Jindani 2014.

Methods	Study design: randomized, multi‐centre, parallel‐group, open‐label, 3‐arm, active‐controlled, equivalence trial Study period: August 15, 2008, and August 1, 2011 Recruitment sites: Worcester, Johannesburg, Harare, Marondera, Francistown, and Macha Countries where the trial was undertaken: Botswana, South Africa, Zambia, and Zimbabwe Length of follow‐up: 18 months after randomization in 86%; in Botswana and South Africa, 6% of those randomized in the last 6 months of enrolment were followed up for 12 to 15 months and 8% for 15 to 18 months
Participants	No. of participants randomized: 827 (of the estimated sample of 1095) Interventions: 275 in 4‐month regimen (277 in 6‐month regimen) Control group: 275 in the control regimen Age: 18 to 34 years 61% in the control regimen and 68% in the 4‐month regimen Gender: male 64% in the control regimen, 63% in the 4‐month regimen Inclusion criteria: Newly diagnosed pulmonary tuberculosis 2 sputum specimens positive for tubercle bacilli on direct smear microscopy Either no previous anti‐tuberculosis chemotherapy or less than 2 weeks of previous chemotherapy at enrolment Aged 18 years and older Firm home address that is readily accessible for visiting and intending to remain there or within the recruitment area for the entire treatment and follow‐up period Willing to agree to participate in the study and to give a sample of blood for HIV testing (and in Botswana to have HIV status disclosed to them) Pre‐menopausal women must be using a barrier form of contraception or must be surgically sterilized or have an IUCD in place for the duration of the treatment phase Exclusion criteria: Any condition (except HIV infection) that may prove fatal during the study period Tuberculosis meningitis Pre‐existing non‐tuberculous disease likely to prejudice the response to, or assessment of, treatment (e.g. insulin‐dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis) Female and known to be pregnant or breastfeeding Condition likely to lead to uncooperative behaviour such as psychiatric illness or alcoholism Contraindications to any medications in the study regimens History of prolonged QTc syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of tuberculosis therapy Haemoglobin < 7 g/L AST or ALT > 5 times the upper range Creatinine clearance < 30 mL/min History of seizures HIV positive with CD4 count less than 150/mm³ Weight < 35 kg Already receiving anti‐retroviral therapy (ART) Proportion with HIV seropositivity: 32% in the control regimen and 28% in the 4‐month regimen Proportion with cavitation: 67% in the control regimen and 65% in the 4‐month regimen Baseline drug resistance: excluded people resistant to isoniazid, rifampicin, or moxifloxacin
Interventions	Interventions: 4‐month (17‐week) ATT regimen: moxifloxacin replacing isoniazid throughout with twice‐weekly administration in continuation phase + rifapentine twice weekly replacing rifampicin in continuation phase: N = 275 randomized; 239 eligible, 165 completed (60% of those randomized; 69% of those eligible) 2 months (8 weeks) of ethambutol, moxifloxacin, rifampicin, and pyrazinamide administered daily, followed by 2 months (9 weeks) of moxifloxacin and rifapentine administered twice weekly 6‐month (26‐week) ATT regimen: moxifloxacin replacing isoniazid throughout with weekly rifapentine + weekly moxifloxacin in the 4‐month continuation phase 2 months (8 weeks) of ethambutol, moxifloxacin, rifampicin, and pyrazinamide administered daily, followed by 4 months (18 weeks) of rifapentine and moxifloxacin once a week Control: 6‐month (26‐week) ATT regimen: N = 275 randomized; 240 eligible, 163 completed (59% of those randomized; 68% of those eligible) 2 months (8 weeks) of isoniazid, rifampicin, ethambutol, and pyrazinamide administered daily, followed by 18 weeks of isoniazid and rifampicin daily Dosage: moxifloxacin 400 mg; rifapentine 900 mg in the 4‐month treatment arm (and 1200 mg in the 6‐month arm). All doses given were based on the weight of the patient
Outcomes	Outcomes reported and used in this review: Relapse after treatment Death from any cause Failure to complete treatment Treatment failure Acquired drug resistance Serious adverse events Outcomes sought for this review and not reported: Sputum positive smear/culture at 8 weeks (disaggregated data from the 2 moxifloxacin arms not reported) Outcomes reported and not used in this review: Culture results at end of follow‐up ART start times in HIV‐infected people Adherence
