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Efficacy of oclacitinib (apoquel) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in clientowned dogs in australia

Vet Dermatol 2014; 25: 512–e86 DOI: 10.1111/vde.12166 Efficacy of oclacitinib (Apoquelâ) compared withprednisolone for the control of pruritus and clinicalsigns associated with allergic dermatitis in client-owneddogs in Australia Caroline Gadeyne*, Peter Little†, Vickie L. King‡, Nigel Edwards†, Kylie Davis† andMichael R. Stegemann* *Veterinary Medicine Research and Development, Zoetis Inc., Mercuriusstraat 20, Zaventem, B-1930, Belgium†Veterinary Medicine Research and Development, Zoetis Inc., 45 Poplar Road, Parkville, VIC, 3052, Australia‡Veterinary Medicine Research and Development, Zoetis Inc., 333 Portage Street, Kalamazoo, MI, 49007, USA Correspondence: Caroline Gadeyne, Zoetis Inc., Veterinary Medicine Research and Development, Mercuriusstraat 20, Zaventem B-1930, Belgium.
E-mail: [email protected] Background – Oral glucocorticoids are widely used to reduce pruritus and dermatitis associated with allergicdermatitis. Data suggest that oclacitinib, a Janus kinase inhibitor, is a safe and effective alternative.
Hypothesis/Objectives – To evaluate the efficacy and safety of oclacitinib compared with prednisolone for thecontrol of pruritus associated with allergic dermatitis in a single-masked, controlled clinical trial with a randomizedcomplete block design.
Animals – Client-owned dogs (n = 123) with a presumptive diagnosis of allergic dermatitis and moderate tosevere pruritus as assessed by the pet owner were enrolled.
Methods – Dogs were randomized to treatment with either oclacitinib (0.4–0.6 mg/kg orally twice daily for14 days, then once daily) or prednisolone (0.5–1.0 mg/kg once daily for 6 days, then every other day) for 28 days.
An enhanced visual analog scale (VAS) was used by owners to assess pruritus and by veterinarians to assessdermatitis, at all time points assessed.
Results – Both treatments produced a rapid onset of efficacy within 4 h. The mean reductions in pruritus anddermatitis scores were not significantly different between the treatments except on day 14, when reductionswere more pronounced for oclacitinib than prednisolone (P = 0.0193 for owner pruritus scores; P = 0.0252 forveterinarian dermatitis scores). Adverse events were reported with similar frequency in both groups.
Conclusion and clinical importance – In this study, both oclacitinib and prednisolone provided rapid, effectiveand safe control of pruritus associated with allergic dermatitis, with substantial improvement in pruritus, reportedby owners, and dermatitis, reported by veterinarians.
of atopic dermatitis in dogs.4,5 It inhibits a number of cytokines that are pro-inflammatory or have a role in Pruritus is the most common clinical sign of many canine allergic responses, including pruritus.3,6 Results from allergic skin diseases, including flea allergy dermatitis, field efficacy studies have demonstrated the efficacy, atopic dermatitis (AD), food allergy and, rarely, contact speed of onset and safety of oclacitinib in the control/ allergy.1 Glucocorticoids are often used to provide relief treatment of pruritus associated with allergic dermatitis of pruritus because they are highly effective and have a and atopic dermatitis.7–9 No results have been pub- rapid speed of onset; however, short-term and chronic lished illustrating field efficacy and safety of oclacitinib adverse events are common.2 compared with other registered treatments, including Oclacitinib (Apoquelâ; Zoetis Inc., Florham Park, NJ, USA) selectively inhibits key pathways involved in itch In spite of the widespread usage of oral glucocorticoids and inflammation associated with allergies in dogs.3 It to treat pruritus and skin lesions of dogs with allergic is approved for the control/treatment of pruritus associ- dermatitis, there are no published studies reporting the ated with allergic dermatitis and the control/treatment efficacy of glucocorticoids in dogs suffering from pre-sumptive allergic dermatitis (not limited to atopic dermati-tis). The dosage regimen and treatment duration ofglucocorticoids used clinically in allergic dermatitides is Accepted 4 June 2014 variable. The International Task Force on Canine Atopic Sources of Funding: This study was initiated and funded by Dermatitis recommends prednisolone be dosed at Pfizer Animal Health, New York, NY, USA.
0.5 mg/kg once or twice daily until clinical remission Conflict of Interest: All authors are current employees of ZoetisInc. (formerly Pfizer Animal Health).
occurs in cases of acute episodes of atopic dermatitis.10 2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Prednisolone and oclacitinib for pruritus The aim of this study was to evaluate the efficacy and Randomization and blinding safety of oclacitinib compared with prednisolone for the Dogs were randomized to one of the two treatment groups, oclaciti- control of pruritus and clinical signs associated with aller- nib or prednisolone, in a 1:1 ratio. Blocking and randomization were gic dermatitis in client-owned dogs.
based on order of enrolment within clinic, and the individual dog wasthe experimental unit.
At each study site, an unblinded treatment dispenser was respon- Materials and methods sible for dispensing the appropriate treatment to the owner, labelledas Treatment A for prednisolone and Treatment B for oclacitinib.
