Press release – Nijmegen, Netherlands / Munich, Germany February 26th 2015:
At the annual Conference on Retroviruses and Opportunistic Infections (CROI), PanACEA, the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics, presented the results of its most recent phase IIb study (MAMS-TB-01). The most exciting finding from the study is that high-dose rifampicin results in faster killing of TB bacilli during treatment, compared to the current standard treatment.
The standard WHO-recommended TB treatment regimen (2 months of daily ethambutol, isoniazid, rifampicin and pyrazinamide followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR)) involves taking the drugs daily for 6 months. This can make adherence to treatment hard, and has substantial costs to the health system and patients. Shortening the length of time treatment needs to be taken for, may help to reduce the burden on health systems, the costs of treatment, and make treatment easier for patients. PanACEA MAMS-TB-01 was set up to address this.
High-dose (35mg/kg) rifampicin, in combination with standard dose of isoniazid, pyrazinamide and ethambutol, showed a significant shortening of time to culture conversion with a covariate-adjusted hazard ratio of 1.75, 95% confidence interval (1.21-2.55) over the 12 weeks of experimental treatment. For comparison to previous TB trials, covariate-adjusted hazard ratios compared to control over 8 weeks were 1.99, 95% confidence interval (1.21-3.29). It was not possible to culture TB bacilli in sputum by 8 weeks in 56% of patients on the 35mg/kg arm compared to 42% of patients on the standard of care arm. These proportions were 80% and 70% respectively after 12 weeks.
Culture on solid media, which was a secondary endpoint, showed a similar although less marked result.
Chief Investigator Martin Boeree (Radboud University Nijmegen) says: “This is the largest reduction in time to culture conversion seen in any previous TB trial, to our knowledge. High doses of rifampicin may be an important component in shorter TB regimens in the future.”
The arm containing moxifloxacin with rifampicin 20mg/kg, pyrazinamide and ethambutol showed a borderline significance, hazard ratio 1.42 (95% confidence interval, 0.98-2.05) for improvement over control.
In an interim analysis conducted in early 2014, recruitment to both arms that included the new drug SQ109 were terminated, as it was clear that both regimens would not meet the predetermined hazard ratio of 1.8 using liquid culture and thus were unlikely to result in substantially improved regimen. Patients on these arms remained on treatment and in follow-up, and the now available data confirms the interim analysis decision.
Preliminary analysis of safety events showed no differences in side-effects in any of the arms as compared to control.
The MAMS-TB-01 trial enrolled 365 patients from 7 sites in Tanzania and South Africa in only 11 months. It used an innovative adaptive clinical trial design that allows several new regimens to be compared to the current standard, and incorporates interim analyses that allow for regimens that show little treatment shortening potential to be excluded from the trial at an early stage.
Data on treatment up to week 26 and post-treatment follow-up will be analyzed and reported together with the results mentioned above in the main publication.
“We would like to thank our main donor, the EDCTP, for its support of this African-European consortium,” said Michael Hoelscher, sponsor representative. “We are pleased to have optimized one potential component of a future treatment-shortening regimen. This is, however, only the beginning of a series of phase I and II studies that will evaluate in a systematic manner at least 5 novel and improved TB drugs.“
Link to CROI Webcast: http://www.croiwebcasts.org/console/player/25685?mediaType=slideVideo&