are made using the electronic device, and then averaged to determine the mean BP for that visit. The Colin automated BP machines will be centrally calibrated annually during • BP Checks During Home Visits: Because the initial months of SPS3
participation require multiple clinic visits (averaging 4-6 during the first few months), BP checks by SPS3 personnel at the participant's home may be selectively used to decrease the burden on the participant (and increase protocol adherence). Post- randomization BP checks may be occasionally done by the research coordinator or physician using the standardized protocol. BPs from home visits are identified in the computerized database for comparison with those obtained from clinic measurements. If the home visit is carried-out by the research nurse, an SPS3 physician must be contacted via telephone to discuss any elicited side effects and for verbal orders regarding adjustment of anti-HTN meds. • 24-hour ambulatory blood pressure monitoring: A Spacelabs 24 hour blood
pressure monitoring device is provided to selected sites to record ambulatory BPs and to categorize as dippers/nondippers: 1. In each participant, at the selected site, as soon as possible after becoming stable on antihypertensive medications and achieving target BP 2. In participants who are having difficulty staying within the assigned target, i.e. when you declare Failure-to-Achieve Assigned Target (FAAT) 3. In normotensive patients See Instructions for the Ambulatory BP -13 form and Section XXVIII for more detail. ManOp section VIII - 07/01/07 Secondary Prevention of
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IX. CHARACTERIZATION OF HYPERTENSION AT STUDY ENTRY
All SPS3 participants will have their blood pressure (BP) carefully measured on at least two occasions as outpatients before randomization, with the first SPS3 BP measurement done at least one week after the qualifying stroke. (see below) Qualifying
Consecutive BP Measurements Participants will not be randomized (and consequently will not have medications adjusted to reach the assigned BP target) sooner than two weeks after their qualifying Characterization of hypertension at study entry is based on two criteria: 1. A definite history of hypertension prior to the qualifying stroke and currently receiving medications given to lower blood pressure. 2. The SPS3 BP at entry: the average reading in the "selected" arm from at least two consecutive outpatient visits, the first at least one week after the qualifying stroke and at least one week prior to the second. A definite history of hypertension prior to the qualifying stroke is based on: • consistent recording of "hx of HTN' in medical records spanning > 1 yr prior to qualifying stroke • medical records or clear patient report describing treatment with anti-HTN meds prior to qualifying stroke ManOp section IX - 07/01/07 Secondary Prevention of
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• medical records prior to qualifying stroke showing elevation of outpatient BPs sustained spanning > 3 months • use of one or more meds specifically and unequivocally for BP lowering by medical records or patient report prior to qualifying stroke • history of HTN coupled with target organ damage attributed to HTN (e.g., left ventricular hypertrophy) The SPS3 BP at entry is based on the average measured BP of six BP measurements taken during two (2) consecutive outpatient visits, the first at least one week after stroke and the second at least one week later (see technique above) and done prior to randomization. An average systolic > 140 mmHg or average diastolic >90 mmHg is required to meet this criterion for hypertension, regardless of concurrent anti-HTN SPS3 participants will be considered to have "high-normal" BP if there is no history of hypertension, and their SPS3 BP average systolic is 130-139 mmHg or the average diastolic is 85-89 while on no hypertensive medications. All patients regardless of hypertension and SPS3 BP at entry will be randomized to blood pressure treatment target ranges. If a normotensive patient subsequently becomes hypertensive during follow-up, blood pressure will be managed according to the assigned blood pressure target. No systematic blood pressure management will be provided to those participants who are normotensive at baseline and remain normotensive throughout follow-up. ManOp section IX - 07/01/07 Secondary Prevention of
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X. STUDY ENTRY/RANDOMIZATION
After a patient is determined to be eligible to participate in SPS3 and written informed consent has been obtained, there are six steps to complete study entry: 1. Be sure that results of all required tests/procedures are available. 2. Have physician investigator complete necessary forms required prior to 3. Complete other forms necessary at study entry. 4. Randomize the patient into SPS3. 5. Dispense study medications and review excluded meds. 6. Schedule next study visit. Remember: Once a patient has been randomized, the patient must be followed, on or off therapy, wherever he/she lives, until the end of the study.
1. Tests/Procedures Required Before Randomization
Results of the following tests/procedures must be available and reviewed prior to randomization, primarily for the purpose of being certain that the patient meets eligibility criteria for the study: ¾ Neuroimaging – MRI ¾ ECG – most recent since qualifying stroke ¾ Transthoracic or transesophageal echocardiogram – since qualifying stroke ¾ Cervical carotid imaging – since qualifying stroke: sonography, MRA, spiral CT, and/or angiography ¾ Lab tests – since qualifying stroke: hemoglobin, hematocrit, platelet count, BUN, creatinine, INR, sodium, potassium, lipids, glucose, HbA1C (diabetics only, may be within 6 mo preceding the qualifying stroke) If any of these tests/procedures have not been done or the results are not available to you, arrange with the patient's personal physician to obtain them, as appropriate, ManOp section X - 08/15/09 Secondary Prevention of
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so that the patient is inconvenienced as little as possible, but before randomization. All are considered part of routine clinical work-up for the acute stroke. If an MRI was not done as part of the clinical work-up following the qualifying stroke, contact the principal investigator at the Coordinating Center for permission to obtain an SPS3- funded MRI prior to randomization. 2. Forms to be Completed Prior to Randomization
All patients will have their medical history taken and undergo a general physical and neurological examination by the SPS3 neurologist investigator within the four weeks prior to study entry. Additionally, the Edinburgh Stroke Outcome questions will be asked, and the modified Rankin Scale and Barthel Index administered. SPS3 blood pressures measured on two occasions using the SPS3 technique at least one week after the qualifying stroke and at least one week apart must be done (see Section VIII above). Hypertension status must be determined prior to randomization into SPS3. The following forms must be completed by a study physician prior to randomization (may be completed within four weeks prior to randomization): ¾ Baseline History – Medical History section ¾ Qualifying Stroke Additionally, the following forms must be carefully reviewed by a study physician prior to randomization: ¾ Eligibility/Randomization The Patient Contact form must also be completed. Since all randomized patients are followed until the end of the study, it is important to collect contact information ManOp section X - 08/15/09 Secondary Prevention of
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about family members and friends. You may assure the patient that this confidential information will only be kept in a file at your site and will be destroyed after the study 3. Other forms to Complete at Study Entry
The following forms must be completed on or prior to date of randomization. They may be completed at a patient visit within the four weeks prior to the randomization visit, or sometime during the randomization visit. ¾ Baseline History – non-physician portion of the form ¾ Post-Stroke Disability ¾ Hypertension QOL ¾ Cognitive Scales - to be completed by neuropsychological test administrators ¾ Intracranial Vascular Imaging - complete if IC imaging done, otherwise complete 4. Randomizing the Patient
The decision to randomize a patient is not made lightly. All patients that are randomized will be followed until the end of SPS3. Randomizing an ineligible patient or one that will be lost-to-follow-up or withdraw consent is a big mistake, so before you push the button, be sure that the patient is eligible, has signed the consent form, and is likely to adhere to the SPS3 protocol until the end of SPS3. Patients who have reached 4.5 years of follow-up (as stated on the SPS3 consent form template and most clinical site consent forms) will be invited to re-consent and be followed until the common study end date. To avoid a potential selection bias, it is critical that as many patients as possible agree to be re-consented and continued to be followed as per protocol. ManOp section X - 08/15/09 Secondary Prevention of
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Participants are randomized into SPS3 using a password protected Web based system accessible from a "preloaded" PC with web access (see section XXVI for details). To randomize a patient, have the completed Patient Contact and Eligibility/Randomization forms with you at the PC. Be sure that the antiplatelet drug kits are proximate to the PC, as you will need to select the assigned kit for the participant. Randomization of the participant into the antiplatelet portion of the trial and the HTN trial are done concurrently. About 10-15% of SPS3 patients are anticipated to be normotensive at study entry. These patients will be randomized into the HTN trial, and if they become hypertensive during follow-up, their target BP will be that which was assigned at Access the SPS3 web site by entering your username and password from a previously "loaded" PC (see section XXVI for details), and then click on the Randomization box. You will then enter the responses for the series of questions on the Eligibility/Randomization form leading up to the question of whether you are ready to randomize the patient, and the patient's acrostic (see next paragraph). After you have confirmed that you wish to randomize the patient, the patient is officially considered an SPS3 patient, and a unique id number (corresponding to the AP therapy kit number) and target BP group assignment for that patient will be assigned. Print off the Randomization form using the Print Forms option under the Reports/Labels/Forms option in the data entry system and keep in the patient's ID numbers have the format ss-ppp-c AAAA, where ss is your site number, ppp is the patient number at your site, c is a check digit, and AAAA is the patient's acrostic. Randomization is stratified by hypertension status. This means that patients with hypertension by SPS3 criteria (see Eligibility/Randomization form) are assigned patient numbers between 000-099, while normotensive patients are assigned patient ManOp section X - 08/15/09 Secondary Prevention of
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numbers starting at 100. The patient acrostic is composed of the first letter of the patient's first name followed by the first three letters of the patient's last name, e.g. John Smith has the acrostic JSMI. The patient id number is used on all forms to uniquely identify a patient and also appears on all antiplatelet study drug kits dispensed to that patient. For example, patient id 01-011-1 LCHA belongs to a patient 011 randomized into the hypertension stratum at site 01. The patient's first initial is L and the first 3 letters of his last name are CHA. A summary of the randomization process, the study id number assigned, the target BP assigned, and a schedule of quarterly follow-ups visits are generated and printed at this time. For additional information, see Sections XII (follow-up) and XXVI (training materials). 5. Dispensing Study Medications
The antiplatelet study kit that you dispense to the patient has the same study id number on it (without acrostic) as that assigned to the patient at the time of randomization. Two bottles are dispensed to the patient: one bottle contains aspirin and one bottle contains clopidogrel or placebo. Before you dispense each bottle of study drug, remove the part of the perforated label that contains the patient ID and place this in the patient file. If the bottle number is not noted on the label, please write it on the label along with the date dispensed and the patient's acrostic. You can decide where you wish to place this but please be consistent in its placement so that it can be easily located. Add the patient's name and your contact information to each bottle, and instruct the patient to take one tablet daily from each bottle at approximately the same time of day. Also, review with the patient the list of excluded medications. It is very important that the patient take only the antiplatelet therapy assigned and dispensed to him/her by you, and not others. A list of excluded medications is included in the participant brochure, which should be reviewed with the patient. Encourage the patient to contact you about any questions ManOp section X - 08/15/09 Secondary Prevention of
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Excluded medications: Non-study aspirin containing medications (regularly) Non-study clopidogrel Dipyridamole (Aggrenox) Warfarin (Coumadin) / Ximelagratran/Other oral anticoagulants You will also be dispensing antihypertensive medications to the patient as determined by your hypertension specialist. Again, as common sense dictates, review the instructions for each medication with the patient, and be sure the patient understands and knows how to contact you if he/she has any questions. Make certain that the patients are aware that the SPS3 physicians will be monitoring and supervising their antihypertensive therapy (and not their primary care physician). Let patients know that you will regularly contact their primary care physician regarding their blood pressure status. Give the participant the SPS3 brochure and wallet card. Send or fax a letter to their primary care physician (sample provided in Section XVII) informing the physician of the patient's participation in SPS3 and that SPS3 will manage blood pressure. 6. Scheduling a Follow-Up Visit
There are two types of follow-up visits to schedule: 1) BP Checks: Schedule these as needed between quarterly follow-up visits to check the patient's blood pressure and make any necessary antihypertensive medication changes. All patients (hypertensive and ManOp section X - 08/15/09 Secondary Prevention of
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normotensive) are required to have a BP check during each of month one and month two post-randomization. 2) Quarterly follow-ups: Schedule these every 3 months based on date of randomization into SPS3 (within a 2-week window on either side) To help you with scheduling follow-up for a patient, print off the follow-up schedule available from the report menu options on the data entry system (see section XXVI). All patients need to be scheduled to return in about 1 month for a BP Check. Patients whose blood pressure is not in target range on date of randomization may need their antihypertensive medications changed, and then need to return to clinic in 2 weeks (4 weeks if thiazides) for a BP Check. You will also need to schedule intracranial vascular imaging within 1 mo post- randomization if it was not already done as part of clinical care. If imaging cannot be justified as part of routine clinical care, your neuro-PI will need to contact the Coordinating Center for pre-approval for an SPS3-funded intracranial MRA. 7. Entering Data Forms
Enter and lock the completed data forms into the DE system within one week of randomization - sooner is better. 8. Mailing to Coordinating Center
Obtain the image files on CD or a reprint of the MRI film and mail it to the Coordinating Center. If the intracranial vascular imaging has been done, include a reprint or image files on CD of this as well. You also need to send a copy of the completed Cognitive Scales form (all 18 pages please including the CLOX drawing and the handwriting sample) along with the audiotape to the Coordinating Center, which may go in the same package. ManOp section X - 08/15/09 Secondary Prevention of
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XI. MANAGEMENT OF BLOOD PRESSURES

Overview

Blood pressure management in SPS3 will be based on national guidelines for treatment of hypertension, specifically the Joint National Committee Report (currently VIIth report). SPS3 does not test specific agents (like the recently reported PROGRESS and ALLHAT trials), but rather seeks to lower blood pressure according to best available practice for individual patients, as currently applied in the US. Hypertension management for SPS3 participants will be supervised by the designated SPS3-affiliated hypertension specialist at each clinical site, who has special experience and expertise in management of blood pressure. The local specialist at your site will make the specific management decisions for individual patients beneath the broad umbrella of management guidelines based on co-morbidity and side-effects. The use of specific agents for each SPS3 participant will be recorded during the trial. Blood pressure management at each clinical site will be reviewed on an ongoing basis by the Coordinating Center Hypertension Expert and SPS3 Steering Committee regarding achieving targets, choice of agents (in-line with national guidelines by correlating with baseline demographic features) and side-effects/complications. The local Hypertension Specialist will interact regularly with the Coordinating Center Hypertension Expert about problems with individual participants. There is ongoing controversy about whether specific types of antihypertensive medications offer special protection against stroke and/or other vascular events. Individual SPS3 physicians at clinical sites may well view this controversy differently and may favor use of specific agents, albeit in accordance with practice guidelines. The distribution of antihypertensive drug use across clinical sites will be monitored closely (and individual quirks should average-out!). The SPS3 protocol will be modified if convincing data become available supporting the use of specific agents (such data ManOp section XI – 07/01/07 Secondary Prevention of
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would likely influence national guideline recommendations which form the basis of SPS3 blood pressure management). It is important to communicate with the participant's primary care physician regarding SPS3 management of blood pressure. Prior to study entry, the primary care physician must agree to allow the local SPS3 Hypertension Specialist to supervise the patient's BP management. The primary care physician and the participant may need to be reminded periodically that antihypertensive medications will be adjusted only by the SPS3 team (and not other physicians, except in emergency situations) while he/she is active in the study. Good control of hypertension by experts is one of the benefits of SPS3 Study participation, and this should be emphasized to the participant to encourage commitment to the multiple clinic visits and medication adjustments that are often required to achieve control. All SPS3 participants will be instructed and encouraged to pursue lifestyle modifications for hypertension control (Table below). Lifestyle Modifications for Hypertension Management
Approx Systolic BP
Reduction, Range
Weight reduction Maintain normal body weight (BMI, 18.5-24.9) 5-20 mm Hg/10 kg weight loss Adopt DASH eating plan Diet rich in fruits, vegetables, and low fat dairy products with a reduced content of saturated and total fat Dietary sodium reduction Reduce dietary sodium intake to <100mEq/L (2.4 g sodium or 6 g sodium chloride) Physical activity Engage in regular aerobic physical activity such as brisk walking (> 30 min/day, most days of week) Moderation of alcohol Limit to < 2 drinks per day in most men (i.e.1 oz or 30mL ethanol; e.g. 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey) and < 1 drink per day in women and lighter-weight persons Stop smoking for overall cardiovascular risk reduction. From JNC-VII (JAMA 2003;289:2560-75) ManOp section XI – 07/01/07 Secondary Prevention of
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Antihypertensive Medications
SPS3 antihypertensive drugs are purchased and supplied to each clinical site through collaboration with the VA Cooperative Studies Program Central Research Pharmacy in Albuquerque (the SPS3 Drug Distribution Center). At least one drug from each of the major classes of antihypertensive medications is available, specifically: an ACE inhibitor (lisinopril), a beta-blocker (atenolol), two long-acting calcium channel antagonists (felodipine, verapamil), four diuretics (HCTZ, chlorthalidone, furosemide, spironolactone), two vasodilators (minoxidil, hydralazine), an angiotensin receptor blocker (candesartan), a central alpha agonist (clonidine), a potassium supplement, and additional medications on a case-by-case basis. These meds were chosen based on the JNC-VII recommendations, cost, and strongly favoring ease of dosing for
Treatment of hypertension is good clinical practice, and SPS3 is not obliged to supply
all antihypertensive medications to participants if it is feasible to obtain them through the participant's health plan. For example, if a patient is treated with thiazide, Altace and Norvasc prescribed by the primary care physician prior to SPS3 participation and these medications are deemed appropriate by the local SPS3-affililated hypertension specialist, they should continue to be obtained through the local health plan, both to spare the SPS3 medication budget and to allow the participant to continue on the same medications (it is unlikely that these specific agents will be on the SPS3 formulary). In other situations, good compliance with antihypertensive drug therapy requires that these medications be supplied by SPS3 (e.g. medically indigent participants who would have to pay for drugs out-of-pocket). This decision will be made on a case-by-case basis by the local SPS3 investigators, with the goals of getting BP controlled, encouraging participant compliance with the frequent clinic visits and medication adjustments, and sparing the SPS3 medication budget, when appropriate. To maximize compliance, blood pressure medications will be available to all participants during the titration phase and to selected participants as deemed appropriate by the local ManOp section XI – 07/01/07 Secondary Prevention of
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hypertension expert. Initial Adjustment of Antihypertensive Drugs
The most recent of the pre-randomization SPS3 BPs will be used to assess whether the participant is within the assigned target ("usual care" of 130-149 mmHg vs. "intensive" of <130 mmHg) at time of randomization. (If this SPS3 BP is not at least two weeks post- qualifying event, have the patient return to the clinic for a BP check at that time.) If the participant's blood pressure is not in assigned target range, antihypertensive medications may need to be adjusted by the local hypertension specialist, and the participant should return in two weeks to measure BP (after four weeks if thiazides are added, due to the longer interval to see the full BP lowering effects). In some instances (e.g. the patient had not been taking the medications, concurrent illness), it may be sensible to observe the patient on the same antihypertensive drugs rather than make adjustments. SPS3 participants should return for BP checks and adjustment of antihypertensive drugs every 2-4 weeks until in-target on two consecutive measurements. At that point, the participant will be seen quarterly unless additional medication adjustment is required. Selection of initial antihypertensive medication, adjustment of dosage, addition of other medications, etc will be made following the current JNC guidelines (JNC-VII 2003, see table below). Titration of doses as well as No response or side effects Inadequate response & no side effects addition of agents follows a stepwise approach, monitoring carefully for specific Substitute BP drug Add second BP drug side effects or agents or due to lowering of blood pressure (see Figure). Uncomplicated Figure: General algorithm for treatment of hypertension hypertension warrants starting with a low (adapt to individual patients per JNC guidelines) dose of a long acting once daily drug Continue Adding Agents from Other Classes (diuretic or beta-blocker), and titrating the ManOp section XI – 07/01/07 Secondary Prevention of
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dose. Low dose combination may also be appropriate. The initial drug choice for participants with compelling reasons (e.g. diabetes) or specific indications (e.g. African- American) may be different. Antihypertensive drugs given to participants for reasons other than blood pressure control (e.g. beta-blockers after myocardial infarction, ACE inhibitors for diabetic nephropathy) will not be discontinued in order to achieve the SPS3-assigned BP target. Drugs to increase BP will not be administered to achieve SPS3-assigned targets. Participants will be told of their assigned target level at their request, but they should be encouraged not to undertake extensive home monitoring in most cases and in the event that they provide you with their home readings, these are not to be entered into the DE system. Both target ranges are within generally good control, based on control of hypertension clinics in the U.S.
As you dispense antihypertensive agents to individual SPS3 participants, the type
and dose are recorded on the individual Receiving, Assignment and Destruction records and in your patient records. Please attach the perforated label from each bottle of medication to the patient record. On a weekly basis (at least), please enter dispensed medications into the Drug Distribution web-based inventory and your drug supply will automatically be replenished by the DDC. If you have an emergency, contact the Study Coordinator. Needless to say, SPS3 antihypertensive medications should never be given to nonSPS3 participants. (See section XVIII for additional information about Study ManOp section XI – 07/01/07 Secondary Prevention of
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JNC-VII ALGORITHM FOR DRUG TREATMENT OF HIGH BLOOD PRESSURE
HTN with Compelling Indications for Use of Specific Agent
4. Angina/coronary risk factors ■ Angiotensin receptor blocker ■ Calcium channel blocker ■ Calcium channel blocker 2. Heart failure 5. Chronic kidney disease ■ ARB ■ Aldosterone antagonist 6. Secondary stroke prevention JAMA 2003; 289:2560-75 ManOp section XI – 07/01/07 Secondary Prevention of
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SPS3 Blood Pressure Follow-up

SPS3 includes intensive BP management until the target levels are achieved, often
requiring returning to clinic 4-6 times during the first few months for a "BP Check." (Patients that are not returning to clinic at least monthly for BP checks during the first 6 months ought to be contacted by phone to encourage compliance.) It should be stressed to participants that good control of BP (which is currently achieved in only about one-third of hypertensives in the U.S.) is an investment in good health and that it may take awhile to find the best medicines with the least toxicity to control BP. Close monitoring and good control of BP by experts is a clear benefit of joining SPS3. Noncompliance is a major reason for failure to control BP, and this should be explored by interview and supplemented by pill counts. In selected patients, use of the 24hour ambulatory BP device may help clarify hypertension management. After a patient's BP is "in-target" on two consecutive measurements, then the participant reverts to the quarterly follow-up schedule. ManOp section XI – 07/01/07 Secondary Prevention of
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SPS3 hypertension treatment algorithm:
SBP 15 mmHg above goal
SBP 15 mmHg above goal
Start 1 drug
Start 2 drugs
Thiazide Diuretic1 OR Angiotensin converting enzyme
Thiazide Diuretic1 AND Angiotensin converting
inhibitor2 (ACEI)
enzyme inhibitor2 (ACEI)
SBP not at goal 3
SBP not at goal 3
Increase dose
Increase doses
Diuretic and monitor potassium (high potassium diet Diuretic and monitor potassium (high potassium diet recommended) ACEI (lisinopril) up to 40 mg/day Increase dose ACEI (lisinopril) up to maximal dose (max dose 80 mg/day in single or divided doses) SBP not at goal 3
SBP not at goal 3
Add a drug (3 drugs)
Add the other drug (2 drugs)
If Heart Rate >80 bpm: Beta blocker (BB)4 or a non-
not in the regimen already dihydropyridine calcium channel blocker (CCB)5:
(ACEI or Diuretic, starting dose depends on BP level) atenolol 25 mg/day Or verapamil 120 mg/day
If Heart Rate <80 bpm: add dihydropyridine CCB6:
felodipine 5 mg/day
SBP not at goal 3
SBP not at goal 3
Already on 2 drugs at moderate to maximal doses. Increase dose of 3rd drug
See algorithm for SBP 15 mmHg above goal
• Verapamil up to 360-480 mg/day • Atenolol up to 100 mg/day • Felodipine up to 10 mg/day SBP not at goal 3
Add 4th drug
• If on atenolol (+ diuretic and ACEI or ARB) add felodipine
• If on verapamil (+ diuretic and ACEI or ARB) add felodipine or hydralazine7 25-50 mg (BID)
• If on felodipine (+ diuretic and ACEI or ARB) add atenolol
SBP not at goal 3
Titrate 4th drug
• Felodipine up to 10 mg/day • Hydralazine up to 100-150 mg (BID); it can be given every 6-8 h but not recommended due to poor compliance • Atenolol up to 100 mg/day (some prefer to use atenolol 50 BID instead) SBP not at goal 3
Add 5th drug
• Candesartan 8-32 mg/day (if not already substituted for ACEI in intolerant patients).
• Clonidine8 0.1-0.3 mg BID (OK if young, avoid if >70 y/o or if HR already <70 bpm, monitor side effects).
• Hydralazine or minoxidil to regimens without them (monitor for edema and tachycardia, MUST be on beta
blockers – or other rate control agents – and diuretics before adding direct vasodilators).
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Always recommend a low sodium diet. The DASH diet has been proven to
decrease BP in clinical studies
(www.nhlbi.nih.gov/health/public/heart/hbp/dash/). Smoking cessation is
imperative. Limit alcohol consumption to 1 drink per day in women and 2 in
men. Weight loss and exercise programs also need to be started and
maintained for successful BP control.
Algorithm is based mostly on SPS3 formulary.
1. Thiazide diuretic
: In patients with normal kidney function start chlorthalidone
6.25 to 12.5 mg per day or hydrochlorothiazide (HCTZ) 12.5 mg/day. Increase
either one to 25 mg per day as needed (HCTZ is approximately 60% as potent as
chlorthalidone). In some cases higher doses can be used (rarely >50mg per day)
but must monitor serum potassium frequently. In patients with kidney failure and
decreased GFR loop diuretics may be used instead. Always use furosemide at
least twice a day
. A useful loop diuretic dosed only daily is torsemide (Demadex,
start at 10-20 mg/day).
2. Angiotensin converting enzyme inhibitors (ACEI): Lisinopril is the drug in the
SPS3 formulary. Many other agents are available (in the USA enalapril, captopril and benazepril are also generic and very affordable). Start lisinopril at 10-20 mg per day and increase to the maximum of 80 mg per day. Some experts prefer to use lisinopril twice a day when in high doses (remember compliance decreases sharply if drugs are used more than daily). Can substitute for candesartan (the angiotensin receptor blocker in the SPS3 formulary) if known intolerance to ACEI. Start at 8mg per day, increase up to 32 mg per day in daily doses. Other good ARBs are available but none generic yet (and thus expensive). 3. Blood pressure not at goal: If compliance is good adjust doses of medications
every 4 weeks. In some cases (except for diuretics) changes can be made more
often (every 2 weeks). It is better to start drugs in moderate doses (1 or 2
agents) and wait than start very low and make frequent adjustments (because it
usually takes a minimum of 2 wks to see the full effect of most drugs).

4. Beta Blocker: The beta blocker in the SPS3 formulary is atenolol. Depending on
the desired effect start at no more than 25 mg daily (in some cases,like in patients
with kidney failure, 12.5 mg daily could be adequate). Other generic beta
blockers are also adequate. Bisoprolol and short acting metoprolol tartrate
(Lopressor) are generic drugs also. Always use metoprolol tartrate twice a day.
Metoprolol succinate (Toprol XL) is used once a day. Monitor HR and do not
titrate dose up if resting HR is <60 bpm.

5. Non-DHP Calcium channel blockers (CCB): Verapamil SR (long acting
formulation) is in the SPS3 formulary (the other agent in this class is diltiazem).
These agents are vasodilators but also have negative chronotropic and inotropic
effects. Always use long acting preparations. Do not use in patients with
known congestive heart failure. Peripheral edema is a common side effect.
Monitor HR and do not titrate dose up if resting HR is <60 bpm. Do not use
in combination with BB as life threatening bradycardia can occur.