The materials and methods used for this study were largely identical Upon each dog's enrolment in the study on day 0, the treatment dis- to those described previously.8 penser allocated the dog to the appropriate group according to thesite randomization list. Treatment dispensers and dog owners were instructed not to discuss the description, administration or dosing This study was conducted as a single-masked, positively predniso- regimen with the examining veterinarian at any clinic visits. Owners lone-controlled clinical trial, with a randomized complete block were not aware of treatment group assignment and drug name.
design. The study design was replicated at 12 veterinary clinics in Investigators as well as laboratory staff conducting blood and urine three states of Australia (Queensland, New South Wales and Victo- tests were blinded to treatment group assignment. As owners could ria). All participating veterinarians were general practitioners with an potentially unmask themselves by finding out the treatment group interest in dermatology.
based on the different dosing regimen, the study was considered tobe a single-masked study.
OverviewPrior to initiation, the study protocol was approved by the Director Drug administration General's Animal Care and Ethics Committee, New South Wales Dogs were given oclacitinib tablets orally at a dose of 0.4–0.6 mg/kg Department of Primary Industries. The study was conducted in com- twice daily (as close to a 12 h interval as possible) for 14 days, fol- pliance with national animal welfare regulations relating to the care lowed by the same dose once daily until the conclusion of the study.
and use of animals for scientific purposes and the international stan- Dogs in the other treatment group were given prednisolone 5 mg dards of good clinical practice.11 Written informed consent was tablets (Delta-Cortef Corticosteroid Tablets for Dogs; Zoetis, Sydney, obtained from the owner of each dog.
NSW, Australia) orally at a dose of 0.5–1.0 mg/kg once daily (in themorning if possible) for 6  1 days, followed by the same dose every Inclusion criteria other day until the conclusion of the study. The first dose was admin-istered by the dispenser or dog owner at the clinic; owners were All dogs were client-owned, 12 months of age or older and in over- instructed to give the second dose (for dogs in the oclacitinib group) all good health based on the initial physical examination (day 0).
that evening before going to bed, regardless of the time of day of the Dogs were assessed by their owners as having moderate to first clinic visit. Owners administered both test treatments with or severe itching (pruritus), using a categorical scale.12 A presumptive without food.
diagnosis of allergic dermatitis was established based on the dog'shistory and clinical signs. Veterinarians attributed the dog's pruriticcondition to one or more of the following presumptive diagnoses: Study schedule and variables measured AD, flea allergy dermatitis, food allergy dermatitis or contact der- Following enrolment on day 0, clinic visits for physical examination matitis. Appropriate ectoparasite treatment was implemented and assessment of pruritus and dermatitis were scheduled on days where evidence of ectoparasite infestation was confirmed or sus- 6  1, 14  2 and 28  2. Dogs were withdrawn from the study at pected. All dogs were maintained on appropriate flea prevention study visits on day 6 or 14 if the veterinarian felt that the dog's pruri- for the duration of the study.
tus and/or dermatitis required treatment with a prohibited medication Dogs with other conditions that required concomitant treatment or if there was no improvement in pruritus and/or dermatitis could be enrolled if the treatment remained the same for at least the observed. Additionally, owners were free to withdraw their dog at 6 weeks prior to the study and no change in medication was antici- any point during the study for any reason, such as perceived lack of pated during the study. Dogs that were receiving a hypoallergenic efficacy or intolerable adverse effects.
diet to manage previously diagnosed adverse food reactions had to Owners performed a pruritus visual analog scale (VAS) assessment have been on that diet for at least 6 weeks prior to day 0 and must twice on day 0 (pre-enrolment and 4  2 h following the first treat- have remained on the same diet during the study. Intradermal aller- ment), then on days 1, 6  1, 14  2 and 28  2 (or the final study gen tests had to have been conducted at least 8 weeks prior to the day if the dog was withdrawn early). Veterinarians performed a derma- start of the study. Concomitant allergen-specific immunotherapy had titis VAS assessment on day 0 and at subsequent clinic visits.8 On the to have been ongoing for at least 6 months prior to enrolment, and final day of study (day 28  2), or earlier if the dog was withdrawn the protocol had to be maintained throughout the study. If allergen- from the study, owners and veterinarians assessed the dog's specific immunotherapy was stopped, it had to have been stopped at response to treatment (RTT). Improvement was assessed using a least 8 weeks prior to enrolment.
