Tuberculosis, Pulmonary Clinical Trial
Official title:
A Multiple Arm, Multiple Stage, Phase 2, OL, Randomized, Controlled Trial to Evaluate 4 Treatment Regimens of SQ109, Increased Doses of Rifampicin, and Moxifloxacin in Adults With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis
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.
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.
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