Notes	Funding: European and Developing Countries Clinical Trials Partnership, Wellcome Trust. Some of the trial medications were donated by Sanofi, Genus Pharmaceuticals, and Sandoz Follow‐up method Patients were followed‐up monthly up to 12 months after randomization and thereafter once in 3 months until 18 months. Two sputum samples were collected before treatment initiation for smear and culture, and 1 sample was collected monthly for 12 months and then again at 15 months and 18 months of follow‐up Treatment supervision: treatment was directly observed in all participants in the intensive treatment phase. Drugs were taken under the supervision of a relative or another designated person in the 18‐week continuation phase in the control arm. Moxifloxacin and rifapentine treatment was supervised at the treatment facility twice weekly for the 9‐week continuation phase Trial registration ID: ISRCTN44153044 (prospectively registered) Acronym: RIFAQUIN Comment: data from the 6‐month moxifloxacin intervention arm were not used in this study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from report: "A randomized allocation sequence was generated for each study centre with the use of blocks of varying size by an independent statistician based at the MRC CTU"
Allocation concealment (selection bias)	Low risk	Quote from updated protocol: "Sealed opaque envelopes containing the treatment allocation slips will be held by the pharmacist. When a patient is found to be eligible their details will be entered on the enrolment log by the designated member of the clinic team against the next available study number. These patient details and the study number will be entered on to the patient’s prescription. This will be taken to the pharmacy and the patient details entered onto the pharmacy register by the pharmacist against the next study number which will act as a check that the correct (next available) study number had been used. The pharmacist will then take the envelope corresponding to the study number and reveal the treatment allocation which will be written on the allocation slip. This will then be attached to the prescription and kept in the patient’s Trial folder or other appropriate place and the designated member of the clinic team made aware of the treatment allocation"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This was an open‐label trial. The treating team was aware of allocated treatments. However, this does not seem to have influenced drug administration or use of co‐interventions
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote from report: "Apart from the statisticians reporting to the data and safety monitoring committee, the staff at St. George’s and at the MRC CTU were unaware of treatment assignment except when a lack of awareness would have been unethical (e.g., in some discussions of serious adverse events). Participating laboratories were unaware of treatment assignment throughout the study" Comment: although treatment allocation before the start of the trial was concealed, the clinical team evaluating participants for efficacy and safety outcomes was aware of treatment allocation. However, laboratory assessments were objective and clinical outcomes were mostly based on objective assessments
Incomplete outcome data (attrition bias): At the end of ATT (Treatment failure, positive sputum culture, treatment discontinuation, adverse events)	Low risk	Although overall attrition was over 30%, there was no differential attrition in the 4‐month arm (31%) versus the control arm (32%). In the sensitivity analysis in the supplementary table, S1 attrition was 13% in each arm. We do not think this is likely to alter the estimates of relative effects
Incomplete outcome data (attrition bias): At the end of follow‐up (Relapse, deaths)	Low risk	Modifed intention‐to‐treat and per‐protocol analyses presented in Table 2 of the main report and in the sensitivity analyses in Table S1 in the online supplementary appendix do not indicate that bias due to differential attrition is likely to have affected the estimates of relative effects
Selective reporting (reporting bias)	Low risk	This trial was prospectively registered, and protocol amendments and reporting of results do not indicate selective reporting
Other bias	Low risk	Quote from report: "Some of the trial medications were donated by Sanofi, Genus Pharmaceuticals, and Sandoz, and a representative of Sanofi was a non‐voting observer at meetings of the steering committee, but none of these companies had any role in the study design, data accrual, data analysis, or manuscript preparation"