10 cm VAS line with a descriptor on one end of the line for ‘noimprovement' and a descriptor on the other end of the line for ‘excel- Exclusion criteria lent results'. Owners and veterinarians were instructed to place a markon the VAS line at the location that best represented the effect of treat- Exclusion criteria included the following: dogs with evidence of ment on the dog's skin condition. At the end of the study, the distance malignant neoplasia, severe infections, demodicosis, scabies or (in centimetres) from the ‘no improvement' descriptor to the owner's immune suppression, such as hyperadrenocorticism; dogs that or veterinarian's mark on the line was measured and recorded.
were receiving or should have been receiving antimicrobial/fungal Blood and urine samples (for complete blood count and serum therapy for bacterial folliculitis or fungal dermatitis; and lactating chemistry to investigate liver and renal function and urinalysis) were bitches or dogs (male or female) intended for use as breeding ani- collected, if possible, on day 0 (prior to dosing) and day 28  2 (or the final study day if before day 28  2). All samples were sent toone veterinary diagnostic laboratory (Gribbles Veterinary Pathology, Prohibited and conditionally allowed medications Clayton, Victoria, Australia) for analysis.
and therapiesSystemic and topical antibacterial and antifungal treatment were pro- Efficacy outcome measures hibited at enrolment, but were allowed to commence from day 6 To be included in the efficacy analyses, dogs must have been in the study until at least day 6  1. In addition, they must have received a 2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
Gadeyne et al.
minimum of 80% of their intended doses prior to each assessment, Table 1. Baseline characteristics of 123 enrolled dogs as recorded in a daily log completed by the owner. Data were analy- sed using SAS version 9.2 (SAS Institute, Cary, NC, USA). The level of significance was set at P < 0.05 (two-sided).
The primary efficacy variable was defined as the percentage Breed distribution reduction of owner-assessed pruritus from baseline at day 14 and was used to calculate sample size. Forty-eight animals per treatment group were necessary to detect a difference of 15% change from baseline in Owner Pruritus VAS at one time point using an a of 0.05 (two-sided) and power of 80%.
Additional efficacy variables assessed were as follows: (1) Owner Pruritus VAS score at each assessment time; (ii) percentage change 13.1 (4.0–34.6) 16.2 (3.0–49.4) from baseline in pruritus score at each assessment time; (iii) dogs achieving a reduction of ≥50% compared with baseline in Owner Pruritus VAS scores at each assessment time; (iv) Veterinarian Der-matitis VAS score at each clinic visit; (v) percentage change frombaseline in dermatitis score at each clinic visit; (vi) owner VAS score Table 2. Presumptive diagnoses of 123 dogs at enrolment for overall RTT; and (vii) veterinarian VAS score for overall RTT.
The Owner Pruritus VAS score, Veterinarian Dermatitis VAS score, percentage change from baseline in pruritus and percentage Presumptive diagnosis* change from baseline in dermatitis were each analysed with a gen- Atopic dermatitis eral linear mixed model for repeated measures. The model included Contact dermatitis the fixed effects of treatment, time point and treatment by time point Flea allergy dermatitis interaction, and the random effects of clinic, block within clinic, clinic Food allergy dermatitis by treatment interaction, treatment by block within clinic interactionand clinic by treatment by time point interaction. Contrasts were *Each dog may have had more than one presumptive diagnosis for used to compare treatments at each time point. Treatment least- the pruritus.
squares (LS) means, standard errors, 95% confidence intervals andminimums and maximums were calculated for each time point.
Achievement of a reduction of ≥50% in pruritus score was analy- diagnosis of atopic dermatitis, but only 26% had atopic sed using a generalized linear mixed model for repeated measures dermatitis as a sole diagnosis. Contact dermatitis was with a logit link function and binomial distribution. The terms in the presumed to be the cause of the allergic dermatitis in model and comparisons were the same as those for the continuous 45% of dogs and flea allergy dermatitis in 37% of dogs.
repeated measures variables. The treatment LS means, standard A total of 21% of dogs were presumed to have food errors and 95% confidence intervals were transformed to a propor- allergy dermatitis.
tion scale. Assessment of overall response by the owner and veteri-narian was analysed with a general linear mixed model, including thefixed effect of treatment and the random effects of clinic, block Assessment of efficacy within clinic and treatment by clinic interaction. Treatment LS means, Of the 123 enrolled animals, 61 dogs were randomized to standard errors, 95% confidence intervals and minimums and oclacitinib and 62 to prednisolone treatment. A total of maximums were calculated. For all efficacy outcome measures, two seven prednisolone-treated and five oclacitinib-treated different data sets were analysed, namely ‘per protocol' and ‘inten- dogs were withdrawn prior to day 28. Among the pred- tion to treat'.
nisolone-treated group, in addition to being withdrawndue to owner noncompliance (n = 3), dogs were with- Safety outcome measures drawn for worsening of clinical signs (n = 2) or abnormal All dogs that were administered at least one dose of test drug were clinical pathological data (n = 2). All five oclacitinib-treated included in the safety analysis. For each continuous haematology andserum chemistry measure, summary statistics (mean, median, stan- dogs were withdrawn for owner noncompliance (being dard deviation, minimum and maximum) were calculated by treat- late for scheduled clinic visits). The data sets to assess ment and time point. Frequencies of dogs reported to show at least efficacy were different at each time point owing to errors one abnormal health event were displayed by clinical sign for all in compliance with the trial and data collection protocols.
unique terms.
