Clinical trial NCT01785186
Conditions: Tuberculosis, Pulmonary
Keywords: TB Tuberculosis MAMS - Multiple-arm, multiple-stage Pulmonary SQ109 High dose rifampicin moxifloxacin
Sponsor: Michael Hoelscher
Start date: 2013-04-01; Completion date: 2015-03-01
Enrollment: 365 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized, controlled clinical trial that will compare the efficacy and safety of four experimental four drug regimens with a standard control regimen in patients with smear positive, pulmonary tuberculosis (TB). Patients will be randomly allocated to the control or one of the four experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12 weeks. Thereafter, participants in the experimental arms will receive continuation phase treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold; these arms will then be stopped from further recruitment.

Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on these arms not meeting the pre-specified gain in efficacy over control. Importantly, there was no safety concern that prompted stopping recruitment to these arms. They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.

Detailed description:
This Phase II, multi-arm, multi-stage, open label, prospectively randomized, controlled clinical trial will compare the efficacy and safety of four experimental regimens with the control, standard treatment regimen in patients with smear positive, pulmonary tuberculosis (TB). There will be four experimental regimens. Participants will be randomly allocated to control or one of the four experimental intensive phase regimens in the ratio 2:1:1:1:1. The control and 4 experimental regimens are:

Control: HRZE isoniazid, rifampicin standard, pyrazinamide, ethambutol Arm 1: HRZQlow isoniazid, rifampicin standard, pyrazinamide, SQ109 150 mg Arm 2: HRZQhigh isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg Arm 3: HR20ZQhigh isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg Arm 4: HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400mg

Up to 372 participants will be randomized into this study, with 124 participants being randomized to the control arm and 62 participants to each experimental arm. With an expected loss to follow-up of 5%, the final power of the study to detect a hazard ratio of 1.8 for culture conversion to negative will be 90%, at the 5% significance level.

Participants will be randomised using a probabilistic minimisation algorithm based on site, baseline bacterial load as measured by GeneXpert MTB/RIF®, and HIV status. The allocated intensive phase of the four experimental arms will be administered daily for twelve weeks. During this time, participants will visit the study clinic on a weekly basis for sputum collection, safety monitoring and receipt of study medication. After the completion of the experimental treatment, participants in the experimental arms will receive daily standard continuation phase treatment for 14 weeks containing standard-dose RIF and INH to complete their TB treatment course. Participants in the control arm will receive eight weeks of intensive four-drug treatment (HRZE, followed by 18 weeks of the HR continuation phase treatment in line with the current WHO recommendations.

All participants will receive 25mg of Vitamin B6 (pyridoxine) with every dose of treatment in order to prevent INH-related neuropathy.

Interim analyses will be conducted during the trial for efficacy at predetermined times, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold. There will be no further recruitment to these arms.

Arms: arm 1: Arm 1 (R35): HR35ZE isoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol arm 2: Arm 2 (Q): HRZQ isoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg arm 3: Arm 3 (R20Q): HR20ZQ isoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg arm 4: Arm 4 (R20M): HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg arm 5: HRZE: Isoniazid, rifampicin standard, pyrazinamide, ethambutol
Interventions: intervention 1: SQ109 intervention 2: Rifampicin intervention 3: Moxifloxacin intervention 4: isoniazid intervention 5: pyrazinamide intervention 6: ethambutol intervention 7: pyridoxine
Intervention descriptions: intervention 1: SQ109 300 mg intervention 2: Rifampicin 10 to 35 mg/kg intervention 3: Moxifloxacin 400mg intervention 4: isoniazid 75 mg intervention 5: pyrazinamide 400 mg intervention 6: ethambutol 275 mg intervention 7: pyridoxine 25 mg

Protocol documents: