Background: Shorter regimens are urgently needed for the treatment of TB. The PanACEA MAMS-TB trial was conducted to evaluate whether 12-week combinations of high-dose rifampin, SQ109 and moxifloxacin with standard drugs reduced time to culture conversion on liquid media sufficiently to select for a phase III treatment-shortening trial.
Methods: Adult patients with drug-sensitive smear-positive TB were randomly allocated in the ratio 1:1:1:1:2 to be treated for 12 weeks of 1) Q: SQ109 together with standard dose rifampin (R), isoniazid (H) and pyrazinamide (Z), 2) 20RQ: SQ109 and 20 mg/kg R together with ZH, 3) 20RM: moxifloxacin and 20mg/kg R together with ZH, 4) 35R: 35mg/kg R together with ethambutol (E) and HZ, and a control arm for 8 weeks with standard RHZE. All patients then received standard RH to complete a total of 26 weeks of treatment, and were followed for treatment failure and relapse. The trial had a multi-arm multi-stage (MAMS) design with one interim analysis where recruitment to arms could be stopped due to lack of benefit based on pre-specified stopping rules.
Results: 365 patients were randomised from 7 sites in Tanzania and South Africa, of whom 25 (7%) were HIV positive. Recruitment to both SQ109 arms was terminated after the interim analysis; patients on these arms remained on treatment and in follow-up. At the final analysis, covariate-adjusted hazard ratios compared to control over 12 weeks were 0.82 (Q, 95% CI 0.55-1.24), 0.73 (20RQ, 0.48-1.13), 1.42 (20RM, 0.98-2.05), and 1.75 (35R, 1.21-2.55). For comparison to previous TB trials, covariate-adjusted hazard ratios compared to control over 8 weeks were 1.69 (1.02-2.80) for 20RM and 1.99 (1.21-3.29) for 35R. This is the largest reduction in time to culture conversion seen in any previous TB trial to our knowledge. Grade 3 or higher adverse events were experienced by 7(12%) Q , 7(12%) 20RQ, 9 (14%) 20RM, 9(14%) 35R and 12(10%) control patients, of which 1, 5, 7, 4 and 5 were considered at least possibly related to treatment. Hepatic adverse events leading to a change in treatment were experienced by 10 (2.7%) patients.
Conclusions: These data suggest that 35mg/kg rifampin may reduce the time to culture conversion and may be an important component in future treatment-shortening regimens. For 20mg/kg rifampin and moxifloxacin there was a modest reduction; there was no reduction with SQ109. Adaptive designs such as MAMS are feasible for multi-centre TB clinical trials and could speed regimen development.