Owner Pruritus VAS Pruritus scores (listed as LS means in Table 3) decreasedrapidly in both treatment groups by 4 h post-treatment on day 0, with a 28.1% reduction in the prednisolone group A total of 123 dogs were enrolled (Table 1). A total of and a 31.1% reduction in the oclacitinib group. In the ocla- 40.7% of dogs were purebred, with the Maltese (14.6%), citinib group, the peak percentage reduction from base- Staffordshire bull terrier (7.3%), Jack Russell terrier line occurred on day 14, when it reached 67.5%, which (6.5%) and West Highland white terrier (4.9%) being the coincided with the conclusion of twice-daily dosing in this most frequently represented breeds. Greater than 90% treatment group; thereafter, the percentage reduction of dogs in both treatment groups were neutered.
from baseline reduced to 52.5% by day 28. The reductionin Owner Pruritus VAS scores peaked for the predniso- Presumptive diagnoses lone group on day 6 at 60.3%, coinciding with the conclu- The presumptive diagnoses for dogs enrolled in the study sion of once-daily dosing; thereafter, the percentage are shown in Table 2. Veterinarians attributed the dog's reduction from baseline decreased to 52.2% on day 14 pruritic condition to one or more possible cause of allergic and 55.0% on day 28. A significant difference between dermatitis. More than 97% of dogs had a presumptive the two treatment groups was observed only at day 14 2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
Prednisolone and oclacitinib for pruritus Table 3. Owner Pruritus VAS (least-squares means and confidence intervals; per protocol analyses) Percentage of dogs with ≥50% reduction 7.17 [6.71–7.64]‡ 7.31 [6.86–7.76] 5.32 [4.55–6.09] 28.1 [18.5–37.6] 4.96 [4.23–5.68] 31.1 [21.3–40.9] 4.24 [3.49–4.99] 43.1 [33.6–52.6] 4.22 [3.48–4.95] 41.3 [31.4–51.2] 2.91 [2.29–3.53] 60.3 [51.5–69.0] 3.24 [2.65–3.83] 54.7 [46.3–63.0] 3.45* [2.74–4.16] 52.2** [42.5–62.0] 2.33* [1.73–2.92] 67.5** [59.0–76.0] 3.30 [2.57–4.02] 55.0 [45.4–64.5] 3.33 [2.62–4.05] 52.5 [42.3–62.7] Abbreviations: LS, least squares; VAS, visual analog scale.
*P = 0.0087; **P = 0.0193; ***P = 0.0132.
†Values in curved brackets in this column are the numbers of animals included in least-squares means analysis for VAS scores (prednisolone/ocla-citinib).
‡Values in square brackets throughout the body of the table are 95% confidence intervals.
Table 4. Veterinarian Dermatitis VAS (least-squares means and confidence intervals; per protocol analyses) Percentage reduction from baseline Percentage reduction from baseline 4.89 [4.18–5.60]‡ 4.90 [4.18–5.62] 2.34 [1.70–2.97] 54.0 [43.3–64.7] 2.03 [1.39–2.66] 58.9 [49.7–68.0] 2.34* [1.71–2.97] 53.7** [43.9–63.5] 1.34* [0.71–1.97] 71.0** [59.6–82.4] 2.30 [1.64–2.96] 53.8 [42.3–65.2] 1.63 [0.97–2.29] 64.3 [54.6–74.1] *P = 0.0022; **P = 0.0252.
†Values in curved brackets in this column are the numbers of animals included in least-squares means analysis for VAS scores (prednisolone/ocla-citinib).
‡Values in square brackets throughout the body of the table are 95% confidence interval.
(P = 0.0193), when the LS mean difference in percentage 6.5 cm, respectively). In contrast, investigator RTT scores reduction between treatments was 15.3.
demonstrated that treatment with oclacitinib produced a On day 1, 40% of dogs in both treatment groups significantly (P = 0.0109) better least-squares mean RTT achieved a reduction of ≥50% from baseline in Owner score of 7.3 cm for the oclacitinib-treated dogs compared Pruritus VAS scores (Table 3). On day 14, 74% of the with 6.0 cm for the prednisolone-treated dogs.
oclacitinib-treated dogs and 47% of the prednisolone-treated dogs achieved a reduction of ≥50% from baseline Per protocol versus intention-to-treat analyses in Owner Pruritus VAS scores (P = 0.0132).
In the sections above, the results for the ‘per protocol'analyses are provided. No major differences between the Veterinarian Dermatitis VAS ‘per protocol' and ‘intention-to-treat' analyses were Investigator-assessed dermatitis scores were identical observed (see Tables S1 and S2 in Supporting informa- between treatment groups at the start of the study (Table 4). They decreased rapidly in both treatmentgroups by day 6, with a 54.0% reduction in the predniso- Abnormal health events lone group and a 58.9% reduction in the oclacitinib group.
