PanACEA, the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics aims to develop TB regimens that significantly shorten treatment duration, funded by EDCTP. The consortium’s most recent phase IIb study (MAMS-TB-01) uses an innovative adaptive clinical trial design that allows the efficient evaluation of multiple regimens by incorporating interim analyses that allow for the early exclusion of regimens that show little treatment shortening potential.
Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ. Patients that have already been enrolled into these arms will continue as laid out in the protocol.
The IDMC reviewed safety and efficacy data extensively including a number of sensitivity analyses and secondary efficacy endpoints. To-date the time at which patients have a negative culture is the best indication of future cure. Only treatment combinations that show a significant improvement in the speed at which they render patients culture negative are likely to shorten treatment. The predefined stopping rules of the MAMS trial were set to allow for early exclusion of regimens that were not likely to reach a hazard ratio of at least 1.8 at the end of the trial. This was based on the results from a study that evaluated a moxifloxacin substitution being studied in the ReMOXTB phase III trial that showed a hazard ratio of 1.68 (the OFLOTUB phase II trial). They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ; see below) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.
Since there were no indications of safety or inferiority concerns for SQ109, Sequella and partners will now undertake dose escalation and drug-drug interaction studies to see if a higher dose has potential to make a larger impact on sputum clearance. Analyses of intensive pharmacokinetics of SQ109 in combination with other drugs, especially rifampicin, will be used to determine the relationship between drug levels and bactericidal effects.
This result illustrates the strength of the MAMS approach, as normally the IDMC would not have recommended stopping these arms as there were no safety or inferiority concerns. The pre-specified stopping guidelines allowed the TSC the opportunity to stop these arms early, thereby saving resources and limiting the number of patients allocated to these regimens. This is an important consideration that reduces the number of patients enrolled in studies or arms that are unlikely to result in improved treatments and will speed the development of new TB medicines in the future.
The PanACEA consortium (http://panacea-tb.net/) is a partnership of 11 African and 7 European institutions and is led by three Chief Investigators at University of St. Andrews, Scotland (Prof. Stephen Gillespie), Radboud University Nijmegen / the Netherlands (Prof. Martin Boeree) and Ludwig Maximilians University, Munich / Germany (Prof. Michael Hoelscher). UCL is a major partner with the MRC-CTU at UCL and the Centre for Clinical Microbiology. The MAMS phase IIb trial started in May 2013 and aimed to enroll 372 patients into four intervention and the control arm.
|isoniazid, rifampicin standard, pyrazinamide, ethambutol
|Arm 1 (R35):
|isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol
|Arm 2 (Q):
|isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg
|Arm 3 (R20Q):
|isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg
|Arm 4 (R20M):
|isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg
For more information on the study please see: ClinicalTrials.gov – Identifier: NCT01785186