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6. DHP Calcium channel blockers (CCB): Felodipine is the drug in the SPS3
formulary. Start in doses of 5 mg per day and increase as tolerated to 10 mg per
day. Higher doses do not usually decrease BP more than 10 mg/day would. Can
use felodipine as second line agent after diuretics or ACEI/ARB but do not use
alone as it (like amlodipine and nifedipine) can increase the incidence of
congestive heart failure. Other popular drugs in this class are amlodipine
(Norvasc) and nifedipine (Adalat). These are effective vasodilators. Better
combined with long acting diuretics and ACEI to diminish the peripheral edema
common to these agents. Some peripheral edema may persist despite addition of
diuretics and ACEI, while generally benign, if patient comfort is an issue may
need to discontinue use. NEVER use short acting nifedipine.
7. Hydralazine: This is an effective vasodilator that can be used very successfully
twice a day (never less). Can be added to regimens that MUST include a diuretic and a rate controlling agent like a BB or non-DHP CCB. I have used it in addition to CCB with success. As with minoxidil must monitor for CHF and volume overload carefully. 8. Clonidine: This is a popular centrally acting alpha blocker. It is short acting! BP
tends to oscillate rapidly and the rebound effect can be serious if stopped
abruptly. It is better used as a patch every 7 days (it is expensive if not
covered by a drug plan).
If a centrally acting drug is needed consider reserpine
at low dose (0.1 to 0.2 mg per day). It takes at least 4 wks to see the effect of this
drug but it can be very effective combined with diuretics.

In difficult to control hypertensive patients
BB can be substituted successfully for
labetalol. It is a selective alpha1-adrenergic and nonselective beta-adrenergic
receptor blocker. Labetalol is generic; start at 100 mg twice daily and increase the
dose up to 1200 mg twice a day. Carvedilol another agent in the same class is
typically reserved for patients with CHF (it is expensive).
In elderly patients maximal doses of most agents are typically lower than those
recommended for younger patients.

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Frequently Asked Questions
Q: If an SPS3 participant who is randomized to the "usual care" group (i.e. 130-149 mmHg) has a measured systolic BP of 126 mmHg on an ACE inhibitor and diuretic, should antihypertensive therapy be reduced? Ans: Yes. Either the dose should be reduced or one agent discontinued to bring the patient into the assigned range (it might be sensible to bring the patient back in two weeks for a repeat measurement before changing medications). Is this ethical? Yes. If we were certain that the lower blood pressure range was better for the patient, there would be no need for the trial. A small percentage of patients will be hypertensive with an SPS3-measured systolic BP < 130 on a concurrent antihypertensive medication, which cannot be discontinued due to a co-existing medical condition (e.g. diabetics with microalbuminuria on ACE inhibitors). ACE inhibitors initiated by primary care physicians in diabetic patients will not be discontinued nor dose decreased for the purpose of achieving target blood pressure. The same is true for patients with coronary artery disease on beta-blockers. Q. What about diabetics? If my diabetic hypertensive patient is assigned "usual care", and their systolic BP is 144 mmHg, should it be lowered further?
Ans: It is important to emphasize that no clinical trials have established optimal levels
of BP control for diabetic patients with established cerebral small artery disease. If it were certain that lower BPs were better for these patients, there would be no justification for including them in SPS3. As always, there is legitimate debate about how far to extrapolate observations from other clinical settings, and many physicians might feel uneasy. It should be emphasized to primary care physicians that guidelines for BP management reflect the best practice based on available data, but they should not restrict additional research if they are not based on hard evidence. This is all to say that there has been much debate about this issue, weighing the strength of evidence and its applicability to S3 participants. Of note, the SPS3 PSMB will be asked to monitor the ManOp section XI – 07/01/07 Secondary Prevention of
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hypertension trial separately in the subgroup of diabetic participants and to recommend that the trial be stopped or modified if concerns emerge.
In the situation described above, the patient should continue on the current
antihypertensive regimen, per SPS3 protocol. At the option of the local hypertension specialist, BP in diabetic patients assigned "usual care" can be lowered to <140 mmHg (still within the usual care range of 130-149 mmHg). Actual achieved BP among diabetic participants will be monitored closely during the early course of SPS3, and the protocol modified if need be.
Q: We are having trouble achieving the assigned target. When should the participant
be declared "failure to achieve assigned target (FAAT)?"
Ans: This is a matter of judgment that is influenced mainly by the participant's
willingness to continue vigorous attempts to control blood pressure. Most SPS3 participants will be able to achieve the assigned target BP levels if they are willing to return for regular monitoring and adjustment of antihypertensive medications by a skilled, experienced clinician. The need for frequent clinic visits and medication changes/dosage adjustments should be made clear to potential participants before study entry. At some point after entry, a participant may decide that he/she is unwilling to continue to return to clinic and/or try new antihypertensive medications to control blood pressure (possibly because of minor side-effects, etc). Declaring "failure to achieve assigned target" does not mean that SPS3 management of BP stops, only that it is pursued less aggressively, in accordance with the participant's tolerance. Recall that all participants, whether FAAT or inactive, will be followed every 3 months and their outcomes analyzed according to the original treatment assignment ("intention-to-treat"). Effort to control BP must continue in all active SPS3 participants.
Before declaring a participant "failure to achieve assigned target", the local hypertension
specialist should discuss the situation with the Coordinating Center Hypertension Expert. The number of participants who are "failure to achieve assigned target" will be ManOp section XI – 07/01/07 Secondary Prevention of
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monitored carefully across the study and at each clinical site, seeking common problems that can be avoided. Q: An SPS3 participant is taking ramapril prior to joining the study. The ACE inhibitor available on the SPS3 formulary is lisinopril. Can the patient continue ramapril? Ans: Yes, if the patient is able and willing to obtain the ramapril. We encourage continuing antihypertensive agents initiated pre-SPS3 that can be funded by the participant's HMO/medical insurance (justified as for routine clinical care) as appropriate. If special antihypertensive medications that are not part of the SPS3 formulary are required, as prescribed by the SPS3-affiliated local hypertension specialist for a good reason, efforts will be made to obtain the medication, as the budget allows (usually including solicitation of donations from pharmaceutical companies). E- mail the specific circumstances to the Coordinating Center Hypertension Expert, who will consider the necessity and work to obtain the medication, if deemed appropriate. Sample Cases
For each of the following 10 cases, consider the following options, and select the correct answer based on the SPS3 protocol. Options: ‰ Adjust medications now and recheck in 2-4 weeks. ‰ Recheck at next quarterly follow-up ‰ No meds adjustment, recheck in 1-2 weeks ‰ No meds adjustment, failure to achieve assigned target (FAAT) ‰ Other, explain 1. Hispanic, female patient randomized to BP target 130-149. Current medications: HCTZ 12.5 mg qd, Fosinopril 40 mg qd, Metoprolol 50 mg qd. Patient is seen at the clinic today for her 6 month follow-up visit, and she reports she has not been taking her BP medications for last 2 weeks because "she does not feel like it". Her SPS3 BP is 156/79. Her most recent SPS3 BP prior to today was done at the 3 month follow-up and was 145/75. What is your plan? ManOp section XI – 07/01/07 Secondary Prevention of
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2. 75 year old, white, male with history of HTN was randomized to BP target 130-149 and is in the clinic for his 9 month follow-up. Patient was in target at last quarterly follow-up. Current medications: Terazosin 5 mg every other night, Prinzide 20/25 mg qd. SPS3 BP today is 130/77. What is your plan? 3. Patient was randomized to BP target 130-149 with an SPS3 BP on date of randomization of 170/95. Patient's SPS3 BP has not been in target since randomization. Most recent BP SPS3 BP was 160/88 four weeks ago on atenolol 25 mg qd. Today at his 3 month follow-up, his SPS3 BP is 154/85. Current medications: Atenolol 50 mg qd, HCTZ 12.5 mg qd. What is your plan? 4. 75 year old female patient with history of DM type II was randomized to BP target 130-149. Current medications: Captopril 50 mg qd, HCTZ 12.5 mg qd. Patient comes to the clinic today for a BP check complaining of feeling very tired and getting dizzy every time she stands up. Her SPS3 BP is 125/53. What is your plan? 5. Patient was randomized to target BP < 130. His SPS3 BP today is 125/69, and at his last BP Check it was 128/71. Current medications: HCTZ 12.5 mg qd and Fosinopril 20 mg bid. What is your plan? 6. Diabetic patient is randomized today to BP < 130. His SPS3 BP today is 135/63. Current meds: Verapamil 180 mg qhs. What is your plan? 7. Patient randomized to target BP 130-149 reports today at his regular follow-up that he has not taken his medications for the last week because he lost them vacationing and decided to wait until his appointment today to contact us. His SPS3 BP today is 156/74. Prior to this, patient BP was stable on current meds. Current meds: Propanolol 40 mg bid, HCTZ 25 mg qd. What is your plan? 8. Diabetic patient randomized to BP target 130-149 returns to clinic for a regular ManOp section XI – 07/01/07 Secondary Prevention of
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follow-up. His SPS3 BP today is 137/76, and his only complaint is dry cough once and a while. Current meds: Fosinopril 40 mg bid. What is your plan? 9. Non-diabetic patient randomized to target BP 130-149 comes to the clinic for her first post-randomization BP check. Her BP is 128/75 today with no complaints. SPS3 BP on date of randomization was 132/82 on the same meds. Current medications: atenolol 25 mg qd. What is your plan? 10. Hispanic female with history of DM type II and HTN for 23 years treated with a large number of anti-hypertensives was randomized to target BP <130. Patient comes to the clinic today for her 1 year follow-up; her SPS3 BP is 136/69. Patient states that she is tired of trying a lot of medicines and that her BP is good enough, and she feels well. Current meds: Amlodipine 5 mg qd, Fosinopril 40 mg bid, Furosemide 40 mg bid, Propanolol 40 mg bid, Hydralazine 100 mg bid. What is your plan? ANSWERS AND JUSTIFICATIONS 1. Other. Patient needs to re-start the same therapy she was receiving and return to the clinic for BP check in 2-4 weeks. 2. Recheck at next quarterly follow-up. Stable patients (i.e. on target twice and then seen only at quarterly follow-ups until out-of-range) with an on target BP at a quarterly follow-up return for their next BP at their next regular follow-up in 3 months. 3. Adjust medications now and recheck BP in 2-4 weeks. Increase HCTZ to 25 mg qd and recheck in 4 weeks (2 wks if medication change did not involve thiazide). 4. Adjust medications now and recheck BP in 2-4 weeks. Patient's BP is below assigned target and patient complains of not feeling well, so a decrease in antihypertensive medication is needed. The patient was started on her ACE inhibitor for her diabetes, so it ought not to be discontinued. In this case it is ManOp section XI – 07/01/07 Secondary Prevention of
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appropriate to reduce or stop the HCTZ, and recheck in 2-4 weeks. 5. Recheck at next quarterly follow-up. When the patient completes two consecutive BP checks on target, next appointment will be the next quarterly follow-up. 6. Adjust medications now and recheck in 2-4 weeks. Starting an ACE inhibitor as part of the anti-hypertensive therapy for this patient would be appropriate. Recheck BP in two weeks. Instruct the patient to resume the same medications at the same doses and recheck the BP in two weeks. 8. Recheck at next quarterly follow-up. This patient can be seen again in three months in a regular follow-up. Even though he reports a side effect from the medications, no change of anti-hypertensive therapy is required. Instruct patient to call the study coordinator if the dry cough becomes a problem. 9. No meds adjustment, recheck in 1-2 weeks. Patient needs two consecutive BP checks in target on the same medications to be able to revert to the quarterly follow-up schedule. Patient was either not taking her medications at her post-randomization SPS3 BP that was in target, or the medication was not yet stable. Recheck and if again below target, then either change medication or reduce to q48h. 10. No medications adjustment, Failure to Achieve Assigned Target (FAAT). In this particular case, the patient completed a year in the study suggesting that multiple attempts were done to keep the BP on target assigned. The patient is already showing discomfort with the frequent changes in the therapy and is pleased with her current BP. The physician must declare Failure to Achieve Assigned Target and keep the BP under control, so the patient's compliance will be not jeopardized. The next appointment will be at the one year + 3 month follow-up. ManOp section XI – 07/01/07 Secondary Prevention of
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XII. STUDY FOLLOW-UP
Regular in-clinic follow-up of SPS3 patients is extremely important. Patients seen in clinic on a regular basis are more likely to stay on assigned antiplatelet therapy, have their blood pressures in the target range, take their medications as directed, and have potential events detected and documented in a timely fashion. When you schedule a quarterly follow-up visit, remember that part of the visit is BP measurement, so if the patient is taking any antihypertensive medications, he/she will need special scheduling considerations and prompting about taking medications (see Section VIII). The SPS3 study physician should physically evaluate the patient at all in-clinic visits, even if it is a seemingly routine visit with no suspicious symptoms elicited by the study coordinator. The participant's expectation of being seen by a physician regularly (and for free!) is often a factor that encourages patients to join the study (although it is generally rapport with the study coordinator that keeps them in!). Goals of follow-up are seven-fold:
1. To keep participants on assigned antiplatelet therapy
Analysis of the SPS3 endpoint data is on an intention-to-treat basis. This means that all events that occur after the moment of randomization until the end-of study date are counted against the assigned therapies. Events occurring in patients, whom are non-compliant, discontinue study medication for whatever reason, or take excluded medications are counted the same as those events occurring in the perfectly compliant patients. If excessive numbers of participants are not taking assigned therapies per protocol, the results of SPS3 will be worse than worthless! To minimize such circumstances, we must select patients carefully and encourage compliance during follow-up, avoiding non-clinical withdrawals. Keeping patients active on assigned therapy involves continuous re-education about the rationale and importance of the study. SPS3 physicians should emphasize the ManOp section XII – 07/01/07 Secondary Prevention of
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importance of the project and of the crucial participation of each patient at follow-up visits. Whenever possible, avoid long waiting times for follow-up appointments, and be sure to communicate with the patient's primary care doctor to keep his/her critical Patients who are intolerant of aspirin are ineligible for the study, however, very occasionally a patient will be randomized who is unaware of being aspirin intolerant. During follow-up, if a patient experiences difficulty tolerating the 325 mg aspirin, the clinical decision may be to try a dose of 81mg. If the patient takes the 81 mg aspirin and continues to take the other ‘antiplatelet' medication (clopidogrel/placebo), this patient is still considered active in the antiplatelet arm of the trial. Please contact the Coordinating Center and make them aware of this change in aspirin dose. This change to 81mg of aspirin also needs to be recorded on the next quarterly follow-up form (See specific instructions for ‘Antiplatelet Trial' questions of Follow-Up form in 2. To monitor blood pressures and adjust antihypertensive medications to keep
BPs in target
Management of hypertension is discussed in detail in Section XI. It is imperative that all efforts within the patient's tolerance and limits of safety be made to achieve and maintain blood pressures in the assigned target range. When a blood pressure is out of range, it must be compulsively rechecked in two to four weeks as per protocol. We need to show that the achieved blood pressures are importantly different between the two BP target groups, and this means consistent follow-up and action on out-of-range BPs. If you are having difficulty with a patient, ask for help! If excessive numbers of participants have BPs out of range, the results of SPS3 will be uninterpretable! To minimize such circumstances, we must select patients carefully and work to achieve in target blood pressures. ManOp section XII – 07/01/07 Secondary Prevention of
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3. For patient safety
Remind patients that they need to bring all their medications, both study and non- study, with them to each study visit. This allows you to record which medications the patient takes, not just the ones they can recall. When a patient forgets to bring with them any of either the study or non-study medications, have the patient call you when he/she returns home, or better yet call them. Pill counts for antiplatelet therapy compliance can be done over the phone, but be sure to tell the patient to destroy any pills leftover. Patients should be told to contact you if any medication is changed, if any medication is lost, if they have any symptoms of stroke, TIA, or if they are hospitalized for any reason. Although SPS3 patients have all experienced a stroke, they will still need to be re-educated periodically about the warning signs of stroke. 4. To complete follow-ups as scheduled
Quarterly follow-ups need to be compulsively completed within the follow-up window. Missed or late follow-ups are usually a sign of poor patient compliance or disorganization of study personnel - both of great concern. This will be monitored carefully at each center, and a report will be sent to your center and the Coordinating Each patient is required to have regularly scheduled follow-up visits every 3 months. The follow-up schedule is generated and printed at the time of randomization. Target dates for these visits are based on date of randomization and have a two- week window on either side. A patient randomized on April 4th, 2003 has the following schedule of quarterly follow-ups. ManOp section XII – 07/01/07 Secondary Prevention of
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It is not necessary to schedule these Scheduled follow-up Target Date of Follow-up Follow-up Window quarterly follow-ups on the exact target 3 month 06/20/03 – 07/18/03 09/20/03 – 10/18/03 date. A follow-up is considered "on 9 month 12/21/03 – 01/18/04 time" if it is completed anytime during 1 year 03/21/04 – 04/18/04 06/20/04 – 07/18/04 the follow-up window. In fact, it is 1 yr + 6 mo 09/20/04 – 10/18/04 suggested that follow-ups be 1 yr + 9 mo 12/21/04 – 01/18/05 03/21/05 – 04/18/05 scheduled early in the window; if a 2 yr + 3 mo 06/20/05 – 07/18/05 patient needs to change their 2 yr + 6 mo 09/20/05 – 10/18/05 12/21/05 – 01/18/06 appointment at the last minute, then 3 year 03/21/06 – 04/18/06 there is adequate time to schedule 3 yr + 3 mo 06/20/06 – 07/18/06 09/20/06 – 10/18/06 another within the follow-up window. If 3 yr + 9 mo 12/21/06 – 01/18/07 a patient needs to have a BP check, 4 year 03/21/07 – 04/18/07 06/20/07 – 07/18/07 and the appointment date is within the 4 yr + 6 mo 09/20/07 – 10/18/07 follow-up window, complete only the Follow-up form as blood pressure data are collected as part of the follow-up. In-clinic visits are the expected; however, occasionally it may be necessary to do a follow-up by telephone or with a non-study physician. For example, if a patient moves far away, it may be possible to arrange for a physician in their new location to see the patient, or to alternate follow-ups by phone with in-clinic visits. For some patients, particularly those who come long distances, compensation for travel expenses of taxi fare may be considered, but this is the prerogative of the local clinical center using credit dollars. It is the SPS3 policy that patients will not be paid for participating in the study; non-monetary benefits include potential benefit of study drug and antihypertensive medications, regular follow-up of blood pressure and symptoms, free regular contact with terrific doctors and nurses experienced in stroke prevention. Home visits may be done at the discretion of the local investigators. Follow-ups not occurring in the designated window are considered missed. If a patient misses a follow-up, contact them immediately. A patient may miss a follow- ManOp section XII – 07/01/07 Secondary Prevention of
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up for a number of reasons, e.g. forgot the appointment, had an event, was in the hospital, losing interest in the study, doesn't want to participate in the study, etc. If a patient is hospitalized, you may complete the follow-up in-hospital. This gives you an opportunity to make sure that no unnecessary changes are made in the patient's study drug use, and that the patient is not placed on any excluded or contraindicated medications unless absolutely necessary. If a patient is absolutely unable to come to the clinic during the entire follow-up window, and a home visit is not possible, conduct a phone follow-up, send their antiplatelet medications to them ahead of time, and arrange for an in-clinic BP check as soon as possible. While adherence to this window may seem unduly rigid, it is impossible to analyze the over 40,000 expected follow-up forms on a catch-as-catch-can basis! Patients who discontinue all assigned SPS3 intervention(s), i.e. both their antiplatelet therapy and SPS3 management of their blood pressure, still need to continue to be followed every 3 months in clinic for the purpose of measuring blood pressure and event detection. If this is not possible, at a minimum, have the patient come for annual visits with phone follow-ups for the other quarterly follow-ups. 5. To detect and document events
This involves alerting the SPS3 physician, enlisting the blinded neurologist event assessor (BEA) for ischemic stroke/TIA and CNS hemorrhage events, and timely completion of appropriate forms. Events and their procedures are defined in detail in Section XIII and in the instructions for the forms (section XX). As events occur infrequently, call the Study Coordinator at the Coordinating Center for help if you have any questions. 6. To identify other cerebrovascular risk factors (e.g. diabetes,hyperlipidemia)
and assist their primary care physician with their management
Management of other cerebrovascular risk factors will be under the supervision of the patient's primary care physician; however, the SPS3 study team will assist their ManOp section XII – 07/01/07 Secondary Prevention of
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efforts. Algorithms for management of risk factors other than hypertension are in 7. Establish a good rapport with the patient
The rapport that the study coordinator establishes with the patient is the major factor keeping the patient active in the study. Get to know your patients, their families, their interests, etc. As a general rule, patients are considerate and appreciative of your interest and help. ManOp section XII – 07/01/07 Secondary Prevention of
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XIII. EVENT DOCUMENTATION AND PROCESSING
Event Documentation
There are nine categories of events during SPS3 follow-up that require scrupulous, standardized documentation and validation using separate data forms listed below: 1. Ischemic stroke 2. CNS Hemorrhage 3. Major Cognitive Decline (not due to clinical stroke) 4. TIA 5. Major non-CNS Hemorrhage 6. Serious Complication of Hypotension (e.g. orthostatic fall causing a broken bone, etc.) 7. Other SPS3-related Serious Adverse Event (e.g. T.T.P., severe allergic reaction to an SPS3 prescribed med) 8. Acute MI or other non-CNS Thromboembolism (including venous thrombosis and pulmonary emboli) 9. Death (categorized as vascular, nonvascular, and uncertain) Specific definitions for each study event appear in the line-by-line for the Event Notification form and as part of the protocol. All events, including those that occur in patients who have discontinued all SPS3 antiplatelet therapy and BP management, and in those with previous events of the same type, will be assessed and recorded for central adjudication. All possible events should undergo assessment and central adjudication in order to minimize detection bias. (Note: if all submitted events are verified, then it is likely that minor events are under-detected.) For safety monitoring purposes, all events need to be reported, via the Event Notification Form 20 and the SPS3 Data Entry System (DES), within 24hr of their identification. When you learn of a possible event, carefully review the SPS3 event- specific definition for that event category in the line-by-line of the Event Notification form or event-specific form and discuss with your local physician investigator. Check that the event meets SPS3 criteria, then complete and enter the Event Notification form. If ManOp section XIII – 08/15/09 Secondary Prevention of
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possible, the local physician investigator should complete the narrative summary on the Event Notification form, but occasionally, the SPS3 research coordinator may need to do so in order to submit it within 24 hr. Contact the SPS3 Coordinator if you have any Reporting of four categories of events will be forwarded by the Statistical Center (SC) to the independent Medical Safety Monitor immediately upon their receipt. The Medical Safety Monitor (MSM) uses the web-based monitoring system to process events assessments. First, the clinical coordinator enters an Event Form 20 record into their local DES. Next, the overnight process sends an email to the MSM for major events (event codes: 3 – CNS hemorrhage, 4 – major non-CNS hemorrhage, 5 – serious complication of hypotension, and 6 – other serious adverse event) and to data managers at the SC for all events, both major and minor. Within the SC, the e-mail is forwarded to staff members at four levels of notification, with the level of notification increasing for each day that there is no response from the MSM. Initially, only the data management staff, study statisticians, and programmer receive the notification. Level 2 then serves to resend the e-mail to the initial group of contacts. Level 3 forwards the email to the principal investigator at the SC along with the initial group of contacts. Finally, level 4 adds other key members, including the manager of information systems and other statisticians. The MSM then goes to the specific website (See Fig. 1 and 2), at http://138.26.144.17/evtnot/ack.asp, in order to acknowledge receipt of the event notification. Next, the site coordinator enters into the DES the appropriate auxiliary event form for the event (form 22 for a CNS hemorrhage, form 23 for a major non-CNS hemorrhage, form 24 for a serious complication of hypotension, or form 25 for another type of event). For major events, the overnight process sends an email to the MSM that new information is available regarding the event. The Monitor may then choose either to close the event case, having received enough information, or request more information from the coordinator, with both options being available via the website. If ManOp section XIII – 08/15/09



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the MSM requests more information from the coordinator, the overnight process sends an email to both the coordinator and to the SC data management with the text of request. If no further information is needed, the MSM will finally close the event case by selecting the appropriate box listed on the website. Figure 1 – The Medical Safety Monitor Website – Site 99 Sample Event ManOp section XIII – 08/15/09



