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Edctp.org

TB treatment
Multi-arm multi-stage trial to identify
regimens to include in a phase III trial for
shorter treatment of tuberculosis
The PanACEA consortium aims to
control. A number of interim analyses are The remaining 4 studies that were initially performed during the study to identify shorten TB treatment and consists of
planned in the original PanACEA proposal ineffective experimental interventions three individual Drug Development
at an early stage. In summary, this trial HIGHRIF-3 (n=600, 200 per arm)
methodology enables an efficient evaluation Programs with SQ109, moxifloxacin
A two months follow-up Phase IIb study to of multiple experimental treatment arms determine whether high dose rifampicin within one study in order to eliminate and high dose rifampicin.
(doses based on study 1 and study 2) in inefficient treatment arms at an early stage. Because adding one single new drug
combination with the other standard TB drugs is safe and tolerable and associated In this trial, we combine and streamline our may not be sufficient to significantly
with improved response (proof of principle), so far independent activities and test the before advancing to a pivotal Phase III study.
initially proposed combinations using one shorten TB treatment, investigation
adaptive Multi-Arm Multi-Stage (MAMS) of combination regimens may be
design. In this MAMS study, the treatment A pharmacokinetic interaction study to regimens will be the following: more efficient. In our Multi-Arm
assess the extent of the pharmacokinetic interaction between rifampicin and Multi-Stage (MAMS) trial several
rifampicin standard experimental regimens will be
(R), pyrazinamide (Z), SQ109-2 (n=150, 50 per arm)
simultaneously evaluated against
A Phase 2a, dose-ranging study to assess isoniazid, rifampicin 35 safety, tolerability, and efficacy of isoniazid, mg/kg, pyrazinamide, a control. Interim analyses will be
rifampicin, pyrazinamide, and SQ109 performed to assess whether the
(HRZSQ) for intensive-phase treatment of patients with uncomplicated, smear-positive rifampicin standard, hazard ratio for time to sputum
pulmonary tuberculosis caused by drug- pyrazinamide, SQ109 sensitive Mycobacterium tuberculosis.
culture conversion to negative,
Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 comparing an experimental regimen
SQ109-3 (n=400, 200 per arm)
mg/kg, pyrazinamide, A phase 2b, double-blind comparison of to the control, is less than a pre-
isoniazid, rifampicin, pyrazinamide, and Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 SQ109 (HRZSQ) and isoniazid, rifampicin, mg/kg, pyrazinamide, specified critical value. Ineffective
pyrazinamide, and ethambutol (HRZE) moxifloxacin 400mg experimental regimens will thus
intensive-phase DOTS regimen for treatment of patients with uncomplicated, be identified early and no more
smear-positive pulmonary tuberculosis The general objective is to identify arms caused by drug-sensitive Mycobacterium which are significantly more efficient than participants will be randomized to
the control regimen in terms of reducing this experimental treatment.
bacterial load in sputum, measured by time From the original PanACEA proposals for to culture conversion.
Three dosages of rifampicin and
HIGHRIF and SQ109 the remaining four trials (see section 2.4) will be combined into Secondary objectives are: one dosage of SQ109 will be studied
a single study with an adaptive Multi-Arm • To assess the relative efficacy of the alone and in combination. A
Multi-Stage design (MAMS). In this MAMS experimental four-drug combinations for trial, several experimental interventions are the treatment of pulmonary tuberculosis regimen with moxifloxacin will also
tested simultaneously against a common within the first twelve weeks of treatment, be included.
Martin Boeree/Michael Hoelscher
Martin Boeree/Michael Hoelscher
and select the most efficient experimental Relevance to EDCTP's objectives
Project at a glance
treatment regimen for further and mission
Tuberculosis has been declared a public • To assess the frequency of acquired drug health emergency. The effect of the global Multi-arm multi-stage trial to identify resistance among the experimental four- pandemic is most severe in sub-Saharan regimens to include in a phase III trial for drug combinations Africa, where the pernicious interaction with shorter treatment of tuberculosis • To assess the frequency, severity, and HIV has resulted in a massive increase in type of adverse events (AEs), AE-related the number of cases across the continent. If treatment discontinuations, and changes we are to control this health emergency, new PanACEA-MAMS-TB-01 study tools will be required, and central among • To describe the steady-state these new tools are superior treatment pharmacokinetics of the experimental Martin Boeree, Radboud University new drugs and/or doses used in Nijmegen Medical Centre , Netherlands/ the experimental regimens and to There have been no significant Michael Hoelscher, Klinikum of the assess possible relationships between improvements to tuberculosis treatment University of Munich, Germany pharmacokinetic parameters of the regimens in the last 35 years, when pyrazinamide was introduced into therapy • To describe relationships between allowing the duration of therapy to be • Stephen Gillespie, United Kingdom pharmacokinetic parameters and reduced from nine to six months. • Robert Aarnoutse, Netherlands pharmacodynamic indices on the one • Gibson Kibiki, Tanzania hand and efficacy and safety endpoints on In this PanACEA-MAMS-TB-01 trial, different • Andreas Diacon, South Africa the other hand.
treatment regimens are investigated for • Jeannine du Bois, South Africa their effectiveness in a TB treatment with • Rodney Dawson, South Africa Expected research outcomes
a conventional duration and a shorter • Gavin Churchyard, South Africa As in the original proposal of the year 2008, • Nomagugu Ndlovu, South Africa which consisted of 3 independent studies, • Salim Abdulla, Tanzania the overarching hypothesis for the studies If one treatment regimen would be • Alphonse Okwera, Uganda is to investigate several combinations of more effective than the current standard • Leonard Maboko, Tanzania anti-tuberculosis drugs within the PanACEA treatment and/or the duration of therapy • Nyanda Elias Ntinginya, Tanzania consortium in order to show a better can be shortened, this would have • Timothy McHugh, United Kingdom response in its potential to shorten the enormous implications for public health. • Andrew Nunn, United Kingdom duration of TB treatment and to have a Successful completion of the trials to • Patrick Philips, United Kingdom good safety profile.
regulatory standards will help ensure • Dick van Scoolingen, Netherlands Africa's ability to successfully evaluate and • Gary Horwith, United States The original hypotheses will still be tested: register future improvements in TB (and • Lisa Beth Ferstenberg, United States 1. SQ109 (Q) will synergize with rifampicin other disease) treatments of public health • Karla Mellet, South Africa (R) resulting in greater bactericidal importance through the conduct of high • Lilian Tina Minja, Tanzania activity (arms 2 and 3) quality clinical trials in the future.
2. Compared to the standard intensive Total budget
phase DOTS regimen of HRZE, SQ109, A key priority in the EDCTP Joint as a replacement for E (arm 2), will result Programme and the call text is to support in faster and/or greater clearance of M. studies that evaluate new drugs that may EDCTP budget
tuberculosis from sputum during the first simplify and shorten TB treatment. As all trials conducted within the PanACEA 3. In higher doses and/or in combination consortium, this PanACEA-MAMS-TB-01 Start date
with other new drugs (moxifloxacin (M) study focuses on the shortening and and SQ109), rifampicin will result in simplification of treatment. faster and/or greater clearance of M. tuberculosis from sputum during the first National, African, and International 8 weeks as compared to standard dose regulatory agencies will be approached to HRZE (arms 1, 3 and 4).
ensure that positive results from the study are integrated into policy change.
For more information
EDCTP The HagueT +31 70 344 0880/0897F +31 70 344 0899E [email protected] www.edctp.org

Source: http://www.edctp.org/uploads/tx_viprojects/MAMS_IP_TB_32011.pdf