The first ever randomised controlled trial with a multi-arm multi-stage (MAMS) trial design in infectious diseases was conducted in South Africa and Tanzania. The results of the PanACEA MAMS-TB trial were published this week in The Lancet Infectious Diseases.
Tuberculosis (TB) is the leading infectious disease killer, with a long treatment time of 6 months using a combination of drugs. There is an urgent need to find shorter and safer treatment plans so that patients can recover quickly.
The PanACEA MAMS-TB trial looked at the potential for TB treatment doses to be increased in order to reduce the overall treatment time. It also looked at new combinations of drugs that could be used to treat tuberculosis.
365 adults who hadn't previously had TB treatment were randomised and took part in the trial in Tanzania and South Africa. This included some people with HIV as well as TB, if their CD4 white blood cell count was more than 200 cells/mm3, so that they would be better able to fight the infection. The trial compared four new potential treatment plans with the current standard treatment. These consisted of:
- Rifampicin 35mg/kg, isoniazid, pyrazinamide, ethambutol
- Rifampicin at standard dose (10mg/kg), isoniazid, pyrazinamide, SQ109 300mg
- Rifampicin 20mg/kg, isoniazid, pyrazinamide, SQ109 300mg
- Rifampicin 20mg/kg, isoniazid, pyrazinamide, moxifloxacin 400mg
as well as the standard treatment which consisted of rifampicin at the standard dose of 10mg/kg, isoniazid, pyrazinamide, ethambutol for eight weeks, followed by 18 weeks of rifampicin and isoniazid. The primary outcome was how quickly tuberculosis bacilli were no longer detectable in a patients' sputum within 12 weeks.
The results showed that a dose of 35mg/kg rifampicin resulted in faster killing of tuberculosis bacilli and was safe, showing the potential for a shorter treatment plan for TB in the future. The current treatment uses a lower dose of rifampicin for a longer period of time, so by using a higher dose over a shorter timeframe, it could help to eliminate the disease more quickly at a lower cost. This evidence will be crucial to look back on when deciding how to progress into the next phase of trials.
In order to allow readers to better understand the results of the trial, we have posted interactive graphs.
This is the first randomised controlled trial using a MAMS design for an infectious disease, showing that the design is possible in a high risk TB setting. The MAMS trial design looks at several treatment plans compared to the current standard of care within one trial. Recruitment to these different treatment arms can be stopped if the pre-specified effects are not met; saving time, resource and the risk of exposing patients to ineffective treatments. This is just one of the advantages of the MAMS design, as potential new treatments can be discovered quicker and at a lower cost when tested at the same time.
The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), the Medical Research Council UK (MRC). The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) is a network consisting of European and African research organisations in partnership with pharmaceutical companies with the aim of shortening treatment for drug-sensitive TB and building capacity to conduct clinical trials in Sub-Saharan Africa. MRC CTU at UCL leads on statistics and trial design in the consortium.