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Figure 2 – Medical Safety Monitor's review webpage on MSM website
BEA Assessment
The event-specific form for an event will be completed by an SPS3 physician who may be unblinded to BP target assignment. Separately the Blinded Event Assessor (BEA) will complete the BEA event-specific form, if applicable. Additional forms to be completed and by whom are event-specific and indicated on the relevant event-specific form. The event-specific form, the BEA event-specific form if applicable, and any accompanying forms need to be completed and entered within 30 days of identification of the event. Call the Coordinating Center if you are having trouble doing so! Three event categories require the BEA to evaluate the patient: 1) Ischemic stroke, 2) TIA, and 3) CNS hemorrhage. Since the HTN trial target BP group is not blinded, the BEA will offer unbiased determination of whether a stroke (ischemic or hemorrhagic) or ManOp section XIII – 08/15/09 Secondary Prevention of
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TIA event meets study criteria and, in the case of strokes, whether there is persisting neurological disability. The BEA is an SPS3-affiliated neurologist who is unaware of the assigned BP target and the status of antithrombotic therapy (i.e. active or inactive). During assessment of an event, the BEA should avoid learning about BP meds, compliance, antithrombotic therapy, etc. The specific event-related materials to be collected for an event vary with event type and are listed at the end of each event-specific form. Start collecting event materials in the participant's event folder as soon as you submit the Event Notification form. Adequate documentation is extremely important, so err on the side of collecting too much information rather than too little. Obtaining event materials when participants are hospitalized at non-affiliated hospitals requires extra efforts, but still must be done. Copy the event materials, including the event narrative, and send to the Events Coordinator within 30 days. Clinical neuroimaging following an event will be determined by the participant's personal physician. In the event of a stroke, if a CT was done as part of routine care and demonstrates the lesion, please submit these images. If the CT does not demonstrate the lesion or if neuroimaging was not done as part of routine stroke care, then contact the Coordinating Center principal investigator for approval for an SPS3-funded MRI. In the event of a Major Cognitive Decline event, we want to be sure to obtain an MRI, preferably with vascular imaging. If an MRI + vascular imaging was done as part of routine care, then obtain a reprint/image files on CD. If not, then contact the Coordinating Center for approval to have an SPS3-funded study done. As the diagnosis of TIA is clinical, we are not asking for a CT/MRI in the event of a TIA. If neuro-imaging is obtained as part of the TIA clinical work-up, please submit the images to the Coordinating Center. Note that the permission of the participant and the personal physician should be obtained prior to scheduling this post-event study, which although covered by the initial informed consent, remains voluntary. Send the reprint/image files on CD to the Coordinating Center within 30 days. ManOp section XIII – 08/15/09 Secondary Prevention of
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7 steps to happy and complete event documentation:
Reporting of all possible events must be done on a timely basis with supporting documentation submitted to the Events Coordinator for any necessary blinding and subsequent submission to the Events Adjudication Committee. 1) Complete and enter the Event Notification form for each and every possible event that is identified, within 24 hrs of identification. Report all events considered "possible" by the SPS3 physician. If in doubt, submit! 2) Have the SPS3 physician evaluate the patient and complete the event-specific form and any additional forms indicated on the event specific form within 30 days of event identification. 3) Have the BEA evaluate the patient as soon as possible (within 30 days) for all possible ischemic strokes, TIAs, and CNS hemorrhages. All possible events detected by investigators, all suspicious symptoms elicited by a standardized questionnaire, and all patients at their end-study visit are evaluated by a neurologist blinded to treatment assignments. 4) Collect copies of the specific event-related documents and place in a file folder to remain permanently with the participant's SPS3 records. 5) Copy the narrative summary and the event-related documents and send to the Events Coordinator within 30 days of the event. 6) Send a reprint/imaging files on CD of the relevant neuroimaging study if the event was an ischemic stroke, TIA, CNS hemorrhage, or major cognitive decline to the Coordinating Center. 7) Events occur infrequently. Contact the Study Coordinator or Events Coordinator at the Coordinating Center if you have any questions about what to do. ManOp section XIII – 08/15/09 Secondary Prevention of
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Event Adjudication
After the clinical site has submitted all relevant forms electronically and sent copies of the event documentation to the Events Coordinator, the event will be sent for verification by the Events Adjudication Committee. A report summarizing relevant diagnostic information from the database and the blinded event documentation will accompany an Event Adjudication form for the adjudicator to complete. Ischemic Stroke, TIA, and CNS Hemorrhage events will be reviewed by two members; other event types will be reviewed by one. Clinical Centers • Event Notification form to Statistical Center within 24 hr • Event-specific form (and auxiliary forms, if applicable) to Statistical Center within 30 days • Event documents to Events Coordinator within 30 days • Blinded event assessment for primary events Events Adjudication Committee • Events Coordinator: purge medical records of treatment information • Event reviewed by physician adjudicators within 30 days of receipt • Event tracked by Events Coordinator Event Processing: Safety Events
The processing of Safety Events has two stages: the initial stage occurring within 24 hr of identification of the event, and the subsequent follow-up stage within 30 days of the event when more information becomes available. The adjudication of Safety Events is Clinical Centers • Event Notification form to Statistical Center within 24 hr • Event-specific form (and auxiliary forms, if applicable) to Statistical Center within 30 days ManOp section XIII – 08/15/09 Secondary Prevention of
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Medical Safety Monitor • Notified of Safety events within 24 hr • Interacts with clinical sites re: management p.r.n. • Reports to DSMB every 3 months or p.r.n. • Safety Events include all: CNS hemorrhage Major non-CNS hemorrhage Major Complication of Hypotension Other SPS3-related SAEs ManOp section XIII – 08/15/09 Secondary Prevention of
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XIV. PREMATURE STUDY TERMINATION
All randomized patients should be followed until the end-study date in 2012, regardless of whether or not they are actively receiving assigned SPS3 intervention(s). Patients who end all contact with SPS3 before end-study either by withdrawing consent or losing contact with SPS3 can have a serious impact on the outcome and validity of the study and this should be avoided. It is not unreasonable to expect 100% follow-up at the end of the trial! If a participant indicates that he/she no longer wants to participate in SPS3, ask if you may contact him/her by phone rather than requiring in-clinic follow-up. This compromise allows detection of major study events and avoids "premature study termination". Some participants who may initially request no further contact due to an adverse event, etc. may agree to telephone contact with you or an SPS3 investigator. If the patient is willing to maintain contact but refuses one or both assigned SPS3 intervention(s), complete the Status of Therapy form. If the patient does withdraw consent despite your very best efforts, complete the Study Termination form. If a participant is moving away from your site, they may be followed by another SPS3 site. Contact the Coordinating Center if this is a possibility. If this is not possible, then arrange episodic telephone follow-up with the patient. For the end-study visit in 2012, arrangements may be made with a local physician to complete most of the forms due at end-study. If you are able to maintain contact with the patient, but the patient will not actively receive the assigned SPS3 intervention(s), complete a Status of Therapy form. In the very rare situation that a patient is moving and episodic telephone contact will not be possible, complete the Study Termination form along with the other forms required at No patient is lost to follow-up, but some are harder to find than others. The best protection against "lost" patients is a good relationship with the patients and their ManOp section XIV – 08/15/09 Secondary Prevention of
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families. Prompt attention to missed appointments is also important. The better you know your patients, the more resources you will have for tracking them down if they seem to disappear. Furthermore, ensuring that you record a minimum of two contact persons and their numbers at study entry with quarterly review will ensure that you have current information to locate a participant if necessary. A patient should not be declared lost until all resources (including a house-to-house search) have been exhausted. If you think you have a patient lost-to-follow-up, contact the SPS3 Study Coordinator at the Coordinating Center. A search in the National Death Index will be done at study completion for any patient "lost" during the study. It is critical to have the patient's SSN to do so; be sure to record it on the Patient Contact Sheet at study entry. Completion of the Study Termination form for those patients who terminate early requires contacting the Coordinating Center, either the Study Coordinator, Oscar Benavente, or Bob Hart. Both premature study termination and discontinuing SPS3 assigned interventions are measures of study execution and will be closely monitored by the Steering Committee. If you are having trouble with a patient, don't wait until it is too late - Contact the Study Coordinator at the Coordinating Center for help. Related to the extended follow-up, participants who reach the originally planned 4.5 years of follow-up will be approached to re-consent to further follow-up. It is critical to the validity of the study that re-consenting is not differential by treatment group or in relation to the outcomes under study. The rate of re-consenting and also remaining active in the assigned treatment groups and follow-up is also important for precision of the results. If a patient refuses to re-consent for extended follow-up or re-consents and then at a later time withdraws consent, complete the Study Termination form. ManOp section XIV – 08/15/09 Secondary Prevention of
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XV. COMMON ANTIHYPERTENSIVE MEDICATIONS
This section contains three reference tables. The first table (Table 1 below) lists categories of BP lowering meds and generic names of commonly found meds in each category. The next table is lengthy and lists BP lowering medications by Trade Name (first letter capitalized) and generic name (no capitalization). You may find it useful to help you complete the Medications and BP Check forms. If you need to know how to categorize a medication that is not listed in Table 2, contact the Study Coordinator for help. Table 3 lists the more common side-effects of BP lowering medications by medication category. Table 1. BP Lowering Meds by Category.
Category Generic
Thiazide Diuretic chlorothiazide; hydrochlorothiazide (HCTZ); chlorthalidone; indapamide; metolazone furosemide; bumetanide; ethacrynic acid; torsemide Potassium Sparing amiloride; spironolactone; triamterene; Beta-blocker acebutolol; betaxolol; bisoprolol; carteolol; carvedilol; labetalol; metoprolol; nadolol; penbutolol; pindolol; propranolol; timolol amlodipine, diltiazem, felodipine, isradipine, nicardipine,nifedipine, nisoldipine, verapamil benazepril; captopril; enalapril; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril Angiotensin Receptor candesartan; eprosartan; irbesartan; losartan; olmesartan; Blocker telmisartan; valsartan Central Alpha Agonist clonidine; guanabenz; guanfacine; methyldopa doxazosin; prazosin; terazosin Vasodilator hydralazine; ManOp section XV - 08/15/09 Secondary Prevention of
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Table 2. Classification of BP Lowering Meds by Name
CLASS, category on form acetazolamide acetazolamide Accupril quinapril quinapril + HCTZ ACE inhibitor, other + Diuretic, thiazide Beta blocker, other Aceon perindopril ACE Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Alatone spironolactone Diuretic, spironolactone + HCTZ Diuretic, potassium sparing + Diuretic, thiazide Aldactone spironolactone Diuretic, methyldopa + chlorothiazide Misc, central alpha agonist + Diuretic, thiazide Miscellaneous, central alpha agonist methyldopate HCl Miscellaneous, central alpha agonist methyldopa + HCTZ Misc, central alpha agonist + Diuretic, thiazide ACE inhibitor, ramipril amiloride amiloride Calcium channel blocker, amlodipine Apo-Hydro hydrochlorothiazide Diuretic, Diuretic, thiazide hydralazine + HCTZ Misc, vasodilator + Diuretic, thiazide Miscellaneous, vasodilator - hydralizine Angiotensin receptor blocker, candesartan candesartan + HCTZ ARB, candesartan + Diuretic, thiazide Beta blocker, atenolol irbesartan + HCTZ ARB, other + Diuretic, thiazide Angiotensin receptor blocker, other amlodipine + olmesartan Calcium channel blocker, amlodipine + Angiotensin receptor blocker, other benazepril benazepril bendroflumethazide bendroflumethiazide Angiotensin receptor blocker, other olmesartan + HCTZ ARB, other + Diuretic, thiazide Beta blocker, metoprolol Beta blocker, other hydralazine + isosorbide dinitrate Miscellaneous vasodilator – hydralazine + Miscellaneous long-acting nitrate Beta blocker, other ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form Beta blocker, other Diuretic, furosemide/loop diuretic Diuretic, furosemide/loop diuretic Diuretic, furosemide/loop diuretic amlodipine + atorvastatin Calcium channel blocker, amlodipine + Lipid lowering agent, statin Calcium channel blocker, verapamil Angiotensin receptor blocker, candesartan Capoten captopril captopril + HCTZ ACE inhibitor, other + Diuretic, thiazide captopril captopril Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Cardura doxazosin Beta blocker, other Calcium channel blocker, other Beta blocker, other carvedilol carvedilol Miscellaneous, central alpha agonist Miscellaneous, central alpha agonist chlorothiazide chlorothiazide chlorthalidone chlorthalidone Diuretic,thiazide Calcium channel blocker, verapamil Miscellaneous, central alpha agonist clonidine + chlorthalidone Misc, central alpha agonist + Diuretic, thiazide Coreg carvedilol blocker, carvedilol Beta blocker, other Beta blocker, other nadolol + bendroflumethiazide B-blocker, other + Diuretic, thiazide Calcium channel blocker, verapamil Coversyl perindopril Angiotensin receptor blocker, other Diuretic, furosemide/loop diuretic Miscellaneous, other antihypertensive Diamox acetazolamide Diuretic, Calcium channel blocker, other ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form Calcium channel blocker, other Calcium channel blocker, other Angiotensin receptor blocker, other valsartan + HCTZ ARB, other + Diuretic, thiazide Diuril chlorothiazide Diuretic, reserpine + methyclothiazide Misc, other antihypertensive + Diuretic, thiazide doxazosin doxazosin triamterene + HCTZ Diuretic, potassium sparing + Diuretic, thiazide Calcium channel blocker, other Calcium channel blocker, other Dyrenium triamterene Diuretic, furosemide/loop diuretic enalapril enalapril deserpidine + methyclothiazide Misc, other antihypertensive + Diuretic, thiazide eplerenone eplerenone Angiotensin receptor blocker, other Espirolona spironolactone Diuretic, Diuretic, furosemide/loop diuretic Calcium channel blocker, felodipine ACE inhibitor, fosinopril Diuretic, furosemide/loop diuretic Diuretic, furosemide/loop diuretic Miscellaneous, central alpha agonist guanadrel sulfate guanadrel sulfate Miscellaneous, central alpha agonist Miscellaneous, central alpha agonist hydrochlorothiazide Diuretic, thiazide Hidroclorotiazida hydrochlorothiazide Hidrosaluretil hydrochlorothiazide Diuretic, hydrochlorothiazide + hydralazine Diuretic, thiazide + Miscellaneous vasodilator - hydralazine Miscellaneous, vasodilator - hydralizine hydrochlorothiazide + hydralazine Diuretic, thiazide + Miscellaneous vasodilator - hydralazine HydroDIURIL HCTZ Hydrozide (PLEASE hydrochlorothiazide +/- amiloride Diuretic, thiazide +/- Diuretic, potassium sparing Hygroton chlorthalidone Diuretic,thiazide guanadrel sulfate Miscellaneous, central alpha agonist Hytrin terazosin ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form ARB, other + Diuretic, thiazide isosorbide mononitrate Miscellaneous long-acting nitrate indapamide indapamide Diuretic,thiazide Beta blocker, propanolol Beta blocker, propanolol propranolol + HCTZ B-blocker, propranolol + Diuretic, thiazide propranolol + HCTZ B-blocker, propranolol + Diuretic, thiazide Inhibace cilazapril Beta blocker, propanolol Inspra eplerenone Diuretic, Angiotensin receptor blocker, other Calcium channel blocker, verapamil Calcium channel blocker, other Beta blocker, other Beta blocker, other Diuretic, furosemide/loop diuretic Calcium channel blocker, other Beta blocker, other enalapril + felodipine ACE inhibitor, enalapril + Ca-Channel blkr, felodipine ACE inhibitor, lisinopril Miscellaneous, vasodilator - minoxidil benazepril + HCTZ ACE inhibitor, other + Diuretic, thiazide Beta blocker, metoprolol metoprolol + HCTZ B-blocker, metoprolol + Diuretic, thiazide Angiotensin receptor blocker, other Lotensin benazepril amlodipine + benazepril Ca-Channel blkr, amlodipine + ACE inhibitor, other Lozide indapamide Diuretic,thiazide Lozol indapamide Diuretic,thiazide Mavik trandolapril ACE triamterene + HCTZ Diuretic, potassium sparing + Diuretic, thiazide triamterene + HCTZ Diuretic, potassium sparing + Diuretic, thiazide methazolamide methazolamide methylclothiazide methylclothiazide Miscellaneous, central alpha agonist methyldopate HCl methyldopate HCl Miscellaneous, central alpha agonist metolazone metolazone Beta blocker, metoprolol Angiotensin receptor blocker, other ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form telmisartan +HCTZ ARB, other + Diuretic, thiazide Midamor amiloride Minipress prazosin prazosin + polythiazide Misc, alpha blocker + Diuretic, thiazide Miscel aneous, vasodilator - minoxidil amiloride + HCTZ Diuretic, potassium sparing + Diuretic, thiazide moexipril moexipril Beta blocker, other Beta blocker, other ACE inhibitor, fosinopril fosinopril + HCTZ ACE inhibitor, fosinopril + Diuretic, thiazide Mykrox metolazone Diuretic, Beta blocker, other Beta blocker, other Neptazane methazolamide Diuretic, Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Calcium channel blocker, other Beta blocker, other Calcium channel blocker, other Novo-Hydrazide hydrochlorothiazide Miscellaneous vasodilator - hydralazine Diuretic, furosemude/loop diuretic hydrochlorothiazide + triamterene Diuretic, thiazide + Diuretic, potassium sparing Calcium channel blocker, amlodipine Angiotensin receptor blocker, other Beta blocker, other perindopril perindopril Beta blocker, other Beta blocker, other Calcium channel blocker, felodipine polythiazide polythiazide prazosin prazosin ACE inhibitor, lisinopril lisinopril + HCTZ ACE inhibitor, lisinopril + Diuretic, thiazide ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form Calcium channel blocker, other Calcium channel blocker, other Beta blocker, propanolol quinapril quinapril ACE inhibitor, ramipril Calcium channel blocker, felodipine reserpine + polythiazide Misc, other antihypertensive + Diuretic, thiazide reserpine reserpine Miscellaneous, other antihypertensive Beta blocker, other Beta blocker, other Miscellaneous, other antihypertensive hydralazine + HCTZ + reserpine Misc, vasodilator + Diuretic, thiazide + Misc, other antihypertensive spironolactone spironolactone Calcium channel blocker, other trandolapril + verapamil ACE inhibitor, other + Ca-Channel blkr, verapamil Calcium channel blocker, other Miscellaneous direct rennin inhibitor - aliskiren Angiotensin receptor blocker, other Miscellaneous, central alpha agonist atenolol + chlorthalidone B-blocker, atenolol + Diuretic, thiazide Beta blocker, atenolol terazosin terazosin Angiotensin receptor blocker, other eprosartan + HCTZ ARB, other + Diuretic, thiazide Thalitone chlorthalidone Diuretic,thiazide Calcium channel blocker, other B-blocker, other + Diuretic, thiazide Beta blocker, other Beta blocker, metoprolol Diuretic, furosemude/loop diuretic Diuretic, furosemide/loop diuretic Beta blocker, other trandolapril trandolapril triamterene triamterene moexipril + HCTZ ACE inhibitor, other + Diuretic, thiazide Univasc moexipril Angiotensin receptor blocker, other enalapril + HCTZ ACE inhibitor, enalapril + Diuretic, thiazide ManOp section XV - 08/15/09 Secondary Prevention of
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CLASS, category on form Vasotec enalapril Calcium channel blocker, verapamil Calcium channel blocker, verapamil Calcium channel blocker, verapamil Miscellaneous, central alpha agonist Zaroxolyn metolazone Beta blocker, other lisinopril + HCTZ ACE inhibitor, lisinopril + Diuretic, thiazide ACE inhibitor, lisinopril bisoprolol + HCTZ B-blocker, other + Diuretic, thiazide ManOp section XV - 08/15/09 Secondary Prevention of
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Table 3. More Common Side Effects of Antihypertensive Medications:
Thiazide diuretics: GI complaints, leg cramps, rash, volume depletion and hypokalemia (about 30%), caution in patients on digoxin, arrhythmias, loss of blood sugar control in diabetes Potassium sparing diuretics: gynecomastia (high dose of spironolactone), hyperkalemia Loop diuretics: volume depletion, hypokalemia, GI intolerance, elevated creatinine and Beta-blockers: fatigue, somnolence, nightmares, impotence and cold extremities, bradycardia, bronchospasm (if COPD), inability to sense hypoglycemia and loss of blood sugar control (if diabetic) ACE inhibitors: cough, rash, increased potassium concentration, possible increased creatinine (if hypovolemic or pre-existing renal dysfunction), hypotension is usually dose-limiting adverse effect Ca-channel blockers: constipation (particularly verapamil), hypotension, peripheral edema, bradycardia (verapamil and diltiazem), potential for heart failure (if poor LV function), heart block Angiotension II receptor blocker: dizziness (?hypotension), diarrhea (same frequency as placebo), cough (losartin) same frequency as placebo, hyperkalemia Alpha blocker: postural hypotension (most common with prazosin; give first dose at bedtime), conscious sedation, tachyphylaxis (loss of effectiveness of a given dose with chronic therapy), GI complaints Central alpha antagonist: fatigue, somnolence, depression, hypotension, impotence, Vasodilator: sodium and water retention (edema, heart failure and loss of BP control), lupus syndrome (hydralazine), hypertrichosis (excess hair growth, minoxidil), hepatitis, hypotension ManOp section XV - 08/15/09 Secondary Prevention of
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XVI. MANAGEMENT GUIDELINES FOR OTHER CEREBROVASCULAR
RISK FACTORS
• Pharmacologic for type 2 DM in adults • Exercise algorithm for type 2 DM prevention and therapy • General lipid treatment algorithm • Lipid Treatment algorithm for type 1 and 2 DM in adults ManOp section XVI - 04/15/03



Secondary Prevention of
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ManOp section XVI - 04/15/03


Secondary Prevention of
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ManOp section XVI - 04/15/03 Secondary Prevention of
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General Lipid Treatment Algorithm
Recommendations for evaluation and treatment of high cholesterol in adults are based on the
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or
ATP III). JAMA 2001; 285:2486-2497.
New Features of ATP III:
1. Recommends a complete lipoprotein profile (total, LDL, and HDL cholesterol and triglycerides) as the preferred initial test. 2. Encourages use of plant stanols/stenoids and viscous (soluble) fiber as therapeutic dietary options to enhance lowering of LDL cholesterol. 3. Recommends treatment beyond LDL lowering for persons with triglycerides ≥200 mg/dl. Table 1. ATP III classification of LDL, total
Table 2. Major risk factors (exclusive of LDL
and HDL cholesterol (mg/dl) cholesterol) that modify LDL goals LDL cholesterol
> 140/90 or on antiHTN meds Near or above normal • Low HDL cholesterol (< 40 mg/dl) • Family history of premature CHD* (CHD in male first degree relative < 55 yr; CHD in female first degree relative < 65 yr > 45 yr; female > 55) Total cholesterol
*Diabetes is regarded as CAD risk equivalent. HDL cholesterol
Table 3. LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes
(TLC) and Drug Therapy by Risk Category InitiateTLC if LDL… Consider Drug Therapy if
Category
CHD or risk equivalents (10 years risk >20%) (100-129:drug optional) (10 year risk ≤20%) 10 year risk <10%: ≥160 0 – 1 Risk factor 160-189: LDL-lowering drug opt'l ManOp section XVI - 04/15/03 Secondary Prevention of
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Figure 1. Steps in Therapeutic Lifestyle Changes • Reduction of saturated fat and • Moderate physical activity. • Consider referral to a dietitian. • Reinforce reduction in saturated fat and cholesterol. Consider adding plant stanois/sterois. achieved, intensify If • Increase fiber intake. on atenolol (+ diuretic • Consider referral to a dietitian and ACEI or ARB) • Initiate therapy for metabolic Intensify weight management and physical activity • Consider referral to a dietitian achieved, consider adding drug therapy Every 4-6 Months Subsequent Visit
Monitor adherence to ManOp section XVI - 04/15/03 Secondary Prevention of
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Figure 2. Progression of Drug Therapy in Primary Prevention Initiate LDL-Lowering Start statin or bile acid sequestrant or nicotinic acid Consider higher dose of statin, or adding bile acid sequestrant or achieved, intensify LDL-lowering drug If LDL goal achieved, treat other lipid risk factors achieved, intensify LDL-lowering drug therapy or refer to a Every 4-6 Months Subsequent Visit
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XVII. SAMPLE CONSENT FORM AND PARTICIPANT MATERIALS
Following is a template of the consent form in English. Spanish and French versions are also available from the Coordinating Center. Each IRB has its own slightly different requirements, and you will need to work with your local IRB to meet its specifications. Contact the Study Coordinator at the Coordinating Center if you have any questions or Copies of the SPS3 information brochure, participant booklets, and participant wallet cards will be provided to you by the Coordinating Center. There is space on them to personalize them for your site. Sample letters to a patient's primary care physician are also included in this section. Two additional patient information handouts, "How I Can Reduce High Blood Pressure" and "What is High Blood Pressure Medicine", which are produced by the American Heart Association, are also included here for distribution to your patients if you wish. ManOp section XVII – 08/15/09 Secondary Prevention of
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SUBJECT CONSENT TO TAKE PART IN A STUDY OF SECONDARY PREVENTION OF SMALL, SUBCORTICAL STROKES (SPS3)
The University of Texas Health Science Center at San Antonio University Hospital and University Physicians Group (UPG)
PRINCIPAL INVESTIGATOR:
CO-INVESTIGATOR(S):
SPONSOR:
National Institute of Neurological Disorders and Stroke (NINDS). University of British Columbia, Vancouver, Canada INTRODUCTION
We are inviting you to take part in a research study about stroke prevention. Stroke is
damage to the brain caused by problems in the blood vessels. Strokes often cause
paralysis, loss of sensation, loss of speech and other problems. One type of stroke
affects the inner part of the brain causing small "pea-sized" areas of damage due to
blockage of small blood vessels within the brain. Doctors often call this type of stroke
"lacunar stroke" or "small subcortical stroke." About 150,000 strokes of this type
happen each year in the United States and close to 20,000 in Canada. We are asking
you to take part in this study because you have recently had a transient ischemic attack
or stroke of this type. We are aiming to enroll up to _ participants in this center, and up
to 3000 subjects across North America, Latin America, and Spain. Your participation in
this study could continue until April 2012.
PURPOSE
The purpose of this research study is to gather information about a new treatment that
might help prevent another stroke from happening in people who have suffered a
"lacunar stroke" or transient ischemic attack. Aspirin is the medicine most widely used
and is the standard therapy for this type of stroke. Clopidogrel is another medicine
doctors use to prevent stroke. Both of these medicines have an effect on blood clotting
and are now widely prescribed by doctors for stroke prevention. However, using them
together for the type of stroke that you have had has not been tested. We want to learn
if using them together is more effective than using aspirin alone. We also want to learn if
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lowering a patient's blood pressure below the usual limits will also help prevent stroke and maintain thinking ability. If you do not have hypertension (high blood pressure), your blood pressure will not be lowered. PROCEDURES
If you decide to take part in this research study, you will be assigned by chance (like
flipping a coin, called randomization) to one of two types of treatment to reduce clotting.
You will have an equal chance of being randomized to receive either aspirin alone or
the combination of aspirin and clopidogrel. Neither you, your doctor, nor the research
staff (investigators and nurses) will know until the end of the study whether you are
receiving the combination of aspirin plus clopidogrel or aspirin alone. However, if we
need to know for an emergency situation, we can quickly find out which medicine you
are taking.
We will give you two bottles of pills. One will contain aspirin (325 mg) and will have a label marked "aspirin." The other bottle will be labeled "study drug" and will contain either clopidogrel or placebo (a pill that contains no medicine). You will take one pill from the "aspirin" bottle and one from the "study drug" bottle (a total of two pills a day) every day until the end of the study. You will also be assigned by chance to one of two groups of blood pressure control. The
difference between the two groups is the target level of systolic blood pressure: either
130-149 or below 130. While it is generally recommended that systolic blood pressure
be controlled below 140 for most people with high blood pressure, we do not know what
target levels are best for people who have already had a stroke. No one knows whether
lowering blood pressure after a stroke might help prevent another stroke or cause
further damage; this is the goal of the blood pressure aspect of the study. You will not
be told to which target blood pressure group you are assigned, but we will give you your
blood pressure readings if you wish.
With the permission of your doctor, the study doctors will treat your blood pressure
using standard medicines according to accepted guidelines in order to lower your blood
pressure to the goal assigned to you.
No experimental blood pressure medicines will be used, just those used everyday in
clinic that you may be receiving now. You will know the names and doses of the blood
pressure medications, and these medications will be provided at no cost to you. We will
ask you and your doctor to allow us to adjust your blood pressure medicine during the
study.
STUDY VISITS
At your first two visits, we will review your medical history, give you a physical
examination, and carefully measure your blood pressure. We will also ask you
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questions to test your memory and thinking which will be audio taped. You will then be randomized (assigned by chance) to receive one of two types of treatment to reduce clotting and to one of two blood pressure groups (explained above). These visits will each take about two hours. You will return to clinic to have your blood pressure measured at least once each month for the first two months. If you do not have high blood pressure, you will come to clinic at three months and every three months thereafter. If you have high blood pressure it may take 4 to 5 visits (at least monthly) until your blood pressure meets your assigned goal. At these visits, your blood pressure medications will be adjusted if necessary. Each visit will take about half an hour. After your blood pressure has reached the goal, you will come to the clinic every 3 months. These visits will take about 45 minutes. We will ask you questions about your health, possible side effects of the medicines, examine you, take your blood pressure, and adjust your blood pressure medicines if needed. You will need to bring your bottles of study medicines with you to each clinic visit. Once every year, we will ask you questions to test your memory and thinking and these tests will be audio taped. As part of routine clinical care, we will also obtain a yearly blood sample to look at your cholesterol levels, kidney function, and your sugar control if you are diabetic. We would also like to invite you to participate in an optional sub study. We will collect blood samples (about two tablespoons) at study entry and at your first yearly visit to evaluate for levels of blood proteins that may predict risk of another stroke and the effect of the protocol medicines. There may be minor discomfort associated with the drawing of blood. Apart from this, no blood will be drawn or any special tests done unless you are having symptoms or problems. As part of this research study, we want to learn about changes in a person's brain after a stroke. If you did not have an MRI (magnetic resonance image) and MRA (magnetic resonance angiogram) scan of your brain following your stroke, you will need to have one done. Another scan will also be done if you suffer a stroke or major change in thinking ability during the study. An MRI scan of the brain provides a clear picture of the brain by using magnetic signals (not x-rays) and an MRA provides a clear picture of the intracranial vessels. For this test, you will be asked to lie quietly on a table for about 30 minutes with your head in a tube that extends down over your shoulders. If you have a tendency to get nervous in small spaces, a mild sedative can be given before the test (but you will not be able to drive for 8 hours if a sedative is used). People with artificial heart valves, pacemakers and certain other types of metal in their bodies cannot undergo MRI/MRA safely. If you cannot undergo an MRI/MRA safely, please tell us now. The results of any MRI/MRA done will be provided to you and your doctor, but only at the end of the study. By signing this form, you are giving permission to have these MRI/MRA scans if needed, for the investigators to look at the results, and for a print-out of the scan to be sent to the SPS3 Coordinating Center, with any identifying information ManOp section XVII – 08/15/09 Secondary Prevention of
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kept confidential. Information from this research about individual patients will not be available and will not be used for any future treatment. RISKS AND DISCOMFORTS
If you have high blood pressure and receive medicines to control your blood pressure
as part of this study, there may be side effects of these blood pressure medicines. The
chances for side effects generally increase with the higher doses sometimes needed to
achieve lower blood pressures. Common side effects include impotence and
gastrointestinal side effects. The specific side effects depend on which medications are
used. The choice of blood pressure medicine to be used for you will depend on whether
you have other health problems (such as diabetes or heart failure), what medicines you
are taking now, and how you may have reacted to medicines in the past. When we
determine which medications are best for you (based on standard guidelines and help
from our high blood pressure experts), you will be given an information sheet about the
possible side-effects that might occur with each of the medicines you are taking. These
side effects, if they do occur, are seldom life-threatening, and they usually go away
when the medicine is stopped. We will review possible side effects at each clinic visit,
and you should call us if you have any questions about possible side effects or your
symptoms.
Combination of Aspirin and Clopidogrel
It is possible that treatment with the combination of aspirin and clopidogrel will diminish
the risk of having another stroke. There is also the possibility that the risk of stomach
upset as well as abnormal bleeding might increase. In a study of heart attack patients
and another study of persons who had suffered a stroke, when aspirin and clopidogrel
were taken together, very serious bleeding occurred in about 3 of 100 patients per year.
Clopidogrel
In previous studies of taking clopidogrel alone (without aspirin), side effects have
occurred in a small number of persons. These include petechiae (small, purplish spots
on the skin); bruises (purplish patch on the skin); or bleeding (such as bleeding in the
stomach or nosebleed) (1 in 10) and life-threatening bleeding (about 1 of 100 patients
per year). A serious side effect called thrombotic thrombocytopenic purpura (TTP) which
affects clotting function (marked reduction of the platelets which would cause
hemorrhages), and bone marrow, may affect on rare occasions people taking
clopidogrel (1 in 400,000). Diarrhea (1 in 200), and rashes were also noted. These side
effects went away after stopping the medicine.
Aspirin
Some of the side effects of aspirin include tinnitus (ringing in the ears) (1 in 100), and
stomach upset, nausea and vomiting were present in about 1 in 10 of the people taking
aspirin. The increased risk of bleeding in the stomach while taking aspirin every day is
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about 1%, or 1 chance in 100 per year and life-threatening bleeding is about 1 to 1.5 out of 100 patients per year. If you are going to have general surgery or dental surgery, it is important that you tell
your doctors (surgeon and anesthesiologist) or dentist that you are taking part in a
research study. Both aspirin and clopidogrel are medicines that can increase the risk of
abnormal bleeding during an operation. We will give you an identification card to carry in
case of an emergency or if additional information is needed about the study.
PREGNANCY
If you are pregnant, you cannot take part in this study. We will perform a pregnancy test
for you before you begin taking the medicines to make sure that you are not pregnant.
You should use birth control while you are taking part in the study because we do not
know what effect the combination of aspirin and clopidogrel may have on an unborn
child. If you think you might be pregnant at any time during the study, you should tell us.
BENEFITS
You may benefit from taking part in this study because the medicines may decrease
your chances of having another stroke. You will have your blood pressure checked
more often than usual and you will receive close observation while you are taking part in
the study. We do not guarantee, however, that you will directly benefit from taking part
in the study.