Only one serious adverse event was reported during the The percentage reduction from baseline did not vary study in an animal treated with oclacitinib. The dog was a greatly thereafter for the prednisolone group, averaging 3.5-year-old cross-bred and had a cruciate ligament injury 53.7% on day 14 and 53.8% on day 28. In contrast, for on day 15, requiring treatment with a prohibited drug the oclacitinib group the percentage reduction from base- (nonsteroidal anti-inflammatory drug) and surgery. The line continued to increase to day 14, when it reached dog was not withdrawn from the study early; however, 71.0% (coinciding with the conclusion of twice-daily dos- subsequent time points (i.e. after day 14) were excluded ing in this treatment group). By day 28, the percentage from the efficacy analysis. The incidence of abnormal clin- reduction from baseline was 64.3%. Analysis of treat- ical signs was similar for both groups (see Table 5).
ment contrasts indicated a significant difference betweenthe two groups at day 14 (P = 0.0252), when the LS Clinical pathology mean difference in percentage reduction between the The most common change in biochemistry values in the prednisolone group and the oclacitinib group was 17.3.
prednisolone-treated dogs was elevation of alkaline phos-phatase, for which means increased to above the normal Response to treatment reference range. More animals in the prednisolone group There was no significant difference (P = 0.1665) in the (n = 8, 16%) had a shift to values above the reference owner-assessed response to treatment between oclaciti- range after treatment with prednisolone compared with nib and prednisolone at the end of the study (7.2 and oclacitinib-treated dogs (n = 2, 4.3%). Individual values 2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
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Table 5. Abnormal clinical signs, excluding pre-existing conditions* prednisolone was tapered after 6 days of treatment,while oclacitinib was not tapered until after 14 days, could explain the statistical differences in favour of ocla- [n = 62; n (%)]†,‡ [n = 61; n (%)]†‡ citinib on day 14. In keeping with a previous study, veteri-narians were asked to make only a presumptive diagnosis, with the possibility of identifying several causes at the same time.8 Although participating veteri- narians had an interest in dermatology and were thor- oughly trained to ensure that dogs suffering from pruritus with a nonallergic cause were not enrolled, a precise diag- nosis supported by further testing would have been bene- ficial. Establishing a precise diagnosis would probably have reduced the number of animals enrolled with con- tact dermatitis. The percentage of 45%, based on a pre- Pinnal irritation sumptive diagnosis, has to be considered too high and is *Observed in at least two dogs in one of the two treatment groups.
four times as high as reported recently when using a simi- †Numbers and percentages are given on a per animal basis.
lar study design.8 ‡Reported in decreasing order of frequency in the oclacitinib treat- In addition to assessing the antipruritic activity of the treatments by using a validated tool, the skin conditionwas assessed by a veterinarian-assessed dermatitis VAS, for alkaline phosphatase increased up to 25 times the as previously described.8,12 This scale has not been vali- upper reference range limit in prednisolone-treated ani- dated. It was felt that the assessment of skin using the mals, whereas values did not exceed 29 the upper limit Canine Atopic Dermatitis Extent and Severity Index (CAD- of the reference range in oclacitinib-treated dogs. Mean ESI) might be too time consuming for this study and, values for albumin increased to above the reference while this method is thoroughly validated, it is specifically range after prednisolone treatment (from 37.49 g/L at limited to atopic dermatitis.13 Not surprisingly, the results day 0 to 40.20 g/L at day 28; reference range, 24–38 g/ of the Clinician Dermatitis VAS scores mirror the findings L). Serum cholesterol levels increased in both treatment of the Owner Pruritus VAS scores.
groups, but levels remained within the reference range The 55% reduction from baseline in Owner Pruritus (from 6.36 and 5.73 mmol/L at day 0 to 7.59 and VAS on day 6 agrees well with results reported from a 6.41 mmol/L at day 28 for prednisolone- and oclacitinib- similar population (i.e. allergic dermatitis; presumptive diagnosis only);8 results for other days are identical 3.9–7.8 mmol/L). More animals in the prednisolone-trea- (day 14) or very similar (day 28) to reductions in pruritus ted group had a cholesterol value above the reference reported when treating with oclacitinib animals that had range at day 28 compared with day 0 (n = 11, 21.2% and been diagnosed with atopic dermatitis.7,9 n = 5, 8.9% for prednisolone- and oclacitinib-treated In a systematic review of the pharmacotherapy of dogs, respectively). There were no major changes from canine atopic dermatitis, the authors found three reports reference ranges in the results of the complete blood in which the trial design was of sufficient quality to pro- counts for all dogs.
vide evidence of the effectiveness of glucocorticoid ther-apy.14 The reported mean reduction in pruritus scores in Concurrent medications those studies ranged from 33 to 81%, as follows: 81% A wide variety of concomitant medications were used in with 0.5 mg prednisolone/kg once daily; with prednisone, both groups in similar numbers and percentages of dogs.
67% (0.5 mg/kg) or 58% (0.25 mg/kg) reduction when The following drug classes were administered to >2% of administered first twice daily followed by once daily and the oclacitinib-treated animals: ectoparasiticides (includ- then every other day; and 33% with methylprednisolone ing repellents), endectocides, canine vaccines, shampoos at 0.5–1.0 mg/kg once daily followed by every other day (medicated and nonmedicated), anthelmintics, antifun- dosing and tapered by clinical response.15–17 Different gals for the treatment of Malassezia infection, systemic final assessment times ranging from 4 to 16 weeks after antibacterials, anti-inflammatory products, otologicals and the start of treatment, as well as treatment of a different antiseptics/disinfectants. A variety of other medications population of animals (i.e. only atopic dogs) complicate were administered in <2% of animals, including analge- the comparison of the results reported here with the sics, anaesthetics, antimycotics for systemic use, oph- results of any of these previously published studies. In thalmologicals, skin emollients and skin protectants, general, however, it seems that the reductions in pruritus vitamins and psychoanaleptics. No untoward effects scores reported here for prednisolone of 60% (day 6), resulting from the administration of concomitant medica- 52% (day 14) and 55% (day 28) are within the range of tions were observed during the study.
reductions reported in previous studies.
