MAMS-TB trial stops recruiting patients to two arms
10 March 2014
The MAMS-TB trial, being conducted by the PanACEA consortium is stopping recruiting patients to two of its arms. This follows a meeting of the Independent Data Monitoring Committee (IDMC) which looked at interim analyses. The IDMC recommended that the arms testing the HRZQ and HR20ZQ combinations of drugs should be closed, as the interim results were not promising enough. These two arms include the drug SQ109 instead of ethambutol in the standard 6-month combination with rifampicin given at the higher dose of 20mg/kg in the HR20ZQ arm. Patients are still being recruited to the other three arms of the trial.
The MAMS-TB trial aims to identify combinations of drugs that could shorten tuberculosis (TB) treatment. Standard TB treatment currently lasts around 6 months. The MAMS-TB trial is comparing 4 new combinations of drugs with the standard 6-month combination. It uses the innovating multi-arm, multi-stage approach, which allows several treatments to be assessed against a single control arm. Those that are not sufficiently promising can be dropped after interim analyses. This allows resources to be focused on those treatments that are most likely to be an improvement compared to the current standard treatment.
The role of the IDMC in a MAMS trial is to look at interim analyses, and see if there is sufficient evidence that a new treatment is beneficial to make it worth continuing to investigate it. They also play an important role in making sure the trial is safe, and can recommend stopping a trial (or some of the arms of a trial) if there are signs that too many patients are experiencing serious unexpected side-effects. In this particular case, the IDMC found that there was not enough evidence that the HRZQ and HR20ZQ arms would be able to successfully shorten TB treatment, as they did not improve the speed at which TB bacteria were eliminated from sputum samples from patients compared to standard treatment. There was no evidence that they were worse than the standard treatment, and there were no safety concerns, but the decision was made to stop recruitment to these two arms as there was not enough evidence to suggest that either of these two combinations would be an improvement over standard therapy. Patients already enrolled on those arms will continue their treatment and follow-up as planned.
New patients will still be recruited to the control (standard treatment) arm and the other two intervention arms (HR35ZE and HR20ZM), as there was evidence that the HR35ZE and HR20ZM combinations may be able to successfully shorten TB treatment. These two arms include rifampicin given at the higher doses of 35mg/kg (HR35ZE) or 20mg/kg with moxifloxacin instead of ethambutol in the HR20ZM arm.
Patrick Phillips, Senior Statistician at the MRC Clinical Trials Unit at UCL said: “The closure of the HRZQ and HR20ZQ arms of MAMS-TB illustrates the strengths of the MAMS design. Normally the IDMC would not have recommended stopping these arms as there was no evidence that they are worse than the standard treatment. The pre-specified stopping guidelines allow us to stop these arms early, saving resources and limiting the number of patients allocated to arms that are unlikely to result in improved treatments.”
The MAMS-TB trial is being carried out by the PanACEA consortium (Pan African Consortium for the Evaluation of Anti-tuberculosis agents), and is taking place in Tanzania and South Africa. PanACEA is a partnership of 11 African and 7 European institutions. Chief Investigators are 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). The MAMS phase IIb trial started in May 2013. For more information on the study please see: ClinicalTrials.gov - Identifier: NCT01785186.
UCL is a major partner in the PanACEA consortium. The MRC Clinical Trials Unit at UCL carried out the data analysis that informed the IDMC decision and the UCL Centre for Clinical Microbiology provided the laboratory expertise.