PARTICIPATION COSTS
You will not be charged for the clinic visits, examinations, MRI scans, the anti-clotting
drugs (clopidogrel and aspirin), or the high blood pressure medications that are
provided as part of the study. If you are taking another medication for your blood
pressure that is not provided by the study and your blood pressure is stable, you have
the choice to continue your medications at your own expense. If you were hospitalized
for a stroke before you joined this study, you are responsible for all costs of
hospitalization. If you have another stroke while taking part in this study, you will be
responsible for all costs relating to treatment. If you are injured as a result of the
research procedures, medical care will be provided. You will be responsible for all
charges. We are not able to give you money if you are injured.
CONFIDENTIALITY AND PROTECTED HEALTH INFORMATION
Every effort will be made to protect your privacy and, in so doing, the study will use your
initials and your study number rather than your name on any copies of your study
records, and on any blood/tissue samples and results of investigations that are sent
outside of the local research institution for review or testing. If the results of this study
are reported in medical journals or at meetings, your personal identity will remain
confidential.
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You will be asked to provide your social security number and other identification to the study nurse. This information will be used only to contact you during the study and at the end of the study, if we are unable to locate you. We are also requesting permission to review and obtain copies of your medical records relevant to your recent stroke and any physician visits/hospitalizations during the study. These records are needed in order to have accurate information about your stroke and any medical event that happens to you during the study. This information and all study information will be confidential. Under federal privacy regulations, you have the right to determine who has access to your personal health information (called "protected health information" or PHI). If you choose to take part in this study, you will be giving your permission to the investigators and the research study staff (individuals involved in carrying out the study) to collect and use your personal health information for this research study. In carrying out this research, the PHI we will collect and use about you will include: • information obtained from procedures used to determine your eligibility to participate in the study, including medical history (past and current), vital signs, physical examination, electrocardiogram, echocardiogram, brain MRI/MRA and blood tests; information that is created or collected from you during your participation in the study, including physical exam, current medications, vital signs, results of tests (done for the study or primary care doctor visits), any records from hospitalizations while participating in the study and any information from out patient clinic records; information contained in your underlying medical records related to your medical history and treatment prior to the study; demographic information which includes things like your age, marital status, type of work you do, years of education completed, gender, date of birth, race. We will obtain this information in different ways (mentioned above). We will ask you personally for information and we will get information about you from your physicians and from facilities where you have received health care. Because of the research goals of this study, however, your PHI in the study records cannot be kept absolutely confidential. Your PHI may be shared with other persons and organizations involved in the conduct or oversight of this research including: • the sponsor of this study, National Institute of Health (NIH) and representatives of the sponsor or other agents designated by the NIH, to monitor or inspect study ManOp section XVII – 08/15/09 Secondary Prevention of
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data as well as regulatory authorities such as the Food and Drug Administration and Health Canada, Therapeutic Products Directorate and its agents, the study's Data and Safety Monitoring Board (DSMB); representatives of (your site specific) Institutional Review Board (IRB), the Compliance Office, the research subject advocate and representatives of other groups that have the responsibility of monitoring and overseeing research studies at your institution. parts of your PHI that pertain to your participation in this study may be photocopied and sent to a central location for review or electronically transmitted. You need to be aware that these organizations receiving your PHI may not have the same obligations to protect your PHI and may further disclose your PHI to groups not named here. Information released to these parties is no longer under the control of the study doctor and can no longer be protected by Federal Privacy Rules. The purposes of disclosing your PHI to these entities are to collect the data necessary to complete the research, to properly monitor how this study is carried out and to answer research questions related to this research study. The Institutional Review Board may approve additional use and disclosure of your PHI for other research by qualified researchers under circumstances permitted by the regulations. If you decide to participate in the study, by signing this form you will be authorizing
these uses and disclosures of your PHI. If you choose not to authorize these uses and
disclosures of your PHI, you will not be able to participate in the research study.
Finally, the federal regulations allow you to obtain access to your PHI collected or used in this study. While the research study is in progress, your access to the PHI in your study records will be temporarily suspended. You will be able to access your information when the research study is completed. At that time, you will have the right to see and copy the medical information collected from you in the course of the study, for as long as that information is maintained by the study staff and other entities, subject to federal privacy regulation. The research information from this study will be stored for a period of _ years.

VOLUNTARY PARTICIPATION AND STUDY DISCONTINUATION
Your participation in this study is voluntary. If you decide not to take part in the study,
you will continue with the standard treatment. The treatment recommended to prevent
another stroke is to take either aspirin or clopidogrel. Good control of high blood
pressure is standard care after a stroke, although doctors disagree about what blood
pressure level is best for persons who have suffered a stroke and to control high blood
pressure.
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You are free to choose not to participate in this study or to withdraw from it at any time. You are also free at any time to cancel the authorization of the use and disclosure of your PHI. If you choose to not be in the study or to not authorize the use of your PHI, there will be no penalties. In other words, you will not be denied any treatments you may need and it will not affect your eligibility for any health plan or any health plan benefits or payments for which you may be eligible. You may cancel or "revoke" your authorization for the researchers to collect, use and disclose your PHI at any time. However the request to revoke the authorization must be sent in writing to Dr. or _ at . If you revoke your authorization, your participation in the study will end and the study staff will stop collecting medical information from you and about you. However, the study staff will continue to use the PHI collected about you before you cancelled your authorization to the extent that, in order to preserve the scientific integrity of the study, it is needed to complete the research. Your participation in the study may be terminated if, among other reasons: ƒ You ask to stop taking part in the study; ƒ Your doctor decides to take you off the study should he/she feel that it is in your best interest, for your well being and health; ƒ The sponsor has decided to terminate the study; ƒ Any other exclusion criteria stated in the study protocol. This authorization expires in 2012.
CONTACT PERSONS
If you have any questions now, feel free to ask us. If you have additional questions later
or you wish to report a medical problem that may be related to this study, your doctors
can be reached at the following numbers below:
Coordinator Neuro
To reach someone in an emergency, please page
_
The University committee that reviews research on human subjects
(Institutional Review Board) will answer any questions about your rights as a research
subject (tel: ).
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INFORMED CONSENT FORM
We will give you a signed copy of this form to keep.
Sign this form only if all of the following are true:
ƒ I have read (or someone has read to me) the above information ƒ I have decided to take part in this research study ƒ I understand the information given about my protected health information and authorize the collection, uses and disclosures of my protected health information as described in this form ƒ My questions have been answered to my satisfaction and I believe I understand all of the information given to me about this study Signature of Subject Signature of Witness Signature of Person Obtaining Consent Date/Time Printed Name and Title of Person In addition to the main study for which I have signed above, I also agree to participate in the additional part of the study: □ taking a blood sample at study entry and one year later to see if there are blood proteins which predict the risk of another stroke and also indicate the body's response to the anti-clotting drugs (as explained on page 3) Signature of Subject Signature of Witness ManOp section XVII – 08/15/09 Secondary Prevention of
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S econdary Prevention of
Smal Subcortical Strokes
<physician address> RE: <patient name> This letter is to inform you that your patient has elected to take part in a research study entitled,
"Secondary Prevention of Small Subcortical Strokes (SPS3)." The study is sponsored by the National
Institutes of Health and is being conducted at 70 sites in the US, Canada, Mexico, South America, and
Spain including <name of your site>.
This is a phase III study designed to assess the effect of two interventions on prevention of recurrent
stroke and maintenance of cognitive function. Patients will be randomized to receive 1) either aspirin
alone or aspirin plus clopidogrel (Plavix), and 2) to a systolic blood pressure control target, either 130-
149 or below 130. While it is generally recommended that blood pressure be controlled below 140/85
for most people with high blood pressure, we do not know what target levels are best for people who
have already had a stroke. No one knows whether lowering blood pressure after a stroke might help
prevent another stroke or cause further damage; this is the goal of the blood pressure aspect of the
study. (If your patient does not have high blood pressure, no blood pressure management will be
done.)
We will treat your patient's blood pressure using standard medicines according to accepted JNC
guidelines, lowering your patient's blood pressure to the assigned goal. No experimental blood
pressure medicines will be used. Your patient will have information about the names and doses of the
blood pressure medications prescribed. There is no cost to the patient for anti-hypertensive
medications or antiplatelet therapy.
If you have questions, please do not hesitate to contact our Study Coordinator, _
at ( ) _ or one of us.
Sincerely yours,

<Neuro principal investigator>
<Hypertension specialist> <contact information> <contact information> ManOp section XVII – 08/15/09 Secondary Prevention of
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S econdary Prevention of
Smal Subcortical Strokes
<physician address> RE: <patient name> was seen today in the Stroke Prevention Clinic. The mean electronic blood pressure was _ mmHg. We recommended that the patient continue on the following anti-HTN therapy:
Your patient is scheduled to return to the clinic on _.
Please contact Dr. <neuro PI> at or Dr. <htn specialist> at _
if you have any questions about this therapy or the study.
Thank you,

<study coordinator >
<contact information>
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E. The DASH diet (Adapted from the Mayo Clinic Health Letter)

For years doctors have recommended reducing sodium to help lower your blood pressure. Now they've discovered that a diet rich in fruits, vegetables, and low-fat dairy products also can lower your blood pressure. An eating guide called the Dietary Approaches to Stop Hypertension (DASH) diet may help you lower high blood pressure. And the diet may also provide other health benefits. Diet comparison The DASH diet evolved from the DASH-Sodium study. For 8 weeks, participants followed one of three diets: • A diet that matched the average American diet • A diet rich in fruits and vegetables • A combination diet that was reduced in saturated fat and emphasized fruits, vegetables, and low-fat dairy products Sodium consumption in all three diets was about 3,000 mg per day. The result: The fruit and vegetable and combination diets both lowered blood pressure, but the combination diet was most effective. In that group the decrease was greatest for those with high blood pressure - with an average drop of 11 points in the systolic (top number) and 5 points in the diastolic (bottom number) blood pressure. Researchers aren't sure why the combination diet fared better. However they believe it is due to the mixture of nutrients provided rather than any single ingredient. What about sodium? The benefits of the DASH diet are improved even further by the reduction of salt. A 1997 study of 412 people was conducted at five US hospitals and sponsored by the ManOp section XVII – 08/15/09 Manual of Operations Small Subcortical Strokes
National Heart, Lung and Blood Institute (NHLBI). Those in the study were divided into two groups and put on controlled-salt diets for 14 weeks. One group ate an average American diet composed of foods such as roast beef, ham, turkey, high fat sweets, and some fruit and vegetables. The other group followed the DASH diet. Members of both groups consumed three levels of sodium during different stages of the trial - a higher intake of 3300 mg daily, an intermediate intake of 2400 mg and a lower intake of 1500 mg. Current dietary guidelines say that you should limit your daily intake of sodium to no more than 2400 mg. Government researchers say that many Americans typically consume more than 4000 mg of sodium daily. The group on the DASH diet experienced a dramatic average blood pressure drop of 9 mmHg in the systolic (top number) blood pressure reading and a 4 mmHg drop in the diastolic (bottom number) when ingesting 1500 mg of sodium. This represented the biggest reduction in the study and indicates that sodium is a very important factor in blood pressure control. Widespread benefits The DASH diet may improve your health in other ways. Fruits and vegetables may reduce your risk of some cancers. The calcium in dairy products can lower your risk of osteoporosis. And a diet low in saturated fat and cholesterol can reduce your cardiovascular disease risk. The diet also lowers the amount of homocysteine in your blood, which when high is another risk factor for cardiovascular disease. An additional plus: The diet is made up of foods readily available at your local grocery store. The DASH diet can't do it alone, though. It's important that you take other steps to control hypertension, such as: exercising, losing excess weight, not smoking, and limiting alcohol. ManOp section XVII – 08/15/09 Manual of Operations Small Subcortical Strokes
The Specifics of the DASH Diet Here are the number of servings you should consume daily from each food group. Serving amounts are based on a diet of 2,000 calories per daily. Food: Daily Servings 1 serving equals Grains and grain products: 1 slice bread
Whole wheat breads, Servings: 7-8 daily 1/2 cup dry cereal English muffins, pita bread, bagels, cereals, 1/2 cup cooked rice 1/2 cup cooked pasta 1/2 cup cooked cereal Fruits and Vegetables:
6 oz. Fruit or vegetable juice Apricots, bananas, Servings: 4-5 fruit daily and grapes, oranges, 4-5 vegetable daily grapefruit, melons, 1/2 cup frozen or canned fruit strawberries, tomatoes, 1 cup raw, leafy vegetables peas, carrots, potatoes, broccoli, squash, leafy 1/2 cup cooked vegetables Dairy: (low-fat or non-fat)
Skim or 1% milk, non-fat Servings: 2-3 daily or low-fat yogurt, non-fat or part-skim cheese 1 1/2 oz. Cheese Meats, poultry & fish:
3 oz. cooked meat Lean meats only; trim Servings: 2 or fewer daily 3 oz. cooked poultry visible fat, remove skin from poultry; broil, roast 3 oz. cooked fish Nuts, seeds and legumes:
Almonds, peanuts, mixed Servings: 3-4 per week 2 tablespoons seeds nuts, sunflower seeds, kidney beans, lentils 1/2 cup cooked legumes ManOp section XVII – 08/15/09 Manual of Operations Small Subcortical Strokes
XVIII. STUDY MEDICATIONS
The principal (PI) investigator at each clinical site is responsible for a complete and accurate accounting of all SPS3 study medications received from the Drug Distribution (DDC). The DDC will provide forms, instructions, and assistance as necessary to assure proper use and accountability of all drugs in this regard. Each site must observe local policies and applicable state and federal regulations concerning custody, dispensing, labeling, and disposition of medications. (See http://www.nabp.net for links to individual state pharmacy boards)
A. Antiplatelet Medications
Antiplatelet medications are packaged in kits with each kit designed to last one specific patient six months. There are 4 bottles in a kit, 2 bottles each of aspirin 325 mg and 75 mg clopidogrel/placebo, with each bottle containing a three month supply of medication (100 capsules/tablets). One bottle type contains aspirin and has the manufacturer's label on it. The other bottle type contains either clopidogrel or placebo and is labeled "clopidogrel/placebo" and both these bottles are labeled with the same patient ID. Two bottles (one bottle of each type) are dispensed to a patient at randomization and at each quarterly follow-up with bottles being dispensed consecutively according to the bottle Each kit has a patient id on it. The first two numbers are your site number. The next three numbers tell you whether it is a HTN stratum kit or a normotensive stratum kit. If this number is below 100, it is a HTN stratum kit, and if it is 100 or higher, it is a normotensive stratum kit. For example, the kit with the number 01-000-6 is a HTN stratum kit for site 01, whereas the kit with the number 24-100-8 is a normotensive stratum kit for site 24. B. Antihypertensive Medications
These medications are packaged so that they can be dispensed directly to the patient without transfer to another container. Each bottle contains 100 tablets (the exception is ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
candesartan which contains 90 tablets and depending on the manufacturer, Felodipine may also be packaged in bottles of 90 tablets) and has the manufacturer's label which contains the lot number and expiration date. In addition, a label affixed by the DDC contains study name, bottle number, applicable federal warnings, and a contact number at the DDC. Bottles are shipped in boxes containing 4 bottles. C. Custody and Storage Requirements
SPS3 study meds should be stored at room temperature between 15° and 30°C (59° and 86°F) in a secure area. Drugs may be stored either in the study clinic or pharmacy depending on local policy. If the study drug is not stored in a pharmacy, it must be kept in a locked room or locked cabinet. Each clinical site must be in compliance with state regulations and Board of Pharmacy requirements for storage of study medication. D. Shipment of Study Medications
After receiving notification from the SPS3 Coordinating Center that all required regulatory documents (i.e. IRB approvals) are received and that all necessary training has been completed, the DDC will send the clinical site an initial shipment of study meds. A Shipping Notice listing items and quantities of all supplies shipped is included with each shipment. In addition, a Receiving, Assignment, and Destruction Record is enclosed for each box of medications. Upon receipt of the shipment, check that you have received each medication as listed on the Shipping Notice, and that the Receiving, Assignment, and Destruction Record is correct for each medication. If there appears to ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
be a discrepancy, or you have a question regarding the shipment contents, contact the DDC (Dave Hunt or Robert Ringer (505) 248-3203). We are providing you with a binder in which to file Receiving, Assignment, and Destruction Records for each medication. E. Dispensing Study Meds
When a patient is randomized, the randomization program on the computer assigns a patient id number with the format ss-ppp-c XXXX, where ss is the site, ppp is patient number, c is the checkdigit, and XXXX is the patient acrostic (e.g. 01-011-1 JSMI). The corresponding kit with aspirin and clopidogrel/placebo bottles will have the corresponding label except without the patient acrostic. The clopidogrel/placebo bottles within the kit will have the patient id number on them, but the aspirin bottles will not. You will need to put patient id labels on the aspirin bottles. Dispense the bottles within a kit in order by bottle number. In most cases you will start with bottle 1, bottle 2, etc. Related to expiration of the study drug, there may be occasions where bottle 1 will not be the first bottle dispensed or where you may skip a bottle number. Complete the information for each bottle dispensed on the Receiving, Assignment, and Destruction Record for that kit. Alternatively, you can use the web site to maintain your records and indicate the date the bottle was dispensed and to which patient using the u pop-up menu and print or save the file on your computer. Regardless of whether you use the Receiving, Assignment, and Destruction Record forms or the website, you must have a record of what medication was dispensed to which patient on which day. The bottles of antihypertensive medications do not contain a patient id number, and when you dispense a bottle to a patient, you will need to put a patient id label on that bottle. Complete the information for each bottle dispensed on the Receiving, Assignment, and ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
Destruction Record for that medication or alternatively using the web-based inventory, indicate the patient ID and date of dispensing for each bottle which is dispensed. This information can be printed and filed or stored as a file on your computer. When dispensing study medications, consider whether the medication will expire before the bottle is completely used. Whenever you dispense a study medication, you also need to affix a prescription label to each bottle that is dispensed. Labels need to contain the following information: ƒ Prescription number (if dispensed by pharmacy) ƒ Patient's name ƒ Drug name, strength, and quantity ƒ Directions for use ƒ Prescriber's ƒ Name of facility ƒ Emergency phone number (local) Do not cover labels applied by the DDC or the manufacturer's lot number and expiration date. Formatted prescription labels are supplied by the DDC for those sites not utilizing a pharmacy. The individual dispensing the drug simply fills in the necessary information on the formatted label using a typewriter or with pen and ink. Prescription of study-related medications must be documented as part of the medical record or on a standard prescription blank. Documentation needs to conclude the following information: ƒ Patient's name and current address ƒ Study name [SPS3 Trial] and patient id number ƒ Drug Name, Strength and Quantity to be dispensed ƒ Directions for use ƒ Signature of investigator or other authorized physician ƒ Date prescription or order is written ƒ No refills (applicable only to medications on the SPS3 formulary) ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
Each bottle of medication (blinded study drug, ASA, and antihypertensive medication) has a perforated label on the bottle. Please detach the perforated portion and attach to the patient file in a consistent place. This label provides a space to enter the date and the patient's acrostic (an additional check that the correct bottle is being dispensed to the correct patient). F. Web-Based Drug Inventory
Sites will access their inventory via an Internet web page hosted in Albuquerque. There are no computer system requirements to use this website. Authorized personnel will use the web pages to indicate dispensing of medications from their current inventory. This information will be retrieved from the website by DDC personnel on a weekly basis and used to generate new drug orders. The website address is: https://www.csp.gov/ctsc/login.cfm
Site personnel will register on the website and be authorized to manage inventory by website administrators. This process provides a level of security as well as an opportunity to ensure that users are assigned to the correct site. New users will click on the "Would you like to register?" link and fill out the form which appears. Existing users will enter their User ID and Password and click the Log In button. This will take the user to their site-specific inventory control page. ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
Users will see the current inventory at their site, according to DDC records. The default page is the antihypertensive inventory. By moving the radial button to the Dispensed/Destroyed, you are able to view all antihypertensive medications that you have dispensed or destroyed. By selecting Antiplatelets and clicking on Inventory, you will view your current antiplatelet inventory and you can also view what you have dispensed or destroyed by selecting that option. Drugs listed can be sorted and filtered in many ways, making it easier to locate specific bottle numbers. The inventory can be filtered in a variety of ways including medication name, bottle number, and ship date. Filtering by medication name is most likely how ongoing management will be handled. The screen here shows a filter of "ATEN" applied to this site's Whether or not a filter is applied, records can be sorted in order to facilitate inventory management. To the right of the screen, you will see the options for ordering (sorting) ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
the medications. You have several options for ordering including generic name, bottle number, kit number, and kit by patient. Ordering the antiplatelets by ‘Kit by Patient' sorts your antiplatelet kits in ascending order by patient ID and places the ASA and study drug that make up that kit together in the inventory. This makes it much easier for you for indicating the dispensed study drug and ASA. This report is a little slow and will not function correctly using some filter options. F.1 Indicating Dispensed/Destroyed Medications
To indicate medications as dispensed, please mark the Dispensed box for each item and click the Submit button at the top of the page. If you wish to enter the patient ID and the dispense date if different from current date, please select the update link to the right of the dispense check box. The current date is displayed by default (in the pop-up window) but can be changed. Once you have clicked the "update" button on the small popup window you do not have to press submit unless you have checked off bottles without using the u link (see below). If you do however submit the form after dispensing ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
by using the u update popup this will NOT over-write the date you entered in the popup. After selecting update on the popup the page will not display submitted data until you refresh the page. In this case it will remove records from list under inventory and they will show up in the dispensed/ destroyed page. Until the DDC uploads the information on dispensing/ destroying to their database, you will see that the check mark (in the dispensed/ destroyed window) is still active. This means that if you made an error (for example, indicated the incorrect bottle as dispensed), you could click on this and it would go back into your inventory. If the DDC has already picked up the orders the button is no longer active and if you need to make a change, you will need to contact the DDC directly. F.2 Special Ordering Medication
Clicking on Request Medication brings up the following page where you can order ASA 81mg (with approval from the CC) and extra boxes of medications. After entering the number of boxes, users will click Submit to add the order. The order will be processed by the DDC at the same time as other orders. If your par has been set to 0 for a medication, ordering one box of this medication will re-set your par to one box (4 bottles). If you already have a par level for a certain medication, ordering an additional box will not reset your par. If you determine that you need to keep more of a specific medication in stock, you can contact the DDC (from this page) and request that your par ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
be increased. You can view your par and order level on each medication by selecting that option under the F.3 Re-supplying Study
Medications
The DDC will monitor inventory levels at each site through the web-based inventory. For each medication (based on your usage), you are assigned a par level (order level) and an order point (the number of bottles on hand that will trigger a shipment – this is usually 50% of the order level). You can view this information for your site by selecting Par Levels. This will show you your previous six months usage. As your usage of a medication increases, the inventory level will automatically increase. As well, you can make adjustments to your par levels by contacting the CC or the DDC. Once you dispense or destroy a medication, please indicate this on the website. Once you reach your order level, this will trigger a new shipment of medication. The DDC will upload the information on what you have dispensed and destroyed on a weekly basis (Tuesday morning). Orders will be process for shipment by the DDC the following week. As a shipment leaves the DDC, it is scanned as it is picked up by Fed Ex (for overnight delivery). Once it is scanned, this information will appear on your inventory under Ship Date and you can expect to receive it the following day (or shortly after that if it needs to clear customs). The DDC is only able to re-supply your inventory as you indicate medications as dispensed or destroyed. If you do not complete this step, the DDC assumes this medication is available on your shelf for dispensing and it will not be replenished. Once the two bottles of study drug (from the anti-platelet kit) have been indicated as ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
dispensed, this will trigger a new kit to be sent to your site within 8 working days of the order being picked up by the DDC. Please indicate all dispensed medications on at least a weekly basis (before the weekly upload to the DDC). This will ensure that you have medications available for all patient follow-up visits. F.4 Replenishing Expiring Medications
For the antihypertensive medications and the ASA, you will see the expiration date indicated in the Expiration Date column. When a medication is within 3 months of the expiration date, this will be highlighted in red. Please do not dispense medication that will expire before you have a chance to replace it. Please destroy any medication that is expiring and indicate this as destroyed in your web-based inventory. It will only be replaced as you indicate that it has been dispensed or destroyed. It is important that you do this in a timely manner so that you receive replacements for expiring When ASA that is part of the anti-platelet kit is expiring, please do not destroy the entire kit (the blinded study drug). Destroy the expiring ASA and indicate this as destroyed on the website. To replenish the EC-ASA 325mg, please request the number of boxes needed (4 bottles per box) under Request Medication menu. The expiration date is not provided for the blinded study drug. This is to maintain the blinding. When either the Clopidogrel or the placebo is expiring, the DDC will notify you and will send you replacement kits for the expiring lots of study drug. Unless otherwise directed by the DDC, expired drugs are destroyed by the local clinical sites, in accordance with local policies for drug destruction. ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
G. Unblinding
Antiplatelet therapy (clopidogrel vs. placebo; all patients are assigned aspirin) is given in a double-blind manner. The treatment code will only be broken if the knowledge of whether the patient is receiving clopidogrel vs. placebo is essential to the medical management of the patient. Unblindings are discouraged; however, the patient's safety must always be paramount. Study personnel will remain blinded if at all possible. If the clopidogrel/placebo blind needs to be broken, the site or physician directly involved in the patient's care will contact Benavente/Hart at the CC for permission). Assuming that Benavente/Hart agrees, the physician directly involved in the patient care will then contact the DDC (Rob/Dave (505) 248-3203; pager 1-877-561-1862). H. Completion of Study
At the end of the study, each site will inventory all remaining study medications. Once inventory is complete, all study drugs will be destroyed on site. ManOp section XVIII –08/15/09 Manual of Operations Small Subcortical Strokes
XIX. COMPLETING SPS3 DATA FORMS
Data will be collected and recorded on paper forms at the clinical sites. You will be provided with a CD-ROM from which to print the forms, and you may also print them from the SPS3 Web site. Each form must be completed neatly and carefully to ensure data quality, and then stored securely. Please check your forms for completeness before you enter them. Form Completion Guidelines:
• Affix a patient id label to the top of each page of each form. Do not write the patient's name or other patient identifying information on the form. • Staple all pages for each form together • Use a pen, not a pencil to complete forms. • Mark boxes clearly with an X or 9. • Write numbers clearly in the number of spaces provided. A value of 123 will fit into an area of " " but will not fit into an answer area of " ". Similarly, a value of 0.3 will fit into an area of " ", but is smaller than expected for a
space of " ". If you have a value that appears too large or too small for the
space indicated, check the units of your measurement against that indicated on the form. (Do not write in a decimal point.) If this does not resolve the problem, contact the Study Coordinator. If you have a value that is more precise than requested, round the value (go up on 5). For example, a hemoglobin value of 14.5 would be recorded as 1 5 and a value of 14.2 would be recorded as 1 • Print letters so that they can be clearly read for data entry. It may be necessary to use abbreviations. If specified, do not exceed the number of characters allowed for an answer. ManOp section XIX – 02/01/10 Manual of Operations Small Subcortical Strokes
• If you make a mistake on a form, label the mistake as an "error", indicate the correct response, date and initial nearby. • If you are asked to indicate one answer (i.e. 9one), then mark only one box. If you feel that it is necessary to mark more than one, contact the Study Coordinator for help. • More than one answer may be marked only if indicated (i.e. 9 all that apply). • Record dates in the format given, usually mm/dd/yy or mm/yy where mm indicates the month, dd is the day of the month, and yy is the year. Occasionally you will be asked to record a date with a four-digit year. • Check the alternate responses carefully before you mark the box "Other". It is highly likely that one of the options is appropriate. The forms have been designed to minimize the number of "other" responses. • If you need to write additional information on the form, write in the white space away from the printed questions and answers on the form. • Each form must be signed at the end by the indicated SPS3 personnel. "MD completing form" means that the signature of the physician is required. If you are a research-nurse, do not allow your study physician to coerce you into completing forms that are designated for physicians to complete. During our site inspections, this will become clear (i.e. we'll find out). Call Oscar Benavente or Bob Hart at the Coordinating Center to initiate an attitude adjustment for your study physician. • The paper forms may in some cases be the source documents (i.e. the quality of life forms) so it is essential that the paper form matches the DE system for all • If you don't understand a question, please don't hesitate to contact the Study Coordinator at the Coordinating Center. We are here to help! ManOp section XIX – 02/01/10 Manual of Operations Small Subcortical Strokes
SPS3 Patient Forms: Form Name and Number
Follow-up Contact
Quarterly Annual Add'l
Baseline History Patient Contact (site use only) Review regularly; update as needed Qualifying Stroke Post-Stroke Disability Cognitive Scales* HTN Quality of Life Current Meds (site use only) Update as needed after each patient visit 24 hr Ambulatory BP Stroke Symptoms QOL Intracranial Vascular Imaging Failure to Achieve Assigned Target Stroke Symptoms Questionnaire Event Notification Ischemic Stroke/TIA Event Major non-CNS Hemorrhage Serious Complication of Hypotension Other SPS3-related SAE Acute MI & Other Thromboembolism Major Cognitive Decline Death Notification BEA Ischemic Stroke/TIA BEA CNS Hemorrhage Status of Therapy Premature Study Termination Cognitive Screening ± See HTN trial protocol/form for instructions; * Cog Screening Form 90 completed after year 5 annual šIf indicated. See specific form for instructions. ManOp section XIX – 02/01/10 Manual of Operations Small Subcortical Strokes
XX. SPS3 DATA FORMS AND LINE-BY-LINES
Form version numbers and dates are found in the bottom right hand corner of the form and line-by-line instructions
SPS3 Form/Line-by-Line Name Line-by-Line Version 07/01/07 01.Screening.03 Baseline History 07/01/07 02.Baseline.06 Patient Contact (not entered on PC) 03.02 Medications 04.04 Qualifying Stroke 07/01/07 06.QualStrk.03 Post-Stroke Disability 06/15/04 07.PostStrk.02 06/15/04 08.NeuroExam.01 Cognitive Scales (English, Spanish, French) 09.04 Cognitive Screening Form 08/15/09 90.CogScreen.01 HTN QoL (English, Spanish, French) 10.03 Current Meds (not entered on PC) 11.01 11.CurrentMeds. 01 Eligibility/Randomization 12.03 24 hr Ambulatory BP 06/15/04 13.AmbulBP.02 Stroke Specific QOL (English, Spanish, French) 14.02 14.StrokeSxQOL.01 Intracranial Vascular Imaging 06/01/03 15.ICImage.01 07/01/07 17.BPCheck.04 Stroke Sx Questionnaire 06/06/05 19.StrokeSxQx.02 Event Notification 06/15/04 20.Event.01 Ischemic Stroke/TIA Event 06/15/04 21.StrokeTIA.01 07/01/07 22.CNS-Hemorrhage.01 Major non-CNS Hemorrhage 07/01/07 23.Major-Hemorrhage.01 Serious Comp of Hypotension 06/15/04 24.Hypotension-Comp.01 Other SPS3-related SAE 06/15/04 25.OtherSPS3-SAE.01 Acute MI & Other Thromboembolism 06/15/04 26.MIOther-Thromb.01 Major Cognitive Decline 06/15/04 27.MajorCog-Decline.01 Death Notification 06/15/04 31.BEAStroke-TIA.01 BEA CNS Hemorrhage 07/01/07 32.BEACNSHemm.01 Status of Therapy 06/06/05 36.StatusTherapy.02 Premature Study Termination 04/04/03 37.StudyTerm.01 06/15/04 38.RepeatMRI.01 Cognitive Screening 08/15/09 90.CogScreen.01 03/09/09 99. StrokeSx99.01 ManOp section XX – 02/01/10 Manual of Operations Small Subcortical Strokes
XXI. DATA TRANSFER AND MONITORING
Data will be entered at the clinical sites and transferred electronically to the Statistical Center on a real-time basis by use of a secure web-based system. Each clinical site will receive a CD-ROM with the complete SPS3 randomization/data entry system installation package and receive training on using the system. After the initial installation of the software, whenever a clinic starts up the SPS3 system, the system will automatically communicate with the SPS3 server at the Statistical Center. Data will be continuously transferred to the main SPS3 database, and the local system will be updated with the latest version of the program. No patient-identifying information will be stored in the database. This SPS3 randomization/data entry system is used at a clinical site to randomize a patient, print labels, enter forms, view and edit previously entered data, and print data reports. See Section XXVI for instructions on how to install and use the SPS3 system. Data reports summarize complete forms, locked forms, overdue forms, and forms with questionable data that have been entered at your site. A complete form has all relevant questions answered and no unresolved validation checks. Complete forms should be locked when you are satisfied that the data are accurate, correct and complete. You are encouraged to enter and lock forms as soon as possible so that the procedures/visits are credited as done. Locked forms are required for site payment (see section XXIII). Overdue forms are forms expected to have been done and locked more than 1 week ago, but which have not yet been entered at all, have questionable data, or are complete but not yet locked. Forms with questionable data have at least one of the following: non-confirmed response(s) outside the anticipated range, unexpectedly blank response(s), conflicting responses within or across forms, etc. If you do not understand an item on a report, contact the Study Coordinator at the Coordinating Center or the Data Manager at the Statistical Center. All clinic personnel using the system will be assigned a login name and password. Both ManOp section XXI – 07/01/07 Manual of Operations Small Subcortical Strokes
are required to logon to the system. Use only your assigned login name and password, and do not share them with others. Each user will be trained and certified by the Statistical Center to use the randomization/data entry system. Following training, a mock set of completed forms will be given to you to enter using the system. To obtain certification, you will need to successfully enter these forms with an error rate below 0.5%. Those with higher error rates will need to re-enter these forms until the error rate falls below this threshold. Only those certified will have access to the randomization/data entry system. Data Monitoring
Site visits are undertaken by the Coordinating Center (CC). Frequency of the visit to a particular site varies according to site performance. During the site visit, approximately 50% of the patients' binders are selected for random review for completeness of source documentation, informed consent and verification/accuracy of key fields (e.g. recorded risk factor data at study entry) including inclusion/exclusion criteria. Any site violating inclusion or exclusion criteria will need to contact the CC prior to enrolling each subsequent patient for review of their entry criteria. With initial and ongoing training of physician investigators, few protocol violations are expected. Reports summarizing the completeness and consistency of forms completed at study entry, during follow-up and for events for individual patients are available to the sites weekly via the Data Completeness Report website.
The data entry error rate for each user will be closely monitored during the study.
Specifically, during the study on a regular basis, the Statistical Center will send you a list of patient forms entered at your site to photocopy and send back to them within 2 weeks. Responses recorded on the paper forms will be compared with those entered in the database. Any user with an error rate exceeding 0.5% will be re-trained and required to double-enter forms. ManOp section XXI – 07/01/07 Secondary Prevention of
Manual of Operations Small Subcortical Strokes