A 50% reduction of pruritus scores from baseline rep- resents a clinically relevant threshold above which own- ers are satisfied with treatment.18 This percentage has The findings of the study demonstrated that oclacitinib been used subsequently as a standard for assessing the reduces pruritus in dogs suffering from allergic dermatitis efficacy of treatments for pruritus.14,19,20 By this mea- as well as does prednisolone. The fact that the dose of sure, both of the treatments used in the study reported 2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
Prednisolone and oclacitinib for pruritus here were effective; by day 28, >50% of dogs in both 3. Gonzales AJ, Bowman JW, Fici GJ et al. Oclacitinib (APO- treatment groups achieved a reduction of ≥50% in Owner QUELâ) is a novel Janus kinase inhibitor with activity against Pruritus VAS scores.
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Speed of onset is a crucial element in the treatment of 4. EMA. Press release: CVMP summary of positive opinion for pruritus associated with allergic dermatitis.21 The results Apoquel. Available at: of the study reported here, where prednisolone was ini- tially administered at a dose of 0.5–1 mg/kg, suggest a veterinary/002688/WC500146252.pdf. Accessed Jul 7, 2014.
comparable speed of onset between prednisolone and 5. FDA/CVM. Apoquel Freedom of Information summary. Available oclacitinib within 4 h of administration of the first dose.
The lack of significant difference in speed of onset ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM363901.pdf. 2013. Accessed Jul 4, 2014.
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in these different models.22 The laboratory studies used 7. Cosgrove S, Wren J, King V et al. A multicentre clinical trial to videotaping of the animals and counting the number of evaluate the efficacy and field safety of oclacitinib. Vet Dermatol minutes spent exhibiting pruritic behaviour, whereas this 2012; 23(Suppl 1): 38. (Abstract).
8. Cosgrove SB, Wren JA, Cleaver DM et al. Efficacy and safety of field study used an enhanced Owner VAS scale. It could oclacitinib for the control of pruritus and associated skin lesions be speculated that the objective measurement of min- in dogs with canine allergic dermatitis. Vet Dermatol 2013; 24: utes spent on pruritic behaviour is much more sensitive in detecting changes compared with the more subjective 9. Cosgrove SB, Wren JA, Cleaver DM et al. A blinded, random- Owner VAS scoring system.
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previously published reports.7–9,16 The most commonly 10. Olivry T, DeBoer DJ, Favrot C et al. Treatment of canine atopic observed abnormal health event in the oclacitinib-treated dermatitis: 2010 clinical practice guidelines from the Interna- animals was pyoderma. These cases were assessed as tional Task Force on Canine Atopic Dermatitis. Vet Dermatol mostly mild in nature by the masked veterinarian and 2010; 21: 233–248.
were treated with oral antibiotics or medicated sham- 11. Veterinary International Conference on Harmonization. Interna- poos. The incidence of pyoderma in both treatment tional co-operation on harmonisation of technical requirements groups is not surprising given that allergic dogs are prone for registration of veterinary medicinal products, Good ClinicalPractice. June 2000 effective 1 July 2001. Available at http:// to secondary skin infections;23 given that both predniso- lone and oclacitinib may increase susceptibility to infec- guideline/2009/10/WC500004343.pdf. Accessed Jun 2, 2014.
tions, a possible drug effect cannot be completely 12. Hill PB, Lau P, Rybnicek J. Development of an owner-assessed excluded in either treatment group.
scale to measure the severity of pruritus in dogs. Vet Dermatol In conclusion, this study provides evidence that oclaciti- 2007; 18: 301–308.
nib administered orally in the recommended dosing regi- 13. Olivry T, Marsella R, Iwasaki T et al. Validation of CADESI-03, a severity scale for clinical trials enrolling dogs with atopic dermati- men reduces pruritus and clinical signs associated with tis. Vet Dermatol 2007; 18: 78–86.
allergic dermatitis to a level comparable to the efficacy of 14. Olivry T, Mueller RS. Evidence-based veterinary dermatology: a prednisolone administered at a dose of 0.5–1.0 mg/kg systematic review of the pharmacotherapy of canine atopic der- daily for 6 days followed by the same dose every other matitis. Vet Dermatol 2003; 14: 121–146.
15. Ferrer L, Alberola J, Queralt M et al. Clinical anti-inflammatory efficacy of arofylline, a new selective phosphodiesterase-4 inhib-itor, in dogs with atopic dermatitis. Vet Rec 1999; 145: 191–194.
