Trial Design

MAMS
With new drugs being developed to shorten and improve the treatment of tuberculosis, it is necessary to evaluate a number of different combinations of new and existing drugs in clinical trials. The Multi-Arm Multi-Stage (MAMS) design allows for several different treatment regimens to be evaluated against the standard regimen for TB in a single trial. At planned intervals during the trial, interim analyses are conducted and poorly performing regimens can be dropped using decisions rules that are pre-specified in the protocol. In this way poor regimens are dropped early in the trial and only those that perform better than pre-specified thresholds are continued for evaluation against the common control. With a MAMS design, multiple regimens can be evaluated simultaneously using smaller patient numbers and fewer resources allowing for shorter, safer and more effective regimens to move sooner into clinical practice. Fuller discussion of innovative trials designs, including the MAMS design, can be found in the paper authored by partners in the PanACEA consortium: Innovative trial designs are practical solutions for improving the treatment of tuberculosis. Phillips PP, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, Pletschette M, Lienhardt C, Hafner R, Mgone C, Zumla A, Nunn AJ, Hoelscher M. Journal of Infectious Diseases, 2012; 205 Suppl 2: S250-7.

MAMS

With new drugs being developed to shorten and improve the treatment of tuberculosis, it is necessary to evaluate a number of different combinations of new and existing drugs in clinical trials. The Multi-Arm Multi-Stage (MAMS) design allows for several different treatment regimens to be evaluated against the standard regimen for TB in a single trial. At planned intervals during the trial, interim analyses are conducted and poorly performing regimens can be dropped using decisions rules that are pre-specified in the protocol. In this way poor regimens are dropped early in the trial and only those that perform better than pre-specified thresholds are continued for evaluation against the common control.

With a MAMS design, multiple regimens can be evaluated simultaneously using smaller patient numbers and fewer resources allowing for shorter, safer and more effective regimens to move sooner into clinical practice.

Fuller discussion of innovative trials designs, including the MAMS design, can be found in the paper authored by partners in the PanACEA consortium:
Innovative trial designs are practical solutions for improving the treatment of tuberculosis. Phillips PP, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, Pletschette M, Lienhardt C, Hafner R, Mgone C, Zumla A, Nunn AJ, Hoelscher M. Journal of Infectious Diseases, 2012; 205 Suppl 2: S250-7.

14 + 14
Classical phase IIA, first in patient studies for TB drugs used a 14-day design in monotherapy, and measured decline of sputum bacterial load over this time (“extended early bactericidal activity”, EBA). These studies are similar to a Phase IB multiple dose study performed in patients and can provide information of the treatment efficacy in patients. Due to the short study duration, monotherapy is possible and patients can be closely monitored to identify safety signals. One drawback is that compounds with a delayed onset of action may be misclassified as being inactive. We will update this approach by introducing the 14+14 phase IIA SMART (Sequential, Multiple Assignment, Randomized Trial) design, which addresses the shortcomings of this study type and will generate much-needed information on combination regimens for the drug development within the confines of a single study. This will allow faster progression through the drug development pathway.

14 + 14

Classical phase IIA, first in patient studies for TB drugs used a 14-day design in monotherapy, and measured decline of sputum bacterial load over this time (“extended early bactericidal activity”, EBA). These studies are similar to a Phase IB multiple dose study performed in patients and can provide information of the treatment efficacy in patients. Due to the short study duration, monotherapy is possible and patients can be closely monitored to identify safety signals. One drawback is that compounds with a delayed onset of action may be misclassified as being inactive. We will update this approach by introducing the 14+14 phase IIA SMART (Sequential, Multiple Assignment, Randomized Trial) design, which addresses the shortcomings of this study type and will generate much-needed information on combination regimens for the drug development within the confines of a single study. This will allow faster progression through the drug development pathway.

STEP
A major barrier to identifying improved regimens for the treatment of TB is identifying which regimens should be evaluated in large, expensive, confirmatory phase III trials. In the last 18 months, we have seen three different 4-month regimens fail in large phase III trials at great expense. There are a number of new and repurposed drugs that might contribute to improving the treatment of TB, alongside a better understanding of the current dosages of standard drugs. Thus, here are a large number of possible combination regimens that could be evaluated in phase III. Furthermore, there is increasing evidence that culture conversion during treatment, however measured, has only a limited role in decision-making for advancing regimens into phase III trials. To address this, we have developed the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) trial design to bridge the gap between phase II and phase III clinical trials. With this further innovation, we are building on our previous adaptation of the Multi-Arm Multi-Stage (MAMS) trial design from oncology to TB that we implemented in our PanACEA MAMS-TB trial. We showed that the MAMS design is feasible in a multi-centre high burden setting, where recruitment to poorly performing arms can be stopped early based on pre-specified thresholds, thereby re-focusing resources on the most promising regimens.

STEP

A major barrier to identifying improved regimens for the treatment of TB is identifying which regimens should be evaluated in large, expensive, confirmatory phase III trials. In the last 18 months, we have seen three different 4-month regimens fail in large phase III trials at great expense. There are a number of new and repurposed drugs that might contribute to improving the treatment of TB, alongside a better understanding of the current dosages of standard drugs. Thus, here are a large number of possible combination regimens that could be evaluated in phase III. Furthermore, there is increasing evidence that culture conversion during treatment, however measured, has only a limited role in decision-making for advancing regimens into phase III trials.
To address this, we have developed the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) trial design to bridge the gap between phase II and phase III clinical trials. With this further innovation, we are building on our previous adaptation of the Multi-Arm Multi-Stage (MAMS) trial design from oncology to TB that we implemented in our PanACEA MAMS-TB trial. We showed that the MAMS design is feasible in a multi-centre high burden setting, where recruitment to poorly performing arms can be stopped early based on pre-specified thresholds, thereby re-focusing resources on the most promising regimens.