XXII. SITE VISITS
Site visits are made primarily by personnel from the SPS3 Coordinating Center and occasionally by those from the Statistical Center (e.g. if data entry problems are paramount) or by other members of the SPS3 Executive Committee. All SPS3 sites will be visited within the first year after entering patients, at least one time thereafter during the course of the trial, and more often as needed depending on problems with recruitment, execution, or data-quality concerns. Sites will be notified well in advance of the visits. The study coordinator will need to arrange access to a selected group of participant's medical records. During these visits, the Coordinating Center visitor would also like to meet with key study personnel both together and individually to discuss study progress and to solicit your views about the status at your site. On-site activities will require an average of one-half to one full day to complete. Sites at which there are special problems may require longer visits. Purposes
• To document compliance with human subjects protections • To verify a sample of participant data by comparing medical records with the SPS3 forms, particularly focusing on eligibility criteria, key patient features, and event- related materials • To review local SPS3 study activities and procedures to ensure adequate physician investigator involvement and documentation of day-to-day activities, to ensure adequate commitment of time and resources for SPS3, and to identify areas of • To encourage interest and enthusiasm among SPS3 collaborators and others for study recruitment and execution (via meetings with investigators, presentation of ManOp section XXII – 07/01/07 Secondary Prevention of
Manual of Operations Small Subcortical Strokes
Policies and Procedures
Compliance with Human Subjects Protections The research chart of each SPS3 participant will be reviewed to verify the presence of a signed study consent form that has been approved by the local committee governing research in human subjects. The site visitor will ask the study coordinator to describe the informed consent process including the involvement of study- affiliated physicians. • Verification of Participant Data Baseline data forms will be reviewed and verified against source documentation for 6-12 randomly selected patients enrolled within the previous year or since last site visit. Particular attention will be paid to on-site verification of eligibility criteria (excluding MRI, which is done centrally) including the Qualifying Stroke form and the Medical History and test results sections of the Baseline form. Sites at which ineligible patients were entered will need to contact the Coordinating Center prior to enrolling subsequent SPS3 participants for review of entry criteria. • SPS3 Physician Involvement in Follow-up SPS3 research charts will be reviewed for 6-12 randomly selected patients seeking evidence of on-going physician investigator participation in follow-up visits and BP • Review SPS3 Study Activities and Procedures The site visitor will meet with the SPS3 study coordinator to review day-to-day activities involved in recruitment and execution, including the time allocated to these activities. Emphasis will be on assessing for adequate physician investigator involvement and supervision in recruitment, blood pressure management, and endpoint detection and processing. At centers where recruitment is lagging or ManOp section XXII – 07/01/07 Secondary Prevention of
Manual of Operations Small Subcortical Strokes
follow-up is sub-optimal, options for improvement will be explored with the study coordinator and discussed with the local principal investigator. Competing studies at the site and/or studies or other commitments of the study team will be noted. The site visitor will meet with the local Neurology PI and the local hypertension specialist to discuss problems or issues at the site, make recommendations, and answer questions. Whenever possible, the site visitor will meet again with the local neurology PI at the end of the visit to debrief. • Encourage Interest and Enthusiasm During most site visits, the site visitor will meet with the entire local SPS3 investigators team over breakfast/lunch to present an update on the trial and to discuss local performance, and to initiate discussion of ways to improve recruitment and execution. As appropriate, the site visitor may present lectures to local physicians who might refer participants to encourage their interest in SPS3. • Site Visit Reports Written feedback from the site visitor to the local SPS3 investigators, usually via e- mail, will be provided within a few days of the site visit. This can be addressed to the neurology PI or additionally to the study coordinator and hypertension specialist at the discretion of the site visitor. A site visit report will be prepared within two weeks (see below) and reviewed by the SPS3 Executive Committee at its proximate meeting. Protocol violations involving individual SPS3 participants identified during the site visit will be recorded on the SPS3 Protocol Deviations Form (#40) by the site visitor and entered into the SPS3 database by Coordinating Center staff. A copy of the form will be sent to the site at the reviewer's discretion. ManOp section XXII – 07/01/07 Secondary Prevention of
SPS3 Site Visit Form
Small Subcortical Strokes
SITE VISITED:
Site Number:
Site Neurology PI Study Coordinator 1. Date(s) of visit 2. Site visitor(s) 3. Compliance with Human Subjects Protections Signed informed consent form on file for each participant checked (Append list of patients checked. Indicate status for each.) Adequate consent process with appropriate physician involvement If either not checked, explain: 4. Verification of Participant Data: Complete site visit form below for each patient a) Eligibility criteria (excluding MRI) verified for selected participants b) Key baseline data verified for selected participants c) BP Check/follow-up visits with physician input verified in SPS3 chart If any not checked, explain: ManOp section XXII – 07/01/07 Secondary Prevention of
SPS3 Site Visit Form
Small Subcortical Strokes
5. Review SPS3 Study Activities and Procedures Site visitor met with: Neuropsych test administrator(s) and/or supervisor Blinded event assessor Pharmacist (if meds stored centrally) 6. Summary a) What are this site's strengths? b) What are this site's weaknesses? What problems did you identify during the visit? c) When do you recommend this site be revisited? Please append a copy of your feedback sent to the site and any protocol violation forms resulting from this visit. ManOp section XXII – 07/01/07 Secondary Prevention of
SPS3 Site Visit Form
Small Subcortical Strokes
1. Date of review: Questions 3-7: Obtain the patient's SPS3 chart and medical records. Compare the completed Qualifying Stroke and Eligibility/Randomization forms with the medical records. Discuss any discrepancies with the local investigators and record them below. 3. Records reviewed: † hospital chart from qualifying stroke † outpatient records 4. Patient's date of birth: 5. Do the available medical records support that the qualifying stroke occurred? † Yes, date of stroke † Uncertain/inadeq info 6. Does the qualifying stroke meet SPS3 criteria for S3? † Uncertain/inadequate info 7. SPS3 Eligibility Criteria: † Uncertain/inadeq info Disabled by stroke (modified Rankin ≥4) † Uncertain/inadeq info Prior intracranial hemorrhage or hemorrhagic stroke † Uncertain/inadeq info Prior cortical stroke, clinically or by neuroimaging † Uncertain/inadeq info Prior cortical or retinal TIA † Uncertain/inadeq info Ipsilateral carotid stenosis ≥50% or CEA † Uncertain/inadeq info Major risk for source of cardiogenic emboli † Uncertain/inadeq info Other specific cause of stroke † Uncertain/inadeq info Requirement for long-term anticoagulation/other antiplatelet † Uncertain/inadeq info Intolerance to aspirin or clopidogrel † Uncertain/inadeq info High risk of bleeding † Uncertain/inadeq info Pregnancy or female of child-bearing potential † Uncertain/inadeq info Life expectancy < 2 years † Uncertain/inadeq info Impaired renal function: estimated GFR < 40 cc/min † Uncertain/inadeq info Chronic alcohol use † Uncertain/inadeq info Age < 40 years ManOp section XXII – 02/23/2007 Secondary Prevention of
SPS3 Site Visit Form
Small Subcortical Strokes
Question 8: Compare the responses of the Medical History question on the Baseline form in the SPS3 chart with the medical records. Discuss any discrepancies with the local investigators and record them below. 8. Key participant features Prior to Qualifying Stroke: † Agree † Disagree † Uncertain/inadeq info † Agree † Disagree † Uncertain/inadeq info Hypertension † Agree † Disagree † Uncertain/inadeq info Evidence of coronary artery disease † Agree † Disagree † Uncertain/inadeq info Intermittent claudication/peripheral vascular disease † Agree † Disagree † Uncertain/inadeq info History of major hemorrhage Question 9: Review the BP Check and Fol ow-up forms in the SPS3 chart for documented physician investigator involvement at these patient visits. Discuss any concerns with the local investigators and record them below. 9. Documented appropriate involvement by physician investigator in BP checks: † Uncertain/inadequate info 10. Documented involvement by physician investigator in follow-up visits: † Uncertain/inadequate info ManOp section XXII – 02/23/2007 Secondary Prevention of
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XXIII. SITE PAYMENTS

Payments to the clinical sites will be made on a monthly basis for each of the following: randomization of an eligible patient, follow-up, BEA reports, and in participating sites', sub-study payments (LIMITS, PAS3S, etc). Additional payments will be made for MRIs and MRAs but only if pre-authorized by the Coordinating Center. Payment is initiated in the month following, once the data entry criteria have been met. Typically, from visit date to receipt of payment, the process takes approximately 60 days or longer. ƒ Randomization of an eligible patient: o Forms due at entry have been completed, entered, and closed, specifically the Elig/Rand, Screening, Baseline, Medications, Ethnicity, Qualifying Stroke, Post-Stroke Disability, Neuro Exam, Cognitive Scales, HTN QOL, and Intracranial Vascular Imaging forms o Reprints/image files on CD of the MRI scan documenting eligibility and intracranial vascular imaging study have been received by the Coordinating ƒ Quarterly Follow-up: o Quarterly Follow-up form with the relevant auxiliary* form(s) have been completed, entered, and closed *Auxiliary forms by follow-up: 3 mo: Medications, Post-Stroke Disability, Stroke Symptoms QOL, Stroke Symptoms Questionnaire if applicable Annual: Medications, Cognitive Scales, HTN QOL, Stroke Symptoms QOL, Stroke Symptoms Questionnaire if applicable Other: Medications, Stroke Symptoms Questionnaire if applicable While you are not paid specifically for an event during SPS3, events are part of follow-up. Payment for the next scheduled follow-up visit is predicated on ManOp section XXIII – 07/01/07 Secondary Prevention of
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submission and receipt of event forms and materials. The following are required o Event documentation#, including the narrative summary, received by the Events Coordinator #See individual event-specific forms for listing of event-specific documentation, including neuorimaging study for ischemic stroke, TIA and CNS hemorrhage events o All relevant* forms completed, entered and closed *Relevant forms by event type include the Event Notification, Medications, Status of Therapy and event-specific forms for all event types, plus the Neuro Exam form for Ischemic Stroke event o After assessment and completion of relevant* forms for TIA, ischemic stroke, or hemorrhagic stroke event and 2) after assessment and completion of the BEA Ischemic Stroke TIA form due solely to a positive Stroke Symptoms Questionnaire at a routine follow-up *Relevant forms include: Ischemic stroke: BEA Ischemic Stroke/TIA, Post-Stroke Disability TIA: BEA Ischemic Stroke/TIA CNS hemorrhage: BEA CNS Hemorrhage, Post-Stroke Disability ManOp section XXIII – 07/01/07 Secondary Prevention of
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XXIV. TRAINING MATERIALS: How-to-get started
1. Develop a systematic plan for identifying and screening all patients with subcortical ischemic stroke. This may include informing your potential contacts such as residents, nurses, and those in the investigation labs about the study and setting up a reliable system for ensuring that you are aware of all potential SPS3 participants. Do not rely on others to call you about potential patients – you will need to take the initiative and look actively for patients. Test your procedures by beginning to screen patients using the SPS3 Screening Form. 2. Meet with your SPS3 neurologist, SPS3 hypertension specialist and SPS3 neuropsych test administrator to plan regular clinic times for recruitment and follow- up. Keep in mind that it is optimal to hold SPS3 clinics in the morning. Plan to have a meeting between the research coordinator and these three SPS3 colleagues at least monthly (probably every two weeks during the initial months of the study) to address issues arising (this might be conveniently held immediately before your regular SPS3 clinic). 3. Identify clinic space (per #2). 4. Work with neuropsych test administrator to complete SPS3 certification process. 5. Along with your SPS3 PI neurologist, meet with radiology to arrange: ∗ the process for transferring MRI and intracranial arterial imaging, most preferably image files on CD as opposed to a scan reprint, to the Coordinating Center ∗ negotiate a deal to obtain SPS3-sponsored MRIs and MRAs (without 6. Consider a regular meeting with your SPS3 neurologist for a half-hour early each week to review screening information and address issues. 7. Begin to organize your office with the written materials related to the study, i.e. IRB communication, copies of consent forms, patient filing system, manuals, blank 8. Review local policies for storage and destruction of SPS3-supplied medications and identify suitable storage facilities/cabinets. ManOp section XXIV - 06/01/03 Secondary Prevention of
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9. Work with the Statistical Center to get the Randomization and Data Entry System installed on the PC you will use and the certification process completed for yourself and other persons involved in entering data on the PC. ManOp section XXIV - 06/01/03 Secondary Prevention of
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XXV. TRAINING MATERIALS: Neuropsych Examiners
Cognitive Battery Administration and Instructions
Certification:
Prior to administering the SPS3 Cognitive Battery to an SPS3 participant,
the examiner must be SPS3-certified by the SPS3 Coordinating Center (CC) to administer the test in that language (English, Spanish, or French). Examiners are typically licensed clinical psychologists experienced in standardized neuropsychological assessment, or neuropsychology technicians or graduate students under the direct supervision of the licensed psychologist. Steps for certification: 1) Review these written materials. 2) Complete the Knowledge test - This is a written test about 25 items in length designed to assess familiarity with key administration and scoring procedures for each test. Test is available from the local research coordinator or CC neuropsychology administrative assistant. 3) View a videotaped administration of the battery and score it on the SPS3 Cognitive Scales form. The DVD/VHS tape and documentation on the videotaped individual are available from the CC neuropsychology administrative assistant. 4) Administer the battery to a local study coordinator or other normal volunteer, who will act as a practice patient. This session needs to be audiotaped or recorded on CD with the Cognitive Scales form completed. 5) Send the completed Knowledge test (step 2), Cognitive Scales form for sample patient (step 3), and Cognitive Scales form and audiotape/CD from practice administration (step 4) to the CC in Vancouver, attention: SPS3 Neuropsychology. Completed certification materials received at the CC are electronically tracked by an administrative assistant and reviewed by a neuropsychologist fluent in the testing language. Specifically, the Knowledge test is corrected, the scoring on the sample administration is checked, and the practice administration is reviewed with the aid of an ManOp section XXV - 07/01/07 Secondary Prevention of
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electronic-based checklist consisting of key administration and scoring items for each of the eight tests in the SPS3 battery. After reviewing the certification materials, the neuropsychologist sends the examiner feedback about his/her performance and certification status. Certification date(s) and language(s) of certification for each examiner are tracked electronically at the CC. General Testing Considerations: Testing should be conducted in a quiet office or
exam room with the subject comfortably seated in a chair with a desk or adjustable tray table with the testing materials directly in front of them. Test forms, a stopwatch, an audio-recorder, and the NP materials should be in order and within easy reach. Testing should be completed in a single session on the same day. Brief breaks are allowed, but breaks should be limited to between tests/subtests. Breaks should be avoided between the immediate and delayed recall trials of the CVLT in order to prevent extending the optimal time ( 20 min) between the two trials. Subjects should be reminded that the test battery is designed to measure their thinking/attention/memory skills and that everyone has difficulty with some items. It is important to remember that we are trying to elicit the best performance possible from these subjects with injured brains so we need to pay particular attention to the pace of our administration. Please remember to read directions very deliberately and sometimes even slower than would be considered normal for ordinary conversation. Many of our patients have trouble comprehending, and many others process information very slowly. If we are too fast, s/he may not understand or otherwise feel intimidated and will not give a best effort. Also, please watch the transitions from test to test. A well-placed word of encouragement during these transitions may be very helpful in sustaining motivation. When transitioning from CVLT to COWA remember that these are both word recall tests. Give the subject time to shift attention by asking how s/he is doing or making light conversation appropriate to your particular situation before transitioning between two tests within the same cognitive domain. ManOp section XXV - 07/01/07 Secondary Prevention of
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Feedback on specific test performance/results during testing should be avoided, but patients should be thanked and praised for their efforts during testing to maintain motivation and rapport. If specifically requested, patients can be informed that a brief summary of the test results can be released to their physician by the SPS3 Coordinating Center, but only with their written consent and after the test results have been reviewed by the study neuropsychologist. In these cases, patients must complete a release of information form (local to the site/facility) specifying that test results be released to their physician, who should be listed by name and complete mailing address. A copy of the form and the SPS3 protocol should then be mailed to us in the SPS3 Coordinating Center. HIPAA regulations preclude routine faxing of psychological test results, so the interpretation will be sent by mail. It is not advisable for a family member or any other person to be present in the room during testing. Their presence may distract the patient and could affect the test results. This should be politely explained to the family member with a request that s/he wait outside. If the patient or family member absolutely insists and testing is not possible otherwise, then the family member should be seated behind the patient and instructed not to speak during testing. The battery may be administered in English, Spanish, or French depending on the patient's stated preference. Some bilingual patients tested in one language may ask to have items or instructions translated to another language. If the patient prefers to be tested in English, instructions in Spanish or French may be given if that would help them understand the task. However, all test responses must be given in the language of the test administration. Note that scoring/administration instructions are printed in English on the Spanish and French versions of the protocol; only the verbatim instructions and stimulus items are translated into Spanish or French; therefore test administrators must be fluently bilingual. Tests are not to be administered through an interpreter. To increase standardization and facilitate easy administration, all test record forms with ManOp section XXV - 07/01/07 Secondary Prevention of
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key administration/scoring instructions have been combined into the SPS3 Cognitive Scales form. Tests are administered in the order presented in the form with the exception of adding or postponing tests to maintain the optimal 20 min between the end of the short delay cued recall and the start of the long delay free recall of the CVLT. The research coordinator will provide you with a blank form to be used for each administration, rather than the published record forms. Permission has been received from the test publishers to reproduce these instructions/forms. Quality Assurance: All cognitive test administrations in SPS3 need to be audio-
recorded for quality assurance purposes. Completed forms are entered into the database and filed with the subject's SPS3 records by the local research coordinator. The audiotape or CD, labeled with a patient id label and the date of test, is sent with a copy of the Cognitive Scales form (all 18 pages including copies of the CLOX, handwriting writing sample, and pentagram drawing, any of which may be on the backside of a page) to the neuropsychology administrative assistant at the Coordinating Center in Vancouver. Do not write the subject's full name on the form: this is in violation of HIPAA. Your site coordinator will affix a patient id label in the upper left hand corner of each page and record the testing date on each page. Please do identify and keep the pages together for each test subject until this time. Forms and tapes received at the Coordinating Center are tracked electronically. Site coordinators are notified by the neuropsychology administrative assistant of incomplete materials received on arrival, and outstanding materials are requested on a quarterly basis. Forms and tapes/CD are labeled with patient id and date of testing and stored by site in locked secure areas. At least the first two administrations for each new examiner are fully reviewed by a neuropsychologist and feedback provided to the examiner. As well, at least two ManOp section XXV - 07/01/07 Secondary Prevention of
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administrations each year for any active examiner are randomly selected for full review to identify any drift away from the SPS3 administration and scoring protocol. Feedback on test administration and scoring is given to the examiner, and results of these quality assurance reviews are tracked electronically. In addition, test scores of 0 and missing test scores are reviewed for accuracy. Any necessary changes to the original paper form maintained at the site and/or the study database are done through the site coordinator and tracked electronically for completion. General Instructions
Before examining begins, complete questions 1-4 on the SPS3 Cognitive Scales form: 1. Date administered
2. Reason for form: To be completed by research coordinator
3. Tests are administered in: Indicate language of testing
4. Tests are administered by: Tests need to be administered by certified personnel.
See above for certification process.
Cognitive Assessment Screening Instrument (CASI): Pages 1-4