16. Olivry T, Rivierre C, Jackson HA et al. Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: a blinded The authors would like to thank the following veterinari- randomized prednisolone-controlled trial. Vet Dermatol 2002; 13: ans who participated in this study: Demian Bullock, Angela Steenholdt, Lindsey Thomas, Craig Stewart, Todd 17. Steffan J, Alexander D, Brovedani F et al. Comparison of cyclo- Browning, Mary McClean, Ross McGregor, Sarah Britton, sporine A with methylprednisolone for treatment of canine ato- James Ross, Lucy White, Anna Platt and Jenny Wilsher.
pic dermatitis: a parallel, blinded, randomized controlled trial. Vet The authors would also like to thank the following Zoetis Dermatol 2003; 14: 11–22.
18. Olivry T, Steffan J, Fisch RD et al. Randomized controlled trial of Inc. colleagues for their assistance: Sallie B. Cosgrove, the efficacy of cyclosporine in the treatment of atopic dermatitis Helen Power, Michele Rosenbaum and Candace A.
in dogs. J Am Vet Med Assoc 2002; 221: 370–377.
19. Olivry T, Bizikova P. A systematic review of randomized con- trolled trials for prevention or treatment of atopic dermatitis indogs: 2008–2011 update. Vet Dermatol 2013; 24: 97–117, e25– 20. Olivry T, Foster AP, Mueller RS et al. Interventions for atopic 1. Miller WH, Griffin CE, Campbell KL. Hypersensitivity disorders.
dermatitis in dogs: a systematic review of randomized controlled In: Muller and Kirk's Small Animal Dermatology, 7th edition. Phil- trials. Vet Dermatol 2010; 21: 4–22.
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21. Kircik LH. Efficacy and onset of action of hydrocortisone acetate 2. Miller WH, Griffin CE, Campbell KL. Dermatologic therapy. In: 2.5% and pramoxine hydrochloride 1% lotion for the manage- Muller and Kirk's Small Animal Dermatology, 7th edition. Phila- ment of pruritus: results of a pilot study. J Clin Aesthet Dermatol delphia, PA: W.B. Saunders Co., 2013;108–183.
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2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
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22. Fleck T, Humphrey W, Coscarelli E et al. Comparison of the Supporting Information janus kinase (JAK) inhibitor, oclacitinib, and prednisolone incanine models of pruritus. Vet Dermatol 2012; 23(Suppl 1): 38.
Additional Supporting Information may be found in the online version of this article.
23. Miller WH, Griffin CE, Campbell KL. Bacterial skin diseases. In: Table S1. Owner Pruritus VAS (least-squares means and Muller and Kirk's Small Animal Dermatology, 7th edition. Phila- confidence intervals; intention-to-treat analyses).
delphia, PA: W.B. Saunders Co., 2013; 184–222.
Table S2. Veterinarian Dermatitis VAS (least-squaresmeans and confidence intervals; intention-to-treat analy-ses).
Contexte – Les cortico€ıdes oraux sont largement utilis es pour diminuer le prurit et les l aux dermatites allergiques. Les donn erent que l'oclacitinib, un inhibiteur de Janus Kinase, est une alternative sure et efficace.
Hypoth eses/Objectifs – D eterminer l'efficacit e de l'oclacitinib en comparaison avec la pred- nisolone pour le contr ole du prurit associ e avec une dermatite allergique dans une  etude clinique contr en aveugle avec une structure compl Sujets – Des chiens de propri etaires (n = 123) avec un diagnostic de dermatite allergique et un prurit mod- ere a severe evalue par le proprietaire a l'inclusion.
M ethodes – Les chiens ont  es au traitement oclacitinib (0.4–0.6 mg/kg per os deux fois par jour pendant 14 jours, puis une fois par jour) ou prednisolone (0.5–1.0 mg/kg une fois par jour pendant 6jours, puis un jour sur deux) pendant 28 jours. Une  echelle visuelle analogue (VAS) a  e soumise aux pro- etaires afin d ‘ evaluer le prurit et aux v evaluer les dermatites  a tous les suivis de l' esultats – Les deux traitements ont permis une r eponse rapide en 4h. Les r eductions moyennes du prurit et des scores cliniques n' etaient pas significativement diff erents entre les traitements sauf au jour 14 puis etaient plus prononc ees pour l'oclacitinib que pour la prednisolone (P = 0.0193 pour les scores de prurit par les propri etaires; P = 0.0252 pour les scores cliniques des veterinaires). Les effets sec- etaient aussi fr equents dans les deux groupes.
Conclusions et importance clinique – Dans cette  etude, l'oclacitinib et la prednisolone permettent un ole du prurit rapide, s ur et efficace dans les dermatites allergiques avec une am elioration substantielle du prurit rapport ee par les propri etaires et des scores cliniques rapport on – los glucocorticoides orales son ampliamente utilizados para reducir el prurito y la inflamac- on asociada con la dermatitis al ergica. Los datos indican que oclacitinib, un inhibidor de la quinasa Janus, es una alternativa segura y eficaz.
Hip otesis/Objetivos – evaluar la eficacia y la seguridad de oclacitinib comparado con prednisolona para el control del prurito asociado con la dermatitis al ergica en una prueba clınica controlada y enmascarada, con no completo al azar en bloques.