The CASI is an expansion of the Modified Mini Mental Status Examination, modified for cross cultural use. The SPS3 Cognitive Scales form contains key instructions for administering and scoring the CASI. Examiners should pay close attention to timing, both in delivering the stimuli and scoring of responses. Several items have a limited response window such that any responses given after a specified, short time interval are counted as errors. For example, on the word memory items the examiner's follow- up prompts/cues must be given after a specified number of seconds with a resulting loss of points. Examiners, particularly those accustomed to the MMSE or 3MS which do not have these time limits, need to pay close attention to the instructions on the form for correct administration/scoring. This is likely a less familiar test for most psychologists and technicians. 5. Where were you born? Cue for state if not given spontaneously. Confirm with
significant other if possible, if not go by confidence of answer as this is highly over ManOp section XXV - 07/01/07 Secondary Prevention of
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learned information and rarely missed. 6. When were you born? Prompt for any missing date elements and confirm with
record or site coordinator. 7. How old are you? Score according to accuracy of answer as indicated on test
form. Confirm with birth date in record. 8. How many minutes are there in an hour? If incorrect, ask: How many days are
there in a year?
9. In what direction does the sun go down? (If confused, say north, south, east or
west, or have patient point.) 10. I shall say three words for you to remember. Repeat them after I have said all
three words. Say SHIRT BROWN HONESTY (Presentation rate is 1 word/1.5
seconds.) Score according to test form. Acceptable approximations are given in
parentheses; any other responses are counted as errors. Patients may recall items
in any order. If there are errors on the first trial, repeat the items up to 3 times until
they are learned for later questions. Score on last performance. After the subject
has repeated the three words, do not ask the subject to remember the words again.
This is different from the MMSE procedure, and this subtle difference is intentional.
11. I shall say some numbers, and you repeat what I say backwards. For
example, if I say 1 - 2, then you say 2 - 1. Ok? Remember you repeat what I
say backwards.
Presentation rate is 1 digit/second. On the first item, if incorrect
give the correct response and have subject repeat it, but score as incorrect. If the
first two items are missed, skip the third and score it as 0.
12. What 3 words did I ask you to remember earlier? Time this closely! If no
answer after 3 seconds or response is incorrect, give semantic cue. After 2 additional seconds, give multiple choice cue. Tell the subject the correct answer if response is incorrect or no answer. Whenever recall is not perfect, it is very important that you say the three words once more before proceeding to the next item, e.g. "So the three words I asked you to remember are shirt, brown, honesty." 13. From 100, take away 3, equals how many? Provide the correct answer for the
first incorrect subtraction. Do not correct any subsequent subtractions that are incorrect. Stop after 2 errors and score the remaining subtractions as zero (do not leave blank). If the subject asks for the previous number, provide it but count that trial as incorrect. Score responses as correct based on whether the subtraction is correct. For example, if the subject responds 97-95-92-89-85, the scoring would be 1-0-1-1-0. 14. What is today's date? Cue for missing items in date and score according to test
form. Always consider the month and date together in scoring. For example, if the date is March 3, 2007, and a subject reports February 28, 2007. The score for year is 4, score for month is 2 as February 28 is within 5 days from March, and score for date is 1 as February 28 is within 3-5 days from March 3. ManOp section XXV - 07/01/07 Secondary Prevention of
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15. What day of the week is today? Must be exact day of the week.
16. What season are we in? May cue for spring, summer, fall, and winter, if
necessary. Within 1 month is correct (see test form). Seasons start on the 21st of December (winter), March (spring), June (summer), and September (fall). 17. What state are we in? What city/town are we in? Prompt for things not
mentioned. Ask for province or region or comparable area if your country of residence is not divided into states. 18. Are we in a hospital (clinic), store, or home? Use "hospital" or "clinic" as
appropriate to your setting (not both). 19. What animals have four legs? Tell me as many as you can. Immediately start
stop watch. If no response in 10 seconds, ask What (other) animals have four
legs?
but continue timing. Do not ask "What else?". Do not tell subject about the 30
sec time limit. Allow exactly 30 seconds for response and write responses in
margin of test form. Maximum score is 10, even if more correct responses are
provided. Score one point for each correct animal name. Do not count repetitions
of the same name. Different names for the same animal of different ages or sexes
count as one, e.g. kitten and cat, puppy and dog, deer and doe. Accept marginal
cases such as monkeys, chimpanzees, baboons, and kangaroos.
20. An orange and a banana are both fruit. Pause for 2 seconds, then ask: An arm
and a leg are both…? You may also ask "In what way are and _ alike
(similar)?" to help the subject comprehend what you want.
For the next two items Laughing and crying are both…? and Eating and
sleeping are both…?,
you may repeat the question but no further prompting is
permitted. After each comparison, tell the patient the correct answer if the
response was incorrect. Score according to form. Be stringent in awarding 2
points and lenient awarding 1 point. The response for laughing-crying must include
"emotions" or "feeling" to earn 2 points, and the response for eating-sleeping must
convey "necessary" or "essential" to earn 2 points.
21. What actions would you take if you saw your neighbor's house catching fire?
Prompt "What else might you do?" once only if necessary. Score one point for
each category of correct action. Categories include:
Call 911; inform appropriate authority. Try to alert or evacuate the residents. Try to help put out the fire. Safeguard own property/family. Alert other neighbors. Repeat for What actions would you take if you lost a borrowed umbrella?.
Score one point for each category of correct action. Categories are 1)
inform/apologize and 2) replace/compensate. If the subject says "I'll look for it," ask
"What would you do if you cannot find it?" and score the response.
Repeat for What would you do if you found an envelope that was sealed,
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addressed, and had a new stamp? If the subject asks "Where did I find the
envelope," say "on the street" and score the answer.
22. Repeat exactly what I say: He would like to go home. Score 2 points for correct
repetition, 1 point if 1-2 words are missing/incorrect. Then say Now repeat: This
yellow circle is heavier than blue square.
For each part of this sentence on the
form score 1 point only if the phrase is exactly as given. Note that the omission of
"the" is intentional on the last item. Score as an error if "the" is added to this item.
Say the first sentence in 2 sec and the second one in 3 sec. Do not stop in the
middle of either sentence. If the subject asks for a sentence to be repeated, say
"Just repeat what you think I said."
23. Please do this. Detach stimulus page at the end of test form package and fold it so
that the statement "Raise Your Hand" is showing. If patient does not do within 5
seconds, prompt by pointing to the sentence and saying, "Read and do this". If
the subject merely reads the command aloud, say "Do what it says". Allow up to 5
sec for response. Score according to test form. Raising either or both hands is
acceptable. Reading the statement aloud is not required.
24. Let me have a sample of your handwriting. Please write "He would like to go
home." This item in the CASI assesses the ability to correctly spell and write five
simple and common words. Say the sentence slowly and distinctly. Repeat the
sentence or dictate the sentence word by word if necessary, but allow a max of 1
minute after first reading. Score 0.5 points for each correct word (give no points for
the word "He"). Do not penalize for self corrected errors, printing, all caps, or
capitalization of the first letter of every word. Mixed capitalization usage counts as
one word/error. Each word with a spelling mistake is scored as an error. For
example, HE wood like to Go homE is awarded a score of 1: no points are awarded
for "would" because it is misspelled, "go" because it has the first letter capitalized
when the other words do not, and "home" because it has mixed capitalization.
25. Please copy this. Fold the stimulus page with the intersecting pentagons so that
only the drawing shows. Place it in front of the patient. Only score parts completed in one minute. Do not penalize for non-straight lines, or minor gaps or overshoots at the corners that seem to be caused by poor motor control. If the subject has made more than one attempt, score the best attempt. Five-sided figures with the longest side less than twice as long as the shortest side are awarded 4 points; five-sided figures with the longest side more than twice as long as the shortest side are awarded 3. 26. Take this paper in your left hand, fold it in half, and hand it back to me. Say
instructions in about 6 seconds. Do not repeat instructions or coach. Ask to take in right hand if patient is left-handed, or right hand dominant, but it is dysfunctional. If the subject asks if both hands can be used for folding, answer "yes." If the subject folds the paper more than once, score the second part as 0. 27. What 3 words did I ask you to remember earlier? Time closely! If no
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answer/incorrect, give semantic cue after 3 seconds and multiple choice cue after 2 additional sec. Do not repeat the 3 words or provide the correct answer(s) at the end even if recall is less than perfect. 28. What do we call this part of the face or body? Time this closely! Clearly and
slowly point to your forehead, chin, shoulder, elbow, and wrist (flex it a couple of times) in turn. Allow only 2 seconds for each response. Do not wait for patient to mentally search for name before proceeding to next item. Please do not have another object in your hand, such as a pencil, when administering these questions as this may be confusing 29. What is this? Show items (spoon, coin, toothbrush, key, and comb) one at a time
and lay on table in front of patient. Any order is okay. "Quarter" is also correct for
"coin", but if the patient says "money", ask What kind of money is it? If patient
calls the toothbrush a "brush", ask What kind of brush is it? If the subject gives
an incorrect name, tell the correct name and ask the subject to repeat it. When
testing a bilingual subject, answers in either English or other language are
acceptable. Please do not have another object in your hand, such as a pencil,
when administering these questions as this may be confusing.
30. Remember these 5 objects. Wait exactly 5 seconds, then cover the items and
ask: What 5 objects did I just show you? No prompting is allowed. Money and
brush are acceptable responses when recalling the objects.
CVLT (learning & immediate recall trials): Pages 5-6
In introducing the test, it is recommended that the examiner avoid referring to it as a
"memory" or "learning" task. While examinees should not be told whether their
responses are right or wrong, encouragement for effort may always be given. The
Spanish version of this test contains a different list of words.
Trial 1. Say, Let's suppose you were going shopping on Monday. I'm going to
read a list of items for you to buy. Listen carefully, and when I'm through, I want
you to say back as many of the items as you can. It doesn't matter what order
you say them in – just tell me as many as you can. Are you ready?"
Read List A
at the rate of 1 word per second. After the last item say, Now, tell me as many as
you can.
Record all words verbatim in the order in which they are given. If words are repeated in
the same trial as a way of self-cuing (e.g., "Let me see, I've said ‘drill', ‘plums,'" etc.),
then the response need not be recorded. If the examinee repeats the response in the
same confidence as he or she reported previous responses on that trial, then record the
response and score it as a perseveration (P). Only if it is unclear why a response is
being repeated, then record it and ask whether the examinee thinks the response has
been said before: Have you said that word before this time? If the response is "no"
or "I don't know" then record the word and score it as a perseveration. If the response
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is "yes", then cross through the word and do not count as a perseveration. Watch
carefully for intrusions, e.g. pants instead of slacks is incorrect.
About 10-20 seconds after the subject stops responding, provide a single prompt such
as: Tell me anything else you can or See if you can think of any more. Mark a "Q"
on the record form to indicate a prompt was given. This prompt is provided ONE TIME
ONLY for each and EVERY trial.
Trial 2. Say: I'm going to repeat Monday's shopping list. Again, I want you to say
back as many items as you can, in any order. Be sure to also say the items on
the list that you told me the first time.
Read, record, and prompt as for Trial 1.
Trials 3-5. Say: I'm going to repeat Monday's shopping list. Again I want you to
say back as many items as you can, in any order, including items you may have
already told me.
Read, record, and prompt as for Trial 1.
31. Record the number correct in each of Trials 1-5.
Write the words given by the subject in the order given in the columns provided on the
form. Mark correct responses with a "C", confirmed perseverations with a "P" (cross out
with one line any words determined NOT to be a perseveration), and intrusion errors
(confabulations) with an "I". Count the total number of "C"s and record in the space
provided at the bottom of each column.
Immediate Free Recall, List B (Tuesday List): Say: Now, let's suppose that you
planned to go shopping again on Tuesday. I'm going to read a new list of items
for you to buy. When I'm through, I want you to say back as many as you can, in
any order.
Read and record the words from List B as before using the same prompting
procedures as previously described.
Short-Delay Free Recall, List A. Say: Now I'd like you to tell me all the shopping
items you can from the Monday list.
Record and prompt for responses as before.
Short-Delay Cued Recall, List A. Say: Tell me all the shopping items from the
Monday list that are spices and herbs.
Record responses and give one prompt if all
four items are not correctly recalled. Repeat the same instructions for the Tools,
Fruits,
and Clothing categories. If a subject asks what a particular category name
means, you may provide a general definition. Do NOT tell the subject which category
an item belongs to and do NOT warn subjects that there will be later trials.
32. Record number correct for List A: Short Delay Free Recall and Cued Recall.
Write the words produced by the subject in the order they are given in the columns provided on the SPS3 form. Mark correct responses with a "C", confirmed perseverations with a "P" (cross out with one line any words determined NOT to be a perseveration), and intrusion errors (confabulations) with an "I". Count the total number of "Cs" and record in the space provided at the bottom of each column. ManOp section XXV - 07/01/07 Secondary Prevention of
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33. TIME: Record clock time (24 hr clock) at end of short delay cued recall. WAIS-III Block Design Subtest: Pages 7-8
It is important for the examiner to model the designs in the correct direction relative to the examinee (i.e. booklet with unbound edge closest to patient; test form oriented as labeled). For each design attempted, record the time the subject uses to construct the design. The time limit allowed for each design is listed in the column next to the block design on the scoring page. If the design is incorrect, draw the block design constructed, or write "scattered" if the design is not well formed. Circle the appropriate score in the right-hand column for each design. Credit for designs 1-4 is given when higher level designs are successfully completed and designs were not administered. Discontinue the test after 3 consecutive scores of 0. Start with Design 5. Place 4 blocks in front of the patient. I'm going to ask you to
make some designs. You see these blocks? They are all alike. On some sides
they are all red, on some all white, on some half red and half white.
Turn blocks to
show different sides. Construct Design 5. Do not explain design. Leave model intact.
Place 4 new blocks in front of the patient. Now make one just like this. Tell me
when you have finished.
Begin timing. If patient is successful within 60 sec, proceed
to Design 6. If design is incorrect, proceed to Design 5, trial 2.
Design 5, trial 2: Watch me again. Demonstrate correct design with patient's blocks,
then scramble blocks. Now you try it again and be sure to make it just like mine.
Tell me when you have finished
. Score performance. Regardless of performance,
proceed to Design 4 and administer Designs 1-4 in reverse order until patient obtains
perfect scores (2 pts) on two consecutive designs. When this criterion is met, give full
credit for any preceding items not administered. Proceed to Design 6.
Design 6: Remove the model and scramble the 4 blocks in front of the patient. Turn to
Design 6 in the booklet and place it in front of the patient with the unbound edge closest
to the patient. This time we are going to put the blocks together to make them
look like this picture. Watch me first.
Slowly demonstrate the construction of the
design using the patient's blocks. You see, the tops of the blocks look the same as
this picture.
Scramble the blocks. Now look at the picture and make one just like it
with these blocks. Tell me when you have finished. Go ahead.
Begin timing.
Record score. If patient is successful within 60 sec, proceed to Design 7. If incorrect,
proceed to Design 6, trial 2.
Design 6, Trial 2: Watch me again. Demonstrate correct design with patient's blocks,
then scramble blocks. Now you try it again and be sure to make it just like the one
on this page. Tell me when you have finished
. Begin timing and score performance.
Regardless of performance, proceed to Design 4 and administer Designs 1-4 in reverse
order until patient obtains perfect scores (2 pts) on two consecutive designs. When this
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criterion is met, give full credit for any preceding items not administered, then proceed to Design 7. Designs 7-9: Scramble the 4 blocks in front of the patient. Turn to next page in booklet.
Now make one just like this. Try to work as quickly as you can. Tell me when
you have finished.
Begin timing. When patient has finished or time limit has elapsed,
score performance, scramble the blocks, and present the next design. Be sure to
remind patients that time is relevant here, by reciting the directions precisely.
Designs 10-14: Scramble 9 blocks in front of patient for designs 10-14 and increase
time limit to 120 sec. For designs 13 and 14, do not allow patient to rotate the book. Be
sure to remind patients that time is relevant here by reciting the directions precisely
Now make one just like this. Try to work as quickly as you can. Tell me when
you have finished.

Example: Subject correctly constructs design 5 on 1st trial, then design 6 on 1st trial. Examinee constructs design 7 incorrectly, design 8 correctly in 55 sec, and designs 9, 10, and 11 incorrectly or over time limit. Score for test is 16 points: 8 points for designs 1-4, 2 points for each of designs 5 and 6, 0 points for design 7, 4 points for design 8, and 0 points for each of designs 9, 10, and 11. Example: Subject correctly constructs design 5 on 1st trial, is unsuccessful with design 6 on 1st trial, and constructs design 6 correctly on 2nd trial. Examiner then proceeds to design 4. If constructed correctly on 1st trial, then examiner will proceed to design 7, and the total score is 11 (2 pts for each of designs 1-3, 4, 5, and 1 pt for design 6) plus whatever points are scored in designs 7 and higher. If the examinee is unsuccessful on trial 1 of design 4, then the examiner will administer trial 2 of design 4, then design 3, then design 2. If and when the examinee is successful at 2 consecutive trials without awarding 3 scores of 0, then the examiner will return to design 7. 34. Total Score: Score and record totals per instructions on form. Make sure to
include scores for designs 1-4 when higher level designs are completed, and designs 1-4 have not been administered.
WAIS-III Symbol Search Subtest: Page 9

Remove the next 5 pages from the back of the form, i.e. the Sample & Practice Symbol
Search page and the 4 pages of symbol searches. Page numbers are in the upper right
hand corner of the four Symbol Search pages.
In the next task, I want you to look at two target shapes. Then see if you can find
either one of them in the group of shapes next to them.
Place the Sample &
Practice page in front of the patient. Look over here. Notice there are two shapes
on the left side and a group of shapes on the right side. You are to mark the YES

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box if one of the shapes on the left side is the same as any of the shapes from the
group on the right side. For example, this shape here is the same as this shape
here, so you would mark the YES box like this. For the second item, this shape
here is the same as this shape here, so I will mark the YES box like this. Mark the
NO box if none of the shapes is the same as any of the shapes from the group on
the right side. In this case, none of the shapes here is in the group over here, so
this time, I will mark the NO box like this. Now you do these here. Go ahead.

Give feedback and correct any mistakes made in the practice items.
Give the patient a pen and place the pile of 4 symbol pages (stacked in order) in front of
the patient. When I tell you to start, you do these the same way. Begin here and
do as many as you can. When you finish the first page, go on to the next page
and so on. Most people don't do all of them. Work as quickly as you can without
changing your answers. Don't skip any items and don't stop until I tell you to do
so. Any questions? Ok. Ready begin.
Begin timing. If necessary, remind the
patient to respond to the items in order. Give no further assistance. After 120 sec,
Stop.
35. TOTAL SCORE: Total score is number of correct responses minus number of incorrect responses. Items that the examinee did not attempt (either skipped or did not reach before time elapsed) are not included in the score calculation. For example, if the first 20 items were completed with 12 correct and 8 wrong, the score is 4, 12 correct - 8 incorrect. If the score computes to below zero (e.g. first 20 items attempted, 12 incorrect and 8 correct, 8 - 12 = -4), record a score of zero. Grooved Pegboard - Page 9
Place the pegboard apparatus (25 pegs) in front of the patient on the table. This is a
pegboard and these are the pegs
.
Examiner points out each and then picks up one of
the pegs and continues. All the pegs are the same. They have a groove, that is, a
round side, and a square side and so do the holes in the boards. What you must
do is match the groove of the peg with the groove of the board and put these
pegs into the holes like this
. The examiner demonstrates by filling the top row.
Remove the pegs, putting them back into the tray. When I say go, begin here and put
the pegs into the board as fast as you can, using only your (dominant) hand. Fill
the top row completely from this side to this side. Do not skip any; fill each row
the same way you filled the top row. Any questions? Ready, go
.

Start the stopwatch. Record the number of seconds taken to place all the pegs as well as the number of pegs dropped. Discontinue when all 25 pegs are placed or 5 minutes have elapsed (note number of pegs correctly placed at 5 minutes). Repeat with non-dominant hand. If necessary, remind the patient not to use the other hand to help. You ManOp section XXV - 07/01/07 Secondary Prevention of
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may omit the trial on the affected side for patients who are densely hemiparetic (i.e. unable to pick up one peg with affected hand). In this case, record "0" pegs placed, 0 drops and a time of 300 seconds. Direction of peg placement for the right hand is left to right. Direction of peg placement for the left hand is right to left. Be sure to demonstrate the direction and change in direction of peg placement. 36. Time: Score amount of time elapsed in seconds. Record amount of time that subject attempted task, regardless of whether all pegs were placed correctly. Maximum time is 300 seconds (5 min). Drops: Record number of pegs dropped. If a peg is dropped multiple times, count only once. A drop is limited to unintentional peg dropping. Pegs dropped intentionally are not counted, e.g. subject has multiple pegs in hand and lets go or subject lays pegs on board or table to better manipulate peg. Pegs Placed Correctly: Record number of pegs placed correctly. A peg may be placed correctly even if it is dropped first. Subjects who complete the task will have a score of 25 pegs.
CVLT Delayed (delayed recall & recognition): page 10

37. Time Started: Record clock time at start of Long Delay Free Recall (24 hr clock).
Long Delay Free Recall, List A. Say: I read some shopping items to you earlier. I'd
like you to tell me all the items you can from the "Monday" list—that was the first
list, the one I read to you five times. Go ahead.
Record items and provide prompts
as before.
Long-Delay Cued Recall, List A. Say: Tell me all the shopping items on the Monday
list that are clothing.
Follow the same procedures as on the earlier cued recall trial,
asking in turn for "fruits", "tools", and "spices and herbs" categories and cueing after
each category. Record responses then move immediately to the Long-Delay
Recognition trial.
Long-Delay Recognition, List A. Say: I'm going to read a list of shopping items.
After I read each item, say "Yes" if the item was from the Monday list and say
"No" if it was not.
Read aloud the 44 words on the record form and note the response
as Y or N next to the word. If the subject says "I don't know" or does not respond at all,
provide a single prompt such as: Tell me whether you think (repeat item) was on the
Monday list.
If the subject still says "I don't know" or does not respond, write a "?" and
proceed to the next item.
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38. Number Correct:
As with the Immediate and Short Delay, write the words produced by the examinee in
the order they are given in the columns provided on the SPS3 form. Mark correct
responses with a "C", confirmed perseverations with a "P" (cross out with one line any
words determined NOT to be a perseveration), and intrusion errors (confabulations) with
an "I". Count the total number of "Cs" and record in the space provided at the bottom of
each column.
39. Totals:
Mark a white box for each "yes" response. Do not mark any box for a "no" response.
Words that were on the Monday list have a white box in the "Hits" column and words
that were not on the Monday list have a white box in the "FP" for false positive column.
Count the number of hits (first column - white boxes) and false positives (2nd column -
white boxes) and record the total at the bottom of the column. "No" responses are not
totaled up.
Controlled Oral Word Association Test - page 11

Say: I am going to say a letter of the alphabet, and I want you to say as quickly as
you can all the words you can think of which begin with that letter. You may say
any word except for proper names, such as names of people or places. So you
would not say "Texas" or "Robert". Also, do not repeat the same word or use the
same word again with a different ending, such as "eat" and "eating." Do you
understand? Remember no names or people or places, just ordinary words. You
will have one minute for each letter. The first letter is "F". Go ahead.
Record
words produced in order as you time exactly 60 seconds. Then repeat with the next two
letters. For the English and French versions, the letters read are F-A-S. For the Spanish
version, the letters read are P-M-R.
40. NUMBER CORRECT: Count the number of correct responses. Do not count
perseverative responses or words beginning with letters other than the target letter as correct. Proper nouns other than the names of people or places are acceptable, e.g. Saturday. Also, words from other languages that are familiar in the testing language are acceptable.

Digit Span Subtest - Page 12

There are two trials for each level. Administer BOTH trials for each level. Stop when
the subject gets both trials in one level incorrect. Read the digits evenly at a rate of 1
per second. Do not chunk the digits, e.g. say 6-1-9-4-7-3 rather than 6-1-9-pause-4-7-
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3. Drop your voice inflection slightly on the last digit of each series. Record the
subject's responses verbatim on the answer sheet in the column labeled "Responses".
Score 1 point for each correct trial.
Digits Forward. Say: I am going to say some numbers. Listen carefully, and when
I am through, I want you to say them right after me. Just say what I say.
Start at
Item 1, Trial 1.
Digits Backward: Now I am going to say some more numbers. But this time when
I stop, I want you to say them backward. For example, if I say 7-1-9 what would
you say?
If the patient responds incorrectly, state No, you would say 9-1-7. I said 7-
1-9, so to say it backward, you would say 9-1-7. Now try these numbers.
Remember you are to say them backward: 3-4-8
. Regardless of correctness of this
response, proceed to trial 1 of Level 1.
41. Digits Forward and Backward Total Score: Score one point for each correct item,
i.e. 2 points per level if both were correct.
CLOX - Page 12

The CLOX is administered on the back side of the paper that has the circle drawn on it.
Turn the paper over on a light-colored surface so that the circle shows through faintly.
Instruct the patient to: Draw me a clock that says 1:45. Set the hands and numbers
on the face so that a child could read them.
Repeat the instructions until they are
clearly understood. Do not draw attention to the pre-drawn paper that is faintly showing
through the paper (it's meant to show as a distractor). Once the patient begins to draw,
no further assistance is allowed.
Scoring guidelines and examples are below and on the next page. Some of the CLOX
drawings may not much resemble a clock, but they may have a score greater than zero.

Person completing form
: Record the name of the examiner who administered and
scored the tests on this form.
After the Administration
Re-staple all 18 pages back together. Review the test scoring for completeness. If for some reason a test was not administered, write a brief explanation on that part of the form. If you have any questions about test administration or scoring, the easiest way to contact the SPS3 neuropsychologist is by e-mail at sps3-psych@uthscsa.edu. ManOp section XXV - 07/01/07 Secondary Prevention of
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Figure resembles a clock Circular face present Dimensions > 1-inch All numbers inside perimeter No sectoring or tic marks 12,6,3,& 9 placed first Only Arabic numerals Only #s 1-12 among numerals present Sequence 1-12 intact, no omissions or Only 2 hands present All hands represented as arrows Hour between 1 and 2 o'clock Minute hand obviously longer than hour hand None of the following# SCORE FOR DRAWING ABOVE ”unable to score without observing patient # hand pointing to 4 or 5 o'clock, "1:45" present, any other notation (e.g. "9:00", any arrows pointing inward; intrusions from "hand" or "face" present; any letters/words/pictures; any intrusion from circle below ManOp section XXV - 07/01/07 CLOX Scoring Guidelines Figure resembles a clock Score if position of number(s) or hand(s) suggests a clock. Do not score if both numbers and hands are absent. Circular face present Score if perimeter of shape drawn approximates a circle even if traced. Do not score if no boundary, e.g. patient uses circle from below but doesn't trace it. (Also, do not score if patient turns paper back over and uses pre-drawn circle.) Dimensions > 1-inch Score if largest clock dimension is at least 1 inch wide even if traced. Do not score if largest dimension is smaller than 1 inch. All numbers inside perimeter Score if all numbers present are inside boundary of the shape. Do not score if no numbers are present; do not score if figure drawn does not have a perimeter drawn or traced. No sectoring or tic marks Score if no lines dividing up the shape or its perimeter. Do not score if dividing marks are present around perimeter; do not score if lines divide up the shape. Be aware that line(s) without arrow(s) may represent sectoring. 12,6,3 & 9 placed first Score if all 4 of these numbers are present and written in any order before Do not score if any of these 4 numbers are absent from figure; do not score any other numbers are written. if any other number is placed before any of these numbers is placed. Only Arabic numerals present Score if all of numbers written are standard numbers. Number may be Do not score if no numbers are present; do not score if Roman or other written backwards/mirror-imaged. language numerals written. Spacing intact (symmetry on either sides of 12 and 6 Score if numbers 1-12 are roughly spaced equally and numbers 12 and 6 Do not score if any of numbers 1-12 are absent; do not score if more are opposite each other and roughly top and bottom. Numbers may be numbers are on one side than other; do not score if spacing is grossly inside or outside of perimeter. unequal between numbers. Only #s 1-12 among numerals present (ignore notation) Score if whatever numbers present on drawing are 1-12 (not all of 1-12 Do not score if no numbers are present on figure; do not score if additional need to be drawn) numbers besides 1-12 are on drawing, e.g. "45". Sequence 1-12 intact (no omissions or intrusions) Score if all of numbers 1-12 are in order in a clockwise direction on the Do not score if any number is omitted or out of sequence; do not score if drawing and no additional numbers are present. any number is mirror imaged/backward; do not score if additional numbers are present. Only 2 hands present (ignore sectoring/tic marks) Score if exactly 2 hands are present. Do not score if no hands or 1 hand is present. All hands represented as arrows Score if each hand, regardless of number of hands, is drawn as a line with Do not score if no hands are present; do not score if one or more hands a < or > somewhere along its length. does not have an < or > somewhere along its length. Be aware that lines without arrows may represent sectoring rather than hands particularly if more than 2 lines present. Hour hand between 1 & 2 o'clock Score if a hand drawn is between the numbers 1 and 2 even if 1 and 2 are Do not score if no hand or only hand between 1 & 2 o'clock is the in the incorrect position or if the hand between 1 and 2 o'clock is the same obviously longer hand. Do not score if numbers 1 and 2 are not both on length as the other hand. drawing or if it is not clear through tics and numbers present where the 1 and 2 positions are. Minute hand obviously longer than hour hand Score if hand not between 1 and 2 o'clock is obviously longer than the Do not score if none or one hand is drawn. Do not score if both hands other as indicated by arrows, or length of lines if no arrows. Score if both equal in length based on arrow position, or if no arrows, by length of lines. hands between 1 and 2 o'clock and one obviously longer than other. None of the following present: Score if all of these are absent. Do not score if any are present: - any hand pointing to 4 or 5 o'clock i.e. either hand points to the 4 or 5 i.e. 1:45 written as part of the clock or outside of the clock - any other notations (e.g. 9:00) i.e clock time is other than 1:45 - any arrows pointing inward i.e. arrow points toward center of clock rather than outside perimeter - intrusions from "hand" or face" present i.e. patient draws part of a hand or face - any letters/words/pictures, e.g. smiling face in center of clock - any intrusion from circle below i.e. traces or uses in any way the circle that is faint through the paper *** Do not score any points for a strictly digital clock unless a circular face is present, in which case, a point for "circular face" , "dimension > 1 inch", and "resembles a clock" may be possible. ManOp section XXV - 07/01/07 Secondary Prevention of
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XXVI. TRAINING MATERIALS: Randomization & Data Transfer System
The SPS3 Data Entry System (DES) is used to randomize patients into the study, edit data, and print labels, data collection forms and reports. If you require further assistance beyond the material related to the DES in this chapter, please contact the UAB SPS3 Statistical Center. Section XXVI Contents
Introduction . 2 System Requirements . 3 Installing the SPS3 DE System . 3 Login and password . 9 Randomizing a Patient . 9 Entering and Viewing Data . 11 A. Entering data . 11 B. Navigating through a form . 12 C. Locking a form . 14 D. Viewing and updating a form . 15 Entering Ineligible Subjects' Screening Forms . 15 Printing Patient ID Labels . 16 Printing Forms . 17 IP Address Notification Form . 22 Login and Password Request Form . 23 ManOp section XXVI – 07/01/07 Secondary Prevention of
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The SPS3 Data Entry System (DES) is used to randomize patients, enter data and print labels, reports (including follow-up schedules) and data forms. If you cannot find an answer to a DES-related question in this section, please contact the Statistical Center (SC) via telephone toll free at 866.304.5010, or via email at sps3@uab.edu . The members of the SC are readily available, during normal working hours/central standard time, to assist with technical troubleshooting issues. The SPS3 DES has been designed to be "user friendly." We have attempted to make navigating the DES as easy as possible. An attempt has been made to have the DES screens look very similar to the SPS3 data collection forms. A required programming difference in the electronic and paper forms accounts for a variety of monitor dimensions. A page from the paper forms is divided in half and listed in two columns on the screen in the DES, with a line on the screen dividing the columns. ManOp section XXVI – 07/01/07 Secondary Prevention of
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Computer System Requirements
Please ensure your computer has the following requirements before attempting to install the SPS3 DES: • Windows XP (with latest service pack) or Windows 2000 (With the latest service pack included) • Minimum screen resolution of 800 x 600 pixels • Minimum 256MB RAM • Pentium III or higher processor • At least 200MB disk space for installation • Antivirus package with scheduled updates to the scanning engine • Desktop fire wall software (the free version of ZoneAlarm is a good choice) • IP Address must be static and visible on the internet • High speed internet access (cable modem, DSL, T1 LAN, T3 LAN, etc.) Installing the SPS3 Data Entry System (DES)
Report your IP Address Before starting to use the CD-ROM to install the SPS3 DES, please make sure your IP address has been allowed access to the UAB's computers. The firewall at the SC blocks all IP addresses except those of sites participating in the study. If you have not reported your IP address to the Statistical Center, please complete the IP address form located at the back of this ManOp section and fax it to 205.975.2540. You may also email your computer's IP address to sps3@uab.edu , including a written request to add the IP address to the SPS3 UAB firewall. Accessing your computer's IP address Log on the IP address website: http://www.soph.uab.edu/soph_catalog/ipaddress.asp . As soon as the website opens in a new window, the information will be displayed, indicating your IP address ManOp section XXVI – 07/01/07 Secondary Prevention of
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Software installation After you have received clearance from the Statistical Center, you may begin the installation of the SPS3 DES. Go to the software installation website, at http://www.soph.uab.edu/sps3/ to install 1) the Microsoft SOAP toolkit and 2) the SPS3 DE software. Please follow the prompts, as the website instructs you to perform specific actions during the installation. Installation Trouble Shooting Do you have Service Pak 1? You can see which service pack you're currently running by clicking on Start Æ Settings Æ Control Panel Æ System. The General tab will say "Service Pack "underneath the "Windows 2000" or "Windows XP" if your Windows has been updated. It needs to be at least service pack 1 for Windows XP, or service pack 1 for Windows 2000. ManOp section XXVI – 07/01/07 Secondary Prevention of
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How to update my Service Pak? • Close all other programs. You will need to restart your computer after the software download. • Go to the SPS3 web-site: http://images.main.uab.edu/isoph/sps3/servicepack • Double click on the correct service pack (SP) to download • Windows 2000: Windows 2000 SP3 • Windows • Choose Open (or Run on some versions of Windows and Internet Explorer). You may be prompted again whether or not you want to run the program, depending on your browser security settings. • Close this browser window • Click • Choose "I agree" and click "Next" • Click • Choose "Yes" to restart Windows. If the install window prompted you the "the specified service already exists", click "ok". ManOp section XXVI – 07/01/07 Secondary Prevention of
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Login and Password Logins and passwords are assigned by the Statistical Center. These are given at the time of IP address notification or by submitting a Login and Password request form (form at back of this ManOp section). After entering a correct login, password, and clicking the Log On button, you are in the SPS3 DE System at the Main Menu and you are ready to randomize a patient, enter data or perform other tasks. Randomizing a Patient Have the patient's completed Eligibility/Randomization form in front of you. You will enter the data from this form as part of the randomization process. Data will be validated as you perform data entry and only eligible patients may be randomized. Remember that randomizing a patient is an irreversible action. Log onto the system • At the main menu, select the first button, "Randomize a New Patient". • On the next screen, again click on "Randomize a New Patient". ManOp section XXVI – 07/01/07 Secondary Prevention of
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• The screen before you contains all the questions from page 1 of the Eligibility/Randomization form. Question 1, Date of randomization, has automatically been completed for you with the current date. Starting at Question 2, Date of Qualifying Event, enter the data recorded on the form. • After you have entered the data for Page 1, click on "Next Page" at the bottom, and enter the data for Page 2 of the form. • When you have finished entering the data, click on "Randomize Subject Into • You are now prompted that once the patient is randomized there can be no changes made to the Eligibility/Randomization form for the subject. "Are you sure you're ready to randomize the subject?" Click on "yes" if you are ready. • A pop-up box will appear with assignment. Record the patient id and BP target assignment on the Eligibility/Randomization form (questions 33 and 34). Click "OK". The randomization process for this patient is now complete. You may either randomize a new patient at this point (click on "Randomize a New Patient") or exit to the main menu (click on "Exit"). ManOp section XXVI – 07/01/07 Secondary Prevention of
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Additional information Unlike most forms in the SPS3 DE system, when entering data on the Eligibility/Randomization screen you cannot partially enter the form and save the data. If the form is exited before you randomize the patient, entered data are lost and need to be entirely re-entered. If the randomization button is depressed before all fields meet the inclusion criteria or are within valid range, a message box will appear saying, "The subject can not be randomized into the study because: …"; this message will list all fields prohibiting the patient from being randomized. Entering and Viewing Data
A. Entering Data After a patient has been randomized other forms for that patient may be entered. Log onto the system At the main menu, select the second button, "Enter/Update/ Review Forms for a Randomized Patient". ManOp section XXVI – 07/01/07 Secondary Prevention of
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Choose the Patient ID from the pull down menu. After clicking on the ID, the window will be populated with a list of forms. Click on the form name or number to select it. Click "Add Form", and a blank form of that type will appear on the screen ready for data entry. The patient id will appear above the page Enter the values as recorded on the form. To exit the form, click on the "Exit" button in the top RH corner. You will be asked whether or not you wish to save your changes. Click "Yes" to save, "No" to exit without saving, and "Cancel" to return to the form. B. Navigating Through a Form In general, questions on one page of a data form appear on one data screen for entry. Enter the values as recorded on the form. When entering a text field, a <Tab> or <Enter> key may be used to progress the cursor to the next field. You may also use the mouse to select a value from the drop down box. When a field is full, the cursor automatically progress to the next field. After all data are entered from one page, the system automatically progresses to the next page or the "Next Page" button is highlighted by the cursor (Use the TAB or ENTER key to change the page). The MOUSE may also be used to change pages by left clicking on the top of the page you want displayed. ManOp section XXVI – 07/01/07 Secondary Prevention of
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At the bottom of each data entry screen are the buttons: NEXT PAGE, SAVE, CLEAR CHANGES, and LOCK FORM. • NEXT PAGE - Takes the screen to the next page of the data form.
SAVE - Saves the current data entered. This allows forms to be entered, saved,
and updates or finished at later time. Note: Data for Eligibility/ Randomization forms and Event Notification forms may not be partially entered and saved - the process of entering and locking these forms must be done all at once. • CLEAR CHANGES - Clears any changes made to the screen since the last
LOCK FORM - Locks the form. When locked, changes cannot be made to the
data entered. This option should be used when you are confident that all outstanding issues have been addressed on the specific form. A form cannot be locked or closed if any fields are highlighted yellow on the screen. Contact the SC if you have incorrect data on a locked form Fields are color-coded to show their status: • PINK - indicates the current data entry field
WHITE - indicates the entered value meets all validation rules
YELLOW - indicates value is incomplete or inconsistent
LIGHT/AQUA BLUE - indicates value does not meet validation rule but data has
been approved by PI After a value has been entered in a field, its validity is checked. If the entry does not meet a criterion, an Invalid Value message box appears explaining the reason and your options: Change the Value, Ignore for Now, or This Value Has Been Approved By a PI. Change the Value – Returns you to the field to correct the value entered Ignore for Now - Skips you to the next field and leaves current field yellow ManOp section XXVI – 07/01/07 Secondary Prevention of
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This Value Has Been Approved By a PI – Confirms value entered is "unusual but correct". It is anticipated that this option will be seldom used. Frequency of its use will be closely monitored to ensure that invalid data are not being routinely approved. Use of this option on the Eligibility/Randomization form 12 requires approval by Oscar Benavente and a one time use password. If an Invalid Value message box pops up, and you don't understand why, contact the Study Coordinator at the CC or Data Manager at the SC. Data-entry Screens are also color-coded to show their status: • SEA GREEN - indicates an unlocked form. Data may be entered, updated or
BLUE - indicates a locked form. Data may only be viewed.
C. Locking a Form A form may be locked when all entered data meet the validation rules. Eligibility/ Randomization forms and Event Notification forms are automatically locked after completion. All other forms may be manually locked using the "Lock Form" button at the bottom of the DE screen. A locked form may only be viewed - no changes can be made to the data. All data editing must take place before the form is locked, and only locked forms are considered complete for site reimbursement and data analysis. Select the "Lock Form" button. You will be prompted to confirm that you wish to lock that form. Click "Yes" to lock. Click "No" to return to ManOp section XXVI – 07/01/07 Secondary Prevention of
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D. Viewing and Updating a Form: • Log on to the system. At the main menu, select the second button, "Enter/Update/ Review Forms for a Randomized Patient". • Choose the Patient ID from the pull down menu. • After clicking on the ID, the window will be populated with a list of forms. Click on the form name or number to select it. Click on the date of the relevant form. Click "View Form". • If the form is not locked, data may be updated and saved. Entering Ineligible Subjects' Screening Forms The Screening form is the only form entered for those subjects who were screened and identified as ineligible for the study. After a patient is identified as ineligible: Click the third button on the main menu, "Enter Screening Form for Ineligible Patient" The window will open and you will have the option of Adding a New Ineligible Subject or Viewing/Editing a previously entered subject. After Clicking "Add New Ineligible Subject", the system will prompt you to make sure you want to enter the subject as ineligible. An ineligible subject cannot be changed to eligible status. The same Screening form will appear for data to be entered as with a randomized subject. The only difference is that there is no randomized ID field and answers to questions 13 and 14 will be accepted as "Yes" or ManOp section XXVI – 07/01/07 Secondary Prevention of
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Printing Patient ID Labels Patient ID labels may be printed for any randomized patient. The format is for Avery 5267 labels (0.5" X 1.75", 80 labels per sheet). • At the main menu, select the bottom button, "Labels/Forms/Reports". • Select "Labels" from the next • Select the patient id from the pull • Insert a sheet a labels in your printer, and click "Print". • You will receive a prompt asking do want to print labels for the selected ID and to make sure Avery 5267 labels are in the printer. • To print additional labels, select "Print More Labels". Click "Exit" to return to the main menu. ManOp section XXVI – 07/01/07 Secondary Prevention of
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Printing Forms The system can be used to print forms for SPS3 randomized patients. There are 33 forms that can be printed from the data entry system; two of which are not entered into the data entry system, Form 03: Patient Contact and Form 11: Current Medications. • Select the last button from the Main Menu "Labels/ Forms/ Reports" • On the next screen, select "Print Labels and Forms" • The next screen that will open lists all of the forms in numerical that can be • Select the form which you would like printed. • The "Choose Printer" button on this screen will allow you to select the printer with which you want to print the forms or labels. • Click on "Open Form" • The Form will open in a PDF format for printing • A full form set can be printed by clicking "Full set" A set of forms specific for a particular visit or event type can also be printed: a BP check, 3 month follow-up, annual follow-up, an event, etc. Click on the visit type to print those forms. ManOp section XXVI – 07/01/07 Secondary Prevention of
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The SPS3 Data Entry system produces multiple reports for your site including: a quarterly follow-up schedule for a patient, a list of patients due for a quarterly follow-up, a list of patients overdue for a quarterly follow-up and a report of overdue forms. Quarterly Follow-Up Schedule • Select the last button on the Main Menu, "Labels/Forms/Reports" • On the next screen select "Reports" • On the next screen click on "Patient Follow-up Schedule" • On the next screen, at the prompt, "Choose the patient's randomized ID for the subject you want to print a follow-up schedule:", select a randomized ID from the • A message box will pop up and prompt "Do you want to print a SPS3 follow-up exam schedule for <patient id selected>?" Click "Yes", if correct ID chosen or Click "No" to pick another randomized Sample patient's follow-up List of Patients Expected for Quarterly Follow-up Visits This report lists patients due for a quarterly follow-up visit over a specified time period. Participants are listed by weeks along with the type of quarterly follow-up visit due and their initial date of randomization. To produce this report: Select the last button on the Main Menu, "Labels/ Forms/ Reports" • On the next screen select "Reports" • On the next screen click on the Patients Expected in Clinic ManOp section XXVI – 07/01/07 Secondary Prevention of
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• On the next screen enter the dates for which you want to produce the list of expected quarterly visits. For example: 06/23/03 to 7/03/03 • After two dates are entered, you will be prompted by a pop up box: "Do you want to print a list of patients due for quarterly follow-ups during the period 07/07/2003 to 7/18/2003?" Click "Yes" to produce the report or Click "No" to change the • Patients will appear on the list based on the beginning of the follow-up window. Remember that a visit is considered on time in the two week period on either Missing Quarterly Follow-up Visits This report lists patients who have a Follow-up Form missing. A follow-up form is missing if data entry has not been initiated within one week following the end of the follow-up window. This report is always produced for "Today's date". Enter forms as quickly as possible to keep this list at a minimum. Select the last button on the Main Menu, "Labels/ Forms/ Reports" On the next screen select "Reports" On the next screen click on the button "Missing Follow-ups" You will be prompted by a pop up box: "Do you want to print a report of SPS3 patients missing their most recent follow-up form?" Click "Yes" to print the report and click "No" to take you back to the screen to select a type of report Sample Patients Missing Most Recent Quarterly Follow-Up Report: Randomization Date Date of Last Follow-up ManOp section XXVI – 07/01/07 Secondary Prevention of
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Data Completeness Report The Data Completeness Report, previously available via the DES, serves as the basis to determine if patient information is overdue at the Statistical Center for any patient visit. As data are received and processed, the SPS3 database is automatically updated to indicate the receipt of data for an individual patient for a specific visit. These overdue notices, as illustrated by the report, are cumulative, so that indications that data are missing remain on the report until the data are provided. This report aids in illustrating any discrepancies discovered in the database for the clinical coordinator's attention for further verification and correction. The SPS3 Data Completeness Report is updated weekly and available by Monday afternoon via the following link to the password- protected website: http://138.26.144.9/sps3_report/login.asp . Coordinators will receive an email alerting them to check the website for an updated report. If you experience any problems accessing the report, or need access to your login name and password, please contact the SC. ManOp section XXVI – 07/01/07 Secondary Prevention of
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Login and Password Request
Please use this form to request a login and password for additional data entry personnel. Fax the completed form to the Statistical
Center (205-975-2540). You will receive verification of receipt and your login and password via the e-mail address you give below
within 24 hours.

Date:


SPS3 Clinic:


SPS3 Site PI:
Clinic Coordinator:
E-mail address:
List name(s) in which SPS3 data entry system login and
password are requested.

Any additional information:
ManOp section XXVI – 07/01/07 Secondary Prevention of
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IP Address Notification Form
Please use this form to notify the Statistical Center of the IP address of the computer in which you are going to perform SPS3 data
entry. You will receive verification of receipt and your login and password via the e-mail address you give below within 48 hours.

Date:


SPS3 Clinic:


SPS3 Site PI:


Clinic Coordinator:
E-mail address:


IP Address:


DCHP Enabled?


Computer System Contact:
List any other names of people at your site who are
trained and will be performing data entry for SPS3.