Animales – se incluyeron perros de propietarios privados (n = 123) con un diagnostico presuntivo de der-matitis al ergica y prurito moderado a severo seg un estaba indicado por el propietario.
etodos – los perros se distribuyeron al azar para el tratamiento con oclacitinib (0,4-0,6 mg/kilo por vıa oral dos veces al dıa durante 14 dıas, y despu es una vez al dıa) o prednisolona (0,5-1 mg/kilo una vez al dıa dur- ante seis dıas, y despu es en dıas alternos) durante 28 dıas. Se utiliz o una escala mejorada visual por los pro- pietarios para evaluar el prurito y por los veterinarios para evaluar la dermatitis en todos los tiemposseleccionados.
Resultados – ambos tratamientos produjeron mejora r apida en cuatro horas. La reducci on media de los de los valores de prurito y dermatitis no fue significativamente diferente entre los tratamientos, con excepci del dıa 14, cuando la reducci as pronunciada para el oclacitinib que la prednisolona (P = 0,0193 para los valores de prurito evaluados por el propietario; y P = 0,0252 para los valores de dermatitis indicados porlos veterinarios). Se mencionaron efectos adversos con similar frecuencia en ambos grupos.
Conclusiones e importancia clınica – en este estudio tanto el oclacitinib como la prednisolona aportan uncontrol r apido, efectivo y seguro del prurito que se asocia con la dermatitis al ergica, con un una mejora su- stancial del prurito indicado por los propietarios, y de la dermatitis indicada por los veterinarios.
ZusammenfassungHintergrund – Glukokortikoide per os sind weitverbreitet im Einsatz, um Pruritus und Dermatitis, die durcheine allergische Dermatitis entstehen, zu reduzieren. Bisherige Daten weisen darauf hin, dass Oclacitinib,ein Janus Kinase Inhibitor, eine sichere und effektive Alternative darstellt.
Hypothese/Ziele – Eine Evaluierung der Wirksamkeit und Sicherheit von Oclacitinib im Vergleich zu Pred-nisolon zur Juckreizkontrolle im Zusammenhang mit allergischer Dermatitis in einer einseitig geblindeten,kontrollierten klinischen Studie mit einem randomisierten kompletten Block Design.
2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.
Prednisolone and oclacitinib for pruritus Tiere – Hunde von Kunden (n=123) mit der mutmaßlichen Diagnose einer allergischen Dermatitis und mod-eratem bis hochgradigem Juckreiz, der durch die teilnehmenden PatientenbesitzerInnen beurteilt wurde.
Methoden – Die Hunde wurden zuf€ allig eingeteilt, um entweder mit Oclacitinib (0,4-0,6mg/kg zweimal aglich per os 14 Tage lang, danach einmal t€ aglich) oder mit Prednisolon (0,5-1,0mg/kg einmal t€ Tage, dann jeden zweiten Tag) 28 Tage lang behandelt zu werden. Eine verst€ arkte Visuelle Analogskala (VAS) wurden von den BesitzerInnen verwendet, um den Juckreiz zu beurteilen und von den Tier€ um die Dermatitis zu allen untersuchten Zeitpunkten zu beurteilen.
Ergebnisse – Beide Behandlungen zeigten innerhalb von 4h einen raschen Wirkungseintritt. Die durch-schnittliche Abnahme des Pruritus und der Dermatitis Werte waren zwischen den Behandlungen nicht sig-nifikant verschieden außer am Tag 14, wo die Abnahme f€ ur Oclacitinib deutlicher als f€ ur Prednisolon war (P=0,0193 f€ur Pruritus Werte durch die BesitzerInnen; P=0,0252 f€ur Dermatitis Werte durch die Tier€arztIn-nen). Nebenwirkungen wurden in beiden Gruppen in einer € ahnlichen Frequenz festgestellt.
Schlussfolgerungen und klinische Bedeutung – In dieser Studie ergab die Verabreichung von sowohlOclacitinib als auch Prednisolon eine schnelle, wirksame und sichere Juckreizkontrolle bei Juckreiz, der mitallergischer Dermatitis auftrat, wobei eine deutliche Verbesserung des Juckreizes, beurteilt durch die Be-sitzerInnen und der Dermatitis, beschrieben von der Tier€ arztInnen, der Fall war.
2014 Zoetis Inc. Veterinary Dermatology published by John Wiley and sons on behalf of the ESVD and ACVD., 25, 512–e86.


Determination of metformin in mouse, rat, dog and human plasma samples by laser diode thermal desorption/atmospheric pressure chemical ionization tandem mass spectrometry

ARTICLE IN PRESS Journal of Pharmaceutical and Biomedical Analysis xxx (2010) xxx–xxx Contents lists available at Journal of Pharmaceutical and Biomedical Analysis Short communication Determination of metformin in mouse, rat, dog and human plasma samples bylaser diode thermal desorption/atmospheric pressure chemical ionizationtandem mass spectrometry John G. Swales , Richard Gallagher, Raimund M. Peter

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Primary Care Prescribing Hywel Dda Health Board Issued: August 2013 Document reference: 424A2013 Status of report This document has been prepared for the internal use of Hywel Dda Health Board as part of work performed in accordance with statutory functions, the Code of Audit Practice and the Statement of Responsibilities issued by the Auditor General for Wales.