Please fax this form to the Statistical Center (205-975-2540
ManOp section XXVI – 07/01/07 Secondary Prevention of
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XXVII. TRAINING MATERIALS: Use of Colin BP Device
The Press-Mate Model 8800 series of monitors have been factory calibrated for all of the test modes by the manufacturer. The standards follow the recommendations of the AAMI, the Academy of Advancing Medical Instrumentation. Each machine will be shipped annually to the manufacturer for calibration/tune-up. Following is a brief summary of operating instructions. A more detailed manual accompanies the machine. • On the rear panel, turn the switch to "ADULT/PEDIATRIC" position, turn the printer switch to "ON", and the display switch to "ON". • Connect one end of the grey hose to the front panel of monitor and the other end to the proper size cuff. • Connect the machine to power. • Press the "ON" switch in the lower RH corner of front panel of monitor. BP measurement may begin when ‘0' is displayed in the "MEAN DISPLAY" window. • Wrap the proper size BP cuff on the patient's bare arm. • To initiate measurements at intervals, press the "INTERVAL" switch. Press again to set interval, e.g. ‘2' = 2 minutes. (Omit this step if single BP is desired.) • Press the "START/STOP" button to start the measurement. It may take up to 3 inflations to obtain a systolic measurement. Systolic and diastolic pressures and pulse rate will be displayed after the measurement. • If interval measurements were specified, the next measurement will automatically begin. If single measurements, then press the "START/STOP" button to begin the next measurement. • "START/STOP" may be pressed at anytime to interrupt a measurement. ManOp section XXVII - 04/15/03 Secondary Prevention of
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XXVIII. TRAINING MATERIALS: Use of Ambulatory BP Device
Ambulatory blood pressure (ABP) measurement will be performed on all patients to better characterize blood pressure while patients are engaging in usual activities and to classify patients as dippers/non-dippers. ABP monitoring will be carried out on: • All patients once they are stable on anti-hypertensive medications (if being prescribed) and are "In Target" (BP falling within their assigned BP target group) at 2 or more consecutive visits. This includes patients who are not taking anti-hypertensive medications whose BP < 130 mmHg, regardless of assigned target. To provide some consistency to the data collection, please schedule the monitor placement at 6 to 12 months post-randomization at the time of a quarterly follow-up or BP Check. This clinic measurement of blood pressure will serve as a comparison to the ABP readings. If you have planned to perform the ABP measurement, but the patient's clinic blood pressure reading that day is outside the assigned target, please go ahead with the procedure as long as the SBP is within 10 mmHg of the target and no adjustments are being made to the medications. If medications need to be adjusted or SBP is more than 10 mmHg away from the target, postpone the measurement until the patient is again in target. • Selected patients with difficult hypertensive management or in the situation where a "white coat" syndrome may be suspected of influencing blood pressure • Patients who are declared FAAT The ABP monitors will be assigned to selected SPS3 sites based on their ability to perform the ABP measurements in order to maximize ABP data collection. The ABP package will be shipped from the Coordinating Center and will contain the monitor, cuffs and a few other accessories, software for installing the system on your computer, a video which will guide you through the set-up as well as a part that can be shown to patients, and a CD from Spacelabs that contains information for troubleshooting the monitor.
Steps for 24-hour ABP Monitoring
1. Install and login to the ABP Report Management System program 2. Program with the SPS3 protocol 3. Initialize the monitor ManOp section XXVIII - 08/15/09 Secondary Prevention of
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4. Instruct the patient 5. Complete the 24-hour monitoring procedure 6. Upload the monitor 7. Record the required information on Form 13 (24 HR AMBULATORY BP) 8. Save file as a pdf or copy the data to a CD (labeled with patient IDs) and send to the Coordinating Center 1. Install and Login to the ABP Report Management System program
• Start Microsoft Windows
• Insert the ABP Report Management System CD – program will automatically load
• Choose the express install which will provide you with all the features you need to run
• Open the Spacelabs ABP Client Application program You will be required to enter an initial password and user information (user ID can be your name – select 123456 for this initial password as you will be required to change password the next time you log on to the program and then you can select whatever password you wish). Almost all sites have had an occasion where they have forgotten their password for the ABP software. Unfortunately the version of the software that we have does not come with a default password and the only option to be able to access the software is to uninstall and reinstall (which is a pain and also means that you will lose all procedures that you have performed to date). Rather than selecting your own username and password, you can also use the following generic username and password: Username: SPS3 Password: lacune (all lowercase) • When you login, you will be required to select a profile and a role. Please select ‘administrator' (this will allow you to change the monitor set-up) and select
‘physician' (need to select physician to initialize the monitor).
• On the right side under ‘password control', changing the password after so many weeks is checked as the default. So that you do not need to be regularly changing your password, please disable this function. ManOp section XXVIII - 08/15/09 Secondary Prevention of
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2. Program monitor with SPS3 set-up
• After opening program and entering username and password, you will come to the Main Menu
• Select View/Change System Settings
• Under Report Format, please leave ‘use standard report' as the default
• Select Statistics Tab
• When the statistics tab is opened, the Factory Default setting, as seen below,
To configure the SPS3 statistical setting: • Click New/Edit and a box called Statistical Settings will pop up
• Where it asks for Item, enter SPS3, click ADD and then click CLOSE
• The Auto Edit Limits boxes define the edit limits for data analysis. You can leave these
ManOp section XXVIII - 08/15/09 Secondary Prevention of
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• Indicate the start hour as 8 in the first row and the start time as 20 in the second row.
You can designate the time starting at 20 as Sleep. Designating the night hours as
‘sleep' is needed for calculating the percent of ‘dipping'. • The systolic and diastolic pressures in this section can be left as seen above (140/90
for 0800 to 2000 and 120/80 for 2000 to 0800). These boundaries are used in the
summary report and the percentage of readings that are above the values entered here will be calculated.Select Monitor tab and you will see the following displayed
To configure the SPS3 initialization setting: • Click New/Edit and a box called Monitor Initialization List will pop up
• Where it asks for Item, enter SPS3, click ADD and then click CLOSE
• Under Wake periods, enter start time as 8, enter 2 readings / hour, and remove the
check mark from the Tone box (so that it will not beep each time the pressure is
• Under Sleep periods, enter start time as 20 and enter 1 reading / hour
• There are 3 boxes in the upper left hand corner that you, in most case, do not want ManOp section XXVIII - 08/15/09 Secondary Prevention of
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Show results of reading check box is selected, the reading results will
appear on the ABP monitor display after each BP reading. Clinical verification setup check box is selected, the monitor will detect
blood pressure levels as low as 40 mmHg (the monitor will always bleed to 40 mmHg). Display Cuff Pressure check box is selected, the cuff pressure will
appear on the ABP monitor display while the cuff is pumping and bleeding. Select OK to save these settings.
You should have to input the SPS3 program only once. Regardless of the time that you start the 24-hour procedure with your patients, there is a built-in clock in the monitor and the data will be summarized as per the protocol above. 3. Initialize the Monitor
• Prior to initializing monitor, ensure that data from previous patient has been down- loaded to your computer (monitor has been uploaded or read) • Insert a new set of batteries for each 24-hour monitoring session (monitor takes 3 AA • Attach the monitor to the computer serial port
• Turn monitor power on
• Under Main menu, select Initialize Monitor
• Enter the patient's demographic information
ƒ Patient ID is a required format – enter SPS3 ID in this format (01-001-7) ƒ First and Last name are required fields – as these reports are sent here, you should NOT enter the patient's name and can enter either their acrostic in both the First and Last name fields ƒ Physician field is required and because you have logged in with this role, you will just select yourself from the pull-down list ƒ All of the other fields are optional and you don't need to enter patient's date of birth, race, and gender as this can be captured from the database. • Scroll to the next window and you should see the SPS3 configuration. If you do not, select it from the pull-down window • Scroll to the next window
• Click Initialize Monitor to complete the initialization process
• Once the monitor is initialized, turn it off
ManOp section XXVIII - 08/15/09 Secondary Prevention of
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The monitor is now initialized, meaning that it is ready for the 24-hour monitoring procedure on your next patient whose information you have just entered. You can initialize the monitor up to several days in advance of the 24-hour monitoring session. 4. Patient Instructions
Prepare the patient for the 24-hour monitoring. Provide them with the following instructions before coming to clinic to be connected to the monitor: • Wear loose clothing and bring a belt for attaching the monitor • Come to clinic accompanied by someone who can drive patient home • Avoid bathing and showering during 24-hour monitoring • Avoid strenuous activities during 24-hour monitoring • Return to clinic after 24 hours to remove monitor The day that the patient comes to clinic to wear the monitor, the following points should be • Explanation of the procedure and the important reasons for undergoing it • Provide a demonstration of attaching the cuff and monitor, re-attaching the cuff as it may loosen with activity during the 24-hour period (can place a mark on the arm for cuff re-attachment), manual inflation and deflation • Explain the frequency of inflation and deflation • Instructions about keeping arm steady during measurement • Ability to engage in normal activities between measurements • Keeping monitor attached at night • Instructions to take all medications as prescribed, in particular their anti-hypertensive In the video that you will receive with the ABP package, there is a section which has been designed specifically for patient instruction and this can be shown to the patient, if you wish, in addition to the teaching that you have provided.
5. Complete the 24-Hour Monitoring Procedure
ManOp section XXVIII - 08/15/09 Secondary Prevention of
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• Turn the monitor on • Attach the cuff to the ‘selected' arm and the monitor to the patient • Manually take the patient's BP at least 2 to 3 times, a few minutes apart, so that the patient can appreciate how it feels • Compare with manual reading • Organize to have patient return to clinic in about 23.5 hours • Inform patient that if she/he does not arrive to clinic on time that the monitor will continue taking her/his BP and to NOT TAKE OFF the machine • Provide the patient with the SPS3 diary for obtaining specific information during the 24- hour monitoring period and instructions on how to complete it • Answer any last questions that the patient may have • Provide patient with a number where they can reach someone over the next 24 hours • When patient returns to clinic, manually take the last BP measurement • Obtain the diary from the patient • Turn the machine off • When you get back to your computer, read the monitor • After reading monitor and turn the machine off 6. Upload the Monitor (down-loading patient information from the monitor to store on your
• Attach monitor to the computer serial port • Turn monitor power on • At the Main Menu, select Upload Monitor
• Click Acquire Monitor Data
• When the download is completed, click Next – you will see Demographic Data and can
make changes if you wish • Click Next – on this field you will see Select Statistical Setting - to apply the SPS3
summary periods to the data, select SPS3
• Click Next – on this field you can enter additional patient information if you wish.
ManOp section XXVIII - 08/15/09 Secondary Prevention of
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• Click Finish
• Patient information opens and you can scroll through this using the Next and Prev buttons seen in the upper left hand corner. • To close the patient file select Close
7. Record the required information on Form 13
• Under Main menu, select Review / Edit Patient Test
• Select specific patient you wish to review and double-click on patient to open the file • You can scroll through the file to see the raw data and the statistical summaries • Information to complete Form 13 can be found on the first screen entitled Patient Information and the second screen which provides the summary data • The only thing that is not provided is scan end date and time. You can obtain this information in two different ways: below scan start date and time (bottom left hand corner), you will see an entry called duration – to get scan end time, you can add this on to the scan start time to get the end time. The other way to do this is to scroll forward to the screen entitled ‘ABP Raw Data Tabular'. Scroll to the last entry in the table and record the time the last measurement was taken. To print patient data:
• Under the Print menu, can print the whole report or select specific pages to print • This can be given to the HTN MD to review and to the PCP (if desired) 8. To Save ABP Report to File and Send to Coordinating Center
• From the Main Menu, select Review / Edit Patient Test
• Highlight the patient file to be saved • Under the File menu, select Save As
• Under ‘Page to Export', select ‘Complete patient Data(PDF format)' • Choose where you wish to store the file (the most convenient is to create a folder under My Documents to save all ABP files) • Click Finish and file will be saved
• New window will pop up confirming where you want to save the file ManOp section XXVIII - 08/15/09 Secondary Prevention of
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• Please send this file to the Coordinating Center as an email attachment Spacelabs Operations Manual
For the most part, the information that you require for setting up the system and monitoring a patient is found in the material that is provided here (Section XXVIII). However, should you wish to read further about the monitor and ABP program, additional information is available in the Operations Manual published by Spacelabs. This manual can be found under the Help Menu
(choose Help Topics). It will provide you with information about the operation of the monitor, the event codes that you may see displayed on the monitor and what they mean, troubleshooting, and information on the ABP Report Management System (the program that you download on ManOp section XXVIII - 08/15/09 The portable automatic blood pressure unit that
you are wearing will record your blood pressure
Ambulatory Blood
and heart rate every 30 minutes during the day
and every hour during the night.

Pressure

9 Be sure that the monitor is comfortably
Monitoring
positioned before you leave the clinic
9 Be sure that you have learned how to re-
position the cuff in case it becomes loose
Patient Diary
during the next 24 hours
9 Go about your normal activities but avoid
Patient ID _
vigorous activities such as going to the gym or
jogging

9 Take all medications including blood pressure
Reason for Test
pills as usual during the next 24 hours
9 When you feel the cuff beginning to
Please return to clinic tomorrow to have the last blood
inflate….STOP all movement and RELAX your
arm during the cuff inflation. KEEP your arm

pressure measurement taken and to have the monitor
still while the monitor is taking a
removed.
reading….once the cuff deflates, resume
Tomorrow's appointment ( ) is at
normal activity
9 Wear the monitor continuously for the next 24
hours….DO NOT REMOVE during the night
9 DO NOT REMOVE the blood pressure monitor
If you have any questions or have any difficulties
from the carrying case
with the ambulatory blood pressure monitor over the next
9 DO NOT get the monitor wet – should it get wet
24 hours, please contact:
there is no electrical shock hazard from the
Complete the diary on the next two pages and
bring it with you to clinic tomorrow
Activities while Wearing the Monitor
PLEASE RECORD TIME INTERVALS YOU PARTICIPATED IN THESE ACTIVITIES
House/Yard Work
Shopping
Watching TV/Reading
Childcare
Other Activities
Please describe work:
Please describe other activities:
How did you sleep during the night? (circle one)
Excellent
What time did you start your longest sleep?
What time did you wake from it?
Did you take your blood pressure pills as prescribed? (circle one)
Each time you take a blood pressure pill, please record the name of it and the time of day:
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Name of BP medication and time of day
Manual of Operations Small Subcortical Strokes
XXIX. TRAINING MATERIALS: Sending Imaging Files on CD
Imaging files or reprints of scans are sent to the Coordinating Center for central reading of the following: • Eligibility MRI scan documenting the qualifying stroke lesion (scan date referenced in question 7 of Qualifying Stroke - 06 form) and MRA done at study entry (date referenced on Intracranial Vascular Imaging - 15 form) • Repeat MRI at 3-6 mo post-randomization, if applicable (see Repeat MRI - 38 form) • After a stroke or TIA during the course of the trial (scan date referenced in question 18 of Ischemic Stroke/TIA -21 form or question 8 of CNS Hemorrhage - 22 form; scan date referenced in question 16 of BEA Ischemic Stroke /TIA - 31 form or question 13 of BEA CNS Hemorrhage Event - 32 form) • Following a major cognitive decline during the course of the trial Most sites have the capability to send imaging files on CD rather than reprints of scans to the Coordinating Center, and this method is usually less costly, easier to obtain, and the preferred method. When sending scans on CD, please be sure that the files are
in DICOM format and that the date(s) of the studies included matches that
reported on the relevant forms. Other formats, e.g. JPEG, TIF, are not acceptable.
Please include studies for only one patient on a CD, including a completed label
on the CD case.
ID - - Acrostic

Event Date / /
MRI Date / / N/A

MRA Date / / N/A

Baseline

ManOp section XXIX - 06/06/05 Manual of Operations Small Subcortical Strokes
XXX. TRAINING MATERIALS: Substudies
ManOp section XXX - 06/15/04
XXXI. STUDY CLOSURE
SPS3 is expected to end on April 30, 2012 and prior to that, all randomized subjects will need to be brought back for an End-of-Study Visit, regardless of whether or not they are actively receiving assigned SPS3 intervention (s). The maintenance of accurate contact details for all participants is therefore of prime importance. If you have difficulty locating a patient, please contact the SPS3 Coordinating Center before designating that person "lost-to follow-up". All available resources should be used to locate these people in order to establish their vital status at the end of the study. To help ensure a successful close-out of SPS3, we ask study sites to ensure timely subject evaluation and data entry and to respond promptly to data queries The procedures will not differ significantly from those used for the Premature Study Termination and will include the following: 1. Recording current medications (Form 04) 2. Assessing Post-Stroke Disability (Form 07) 3. Performing Neuro-psych Testing* (Form 09) 4. Obtaining Quality of Life Information (HTN & Stroke) (Forms 10 & 14) 5. Obtaining Follow-up Information (Form 16) 6. Obtaining End of Study Information (Form 37)  There is no need to complete Form 90 for participants who are beyond 5 years in  There are no new forms for the End of Study visit. Forms 16 and 37 have been revised slightly to capture End-of-Study information.  No labs will be required. ManOp section XXXI – 03/17/11 * Neuropsych testing (09) is only necessary for participants who are 5 years or less in the study. It does not have to be repeated if performed in the previous 6 months. If the participant refuses cognitive testing, an attempt should be made to perform the CASI, at In addition to the above-referenced procedures, patients should be provided with a letter of appreciation which will also include information pertaining to the unblinding process, when and how trial results will be available and other frequently asked questions. A letter should also be sent to the Healthcare Provider regarding the patient's participation in SPS3. Sample letters are included in this section.
Please note that Event counting for individual subjects continues until the
day of their end-study visit.


To recap, please complete the following forms at the End of Study Visit: 04, 07, 09, 10,
14, 16 & 37.
For additional details regarding the closeout of SPS3, please refer to the End of Study
Plan.
ManOp section XXXI – 03/17/11 <physician address> RE: <patient name> On behalf of the Secondary Prevention of Small Subcortical Strokes (SPS3) study team, we would like to thank you for supporting your patient, _, throughout their involvement in this important trial. The treatment phase has now been completed and your patient wil be transitioned back to regular medical care. We are committed to making this as smooth a transition as possible. Patients were randomized to receive 1) either aspirin alone or aspirin plus clopidogrel and 2) to a systolic blood pressure control target, either 130-149 or below 130. Since the results of the study are not yet known, please feel free to manage the antiplatelet and blood pressure therapy according to the current standard of care. Results of the SPS3 study are expected to be available soon. In the meantime, we have discussed with your patient the fact that their medications may need to be changed, particularly if cost is an issue. For the duration of the study, antiplatelet and antihypertensive medications were provided free of charge. When possible, active patients having difficulty paying for these medications have been given up to three month's supply of aspirin and/or antihypertensive medications to aid in the transition. If you have questions regarding your patient or any aspect of the study, please do not hesitate to contact us at ( ) . SPS3 Principal Investigator SPS3 Study Coordinator SPS3 Clinical Center Dear <participant name> / (SPS3 ID number), On behalf of the entire SPS3 Study team, we would like to inform you that the study ended successfully as planned on April 30, 2012. This was a very long and involved trial that required an incredible amount of commitment. We are very grateful for your contribution to this important study, which could not have been accomplished without you. The results are currently being analyzed and wil be communicated to you soon. Only after all of these analyses have been performed, will we be able to tell you what medication you were receiving. Please let us know if you want to be informed of this. Your participation has helped to improve the treatment of stroke and for that we are indebted If you have questions, please do not hesitate to contact us at ( ) _. SPS3 Principal Investigator SPS3 Study Coordinator Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
Af ix Patient ID Label Here 1. DATE OF FOLLOW-UP: 2. TODAY'S SCHEDULED FOLLOW-UP: ( one) 3. TYPE OF FOLLOW-UP CONTACT: ( one) 1 Phone contact 2 Clinic visit, seen by MD Verify patient contact information .If there been a
3 Clinic visit, seen by RN only change of address or phone, update Patient
Information Form.
5 Phone contact with outside clinic BPs 1 Never smoked 2 Former smoker 3 Current smoker If current, average number of cigaret es per day AND/OR 1 Pipe or cigar smoker 1 yes 2 no Does patient regularly use alcohol in a week? If yes, complete the fol owing: Usual number of days per week patient drinks: Usual number of drinks consumed in a week: Maximum number of drinks on any one day: Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
6. IF ANNUAL FOLLOW-UP OR END OF STUDY, EMPLOYMENT STATUS IN LAST 3 MONTHS: ( one) 1 Employed outside the home 2 Not employed outside the home If not, primary reason: (√ one) 1 retirement due to age 2 prior or qualifying stroke 3 other health reason, specify 4 non-health reason, specify Number of days per week patient has sustained exercise for at least 10 min exclusive of work and home activities (e.g. walking, swimming, exercise class…) MEDICATIONS - RECORD ON MEDICATIONS FORM 8. Is patient currently prescribed BP lowering meds? 1 yes 2 no If yes, time since last dose of any BP lowering med hrs

9. BP lowering medication compliance 1 excel ent (takes meds 99% of time) 2 good (misses a dose weekly) 3 poor (misses two or more doses of one or more meds weekly) 10. Side-ef ects possibly related to BP lowering meds 2 yes, mild, no med changes required 3 yes, change prompted in BP lowering meds Secondary Prevention of
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FOLLOW-UP - 16
BLOOD PRESSURE MEASUREMENT 11. Time of first blood pressure: : (24 hr clock) SPS3 BP Measurement Technique…
 Measure BP in the morning with morning BP 12. Sitting BPs in "Selected" Arm medications held. If not possible, avoid Arm measured: 1 Right measurement within 3 hrs of taking BP  No caffeine or tobacco within prior 60 minutes  "Selected" arm relaxed and supported at level of the heart after 15 minutes of sit ing quietly  Minimize physical contact during measurement  Three readings separated by > 2 minutes  If the measured BP is unexpectedly high or low, re-check with a recently calibrated 2 Other (includes other electronic and manual) (preferably mercury) sphygmomanometer (after all sitting BPs done and after standing for 2 min) After standing, does the patient report experiencing: 1 yes light headedness other symptoms, specify HTN TRIAL 14. HTN trial status during follow-up period: ( one) 1 Active, including normotensives not taking BP lowering meds 2 Active, but FAAT 1 systolic BP 130-149 2 systolic BP < 130 16. Is the average systolic BP in assigned target range? 1 yes -> Check plan 1 1st BP in target; wil recheck within 1 mo 2 2nd BP in target, wil recheck at next quarterly fol ow-up 3 recheck at next quarterly follow-up 4 other (explain in progress note) 2 no -> Check plan 1 adjust meds now; recheck within 1 mo 2 no meds adjustment; recheck within 1 mo 3 no meds adjustment, declaring FAAT (-> complete FAAT-18 form) or already FAAT 4 other (explain in progress note) 5 normotensive on no meds Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
DURING THE LAST 3 MONTHS, HAVE YOU… 17. 1 yes 2 no been bothered by flushing (redness) or sensation of warmth in the skin? 18. 1 yes 2 no been troubled by indigestion? 19. 1 yes 2 no had trouble fal ing asleep? 20. 1 yes 2 no been bothered by dizziness? 21. 1 yes 2 no been troubled by headaches? 22. 1 yes 2 no had swollen ankles? 23. 1 yes 2 no suffered from breathlessness? 24. 1 yes 2 no had palpitations (abnormal heart beats)? 25. 1 yes 2 no suffered from constipation? 26. 1 yes 2 no had nightmares? 27. 1 yes 2 no noticed a decrease in your sexual capacity? 28. 1 yes 2 no been bothered by cold hands/feet? 29. 1 yes 2 no suffered a dry cough? 30. 1 yes 2 no had dif iculty concentrating or with memory? 31. 1 yes 2 no had dizziness when standing up? 32. 1 yes 2 no suffered from calf pain or cramps? 33. 1 yes 2 no suffered new onset or change in chest pain? 34. 1 yes 2 no passed out or blacked out? 35. 1 yes 2 no Has your walking or balance changed? 36. 1 yes 2 no Do you get up at night to urinate? If yes, number of times DURING THE LAST 3 MONTHS, HAVE YOU BEEN BOTHERED BY… 37. 1 yes 2 no 38. 1 yes 2 no 39. 1 yes 2 no 40. 1 yes 2 no 41. 1 yes 2 no 42. 1 yes 2 no Urinary tract bleeding 43. 1 yes 2 no Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
ANTIPLATELET TRIAL 44. Antiplatelet study status during fol ow-up period: ( one) 1 Active Complete questions 45 - 48 if active. 45. 1 yes 2 no Patient reports taking antiplatelet medication from both bot les as directed 46. BOTTLE # 1 – ASA Date last bot le dispensed: / / Number of pil s dispensed Number of pil s returned % compliance (computed by PC) Type (prescription of non-study ASA requires CC pre-approval): 2 non-EC 325 mg 47. BOTTLE # 2 – clopidigrel vs. placebo Date last bot le dispensed: / / Number of pil s dispensed Number of pil s returned % compliance (computed by PC) 48. If compliance < 80% or > 105%, indicate reason(s): 1 surgery or medical reason 1 side ef ects 1 did not understand 1 forgetful or careless 1 uncooperative 1 other, specify ANNUAL LABORATORY DATA (collect at indicated follow-ups only, not necessary at end of study) 49. Serum creatinine Al annual follow-ups - within 3 mo prior or 1 wk after follow-up 50. HbA1C - diabetics Al annual follow-ups - within 2 mo prior or 1 wk after follow-up 51. Lipid profile Al annual follow-ups - within 3 mo prior or 1 wk after follow-up total cholesterol mg/dL LDL triglycerides mg/dL Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
ANNUAL PHYSICAL MEASUREMENT (TO BE COLLECTED AT END OF STUDY) 53. Waist circumference: cm or inches (12" = 1 foot) SUBSTUDY DATA (collect at indicated follow-ups only) 54. LIMITS Blood draw 1 non-participant Initial 1 year follow-up only 1 non-participant Initial 6 mo follow-up and all annual follow-ups. Ignore any < signs when recording values. Round non-ratio numbers to nearest whole number. (round any number below 1 to 1) Enter all results available, but do not compute values. albumin/creatinine ratio .
1 no unit 2 mg/g 3 other, STROKE SYMPTOMS 56. 1 yes 2 no In the past 3 months, have you had any sudden loss or major changes in speech? 57. 1 yes 2 no In the past 3 months, have you had any sudden loss or blurring of vision in one eye, complete or 58. 1 yes 2 no In the past 3 months, have you had a sudden spel of double vision, that is, did you see two objects side by side, or one on top of the other? 59. 1 yes 2 no If you closed one eye, did the double vision go away? 60. 1 yes 2 no In the past 3 months, have you had sudden numbness, tingling or loss of feeling on one side of your body, including your face, arm and leg? (must be some combination of face and arm, or arm and leg together, etc , in order to mark yes) 61. 1 yes 2 no Did the feeling of numbness or tingling occur only when you kept your arms or legs in a certain 62. 1 yes 2 no In the past 3 months, have you had any sudden episodes of paralysis or weakness on one side of your body, including your face, arm, and leg? If any of the circled-shaded boxes are checked AND a stroke/TIA has not been reported, complete the Stroke Symptoms Questionnaire form immediately…. Secondary Prevention of
Small Subcortical Strokes
FOLLOW-UP - 16
HEALTH SINCE LAST QUARTERLY FOLLOW-UP 63. How would you say your health is these days? In general would you say your health is: ( one) 64. 1 yes 2 no Has the patient seen a doctor for an unscheduled visit for a new or active health problem? If yes, specify reason: 65. 1 yes 2 no Hospitalization since last follow-up? If yes, specify reason: 66. 1 yes 2 no Epileptic seizure since last fol ow-up? (If initial 3 mo fol ow-up, ask since qualifying stroke.) 67. 1 yes 2 no Coronary angioplasty, coronary stent or CABG Have any of the fol owing events occurred since the last quarterly follow-up? 68. 1 yes 2 no 69. 1 yes 2 no If any yes, complete Event – 20 or
Status of Therapy – 36 form
71. 1 yes 2 no Major non-CNS bleeding 72. 1 yes 2 no Serious complication of Hypotension 73. 1 yes 2 no Other SPS3-related SAE 74. 1 yes 2 no Acute MI or other non-CNS thromboembolism 75. 1 yes 2 no Discontinued or resumed SPS3 AP therapy or SPS3 BP management 76. 1 yes 2 no Major cognitive decline Auxil ary Forms Due by *Required ONLY for patients who have not reached 5 years in the study, and have not had cognitive testing the last 6 months. A form 90 is not required. Secondary Prevention of
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FOLLOW-UP - 16
BP medications at Clinic Dismissal (list all) name (generic preferred), formulation (i.e., extended-release) Date of next appointment Reminder: Send let er to PCP/family physician SPS3 Study Progress note RN and MD completing form Secondary Prevention of
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STUDY TERMINATION - 37
Af ix Patient ID Label Here • Complete this form for al patients who terminate from the study regardless of the reason. • Complete if a participant refuses further SPS3 involvement (i.e. early termination where the participants withdraws consent for al contact including telephone), is truly lost-to-fol ow-up after vigorous ef orts to find him/her, is fol owed for 4.5 years and refuses to re-consent for further follow-up, and for participants who are fol owed until SPS3 study end. • For early termination or lost to fol ow-up, SPS3 physician investigator should contact the Coordinating Center before completing the narrative to discuss the case. • In addition to this form, please complete Forms 4, 7, 9, 10, 14, and 16. If cognitive testing (Form 9) has been completed within less than 6 months, do not repeat for the end study visit. 1. Date of termination: 2. Reason for end of SPS3 participation: 1 unable to locate patient (describe steps taken to locate patient in narrative) 2 patient withdrew consent (describe reason in narrative) 3 physician request for patient to withdraw 4 clinical site closed 6 patient refused to re-consent for extended fol ow-up 7 patient withdrew after re-consenting for extended follow-up 99 STUDY END 5 other reason, 3. Current living arrangements: 1 alone in own home or apartment 2 with spouse/relatives/others in home or apartment 3 assisted living facility or nursing home or other paid caregiver 4 unknown Secondary Prevention of
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STUDY TERMINATION - 37
Af ix Patient ID Label Here 4. Narrative summary: SPS3 physician investigator to complete after discussing the case with the Coordinator Center. Explain all efforts undertaken to avoid study termination. (May be dictated and at ached) 5. Date CC contacted: / / Initials of CC "approver": (Not needed for End of Study Visit) Person completing form

Source: http://med-sps3.sites.olt.ubc.ca/files/2012/06/manual_of_operations.pdf

Http://www.ncbi.nlm.nih.gov/pubmed

Markopoulos C - PubMed - NCBI Display Settings: Abstract, 200 per page, Sorted by Pub Date Filter your results:All (109) Results: 109 c Lancet. 2011 Aug 27;378(9793):771-84. Epub 2011 Jul 28. 1. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R.

Doi:10.1080/08910600410026355

Periodontal Disease, Matrix Metalloproteinases andChemically Modified Tetracyclines From the Department of Periodontology, Faculty of Dentistry, University of Oslo, Oslo, Norway Correspondence to: Svein Steinsvoll, Sagvollveien 1, 2830 Raufoss, Norway. Tel.: / 47 61191481; Fax: /4761191481; E-mail: sebstein@online.no Microbial Ecology in Health and Disease 2004; 16: 1 /7