Merle 2014.

Methods	Study design: randomized, multi‐centre, open‐label, parallel‐group, active‐controlled, non‐inferiority trial Study period: June 2005 to April 2011 Recruitment sites: Conakry, Cotonou, Dakar, Durban, Nairobi Countries where the trial was undertaken: Benin, Guinea, Kenya, Senegal, South Africa Length of follow‐up: 24 months
Participants	No of participants randomized: 1836 Intervention: 917 Control: 919 Age: mean age intervention 30.9 years, control 30.6 years Gender: male: Intervention 73%, control 72% Inclusion criteria: Aged 18 to 65 years (both inclusive) and weighing between 38 kg and 80 kg Recently diagnosed, microscopically proven, pulmonary tuberculosis, defined as 2 consecutively positive sputum smears, of which 1 must be equal to or exceed grade 1 Findings in medical history and physical examination not exceeding grade 2 according to the Division of Microbiology and Infectious Disease grading system tables (DMID) Voluntarily signed informed consent to participate in the study Females of childbearing potential must have a confirmed negative pregnancy test at the screening visit and must employ an effective and acceptable method of birth control during treatment Laboratory values that do not exceed grade 2 using the Division of Microbiology and Infectious Disease grading system (DMID) other than for glycaemia, haemoglobin, and potassium levels Exclusion criteria: Patients with a history of tuberculosis treatment within the last 3 years Concomitant infection requiring additional anti‐infective treatment (especially antiretroviral medication ‐ ARV) HIV‐infected patients with WHO stage 3 infection (except those presenting with only the "loss of weight > 10% body weight" criterion) and all patients at WHO stage 4 (see Appendix 5) History of diabetes mellitus (DM) or non‐insulin‐dependent diabetes mellitus (NIDDM) requiring treatment or diet. Additionally, patients who have a fasting glucose level less than 70 mg/dL (3.9 mmol/L) or above 115 mg/dL (6.4 mmol/L) at screening will be excluded Recreational drug abuse and alcohol abuse that, in the opinion of the investigator, could prejudice the conduct of the study in that patient History of drug hypersensitivity and/or active allergic disease Impaired renal, hepatic, or gastric function that may, in the opinion of the investigator, interfere with drug absorption, distribution, metabolism, or elimination Any other findings in medical history and physical examination exceeding grade 2 in the DMID grading system tables Patient using the following therapies: Other antibiotics with known anti‐tuberculosis activity (i.e. ofloxacin, moxifloxacin, kanamycin) Drugs known to prolong the QT interval (i.e. anti‐arrhythmics, psychotropics (phenothiazines, tricyclics, tetracyclics), erythromycin, pentamidine, and halofantrine) Drugs known to give photosensitivity reactions Receiving oral corticosteroids for longer than 2 weeks immediately before inclusion Use of antacids containing aluminium or magnesium salts or sucralfate Digoxin Drugs that are eliminated via tubular secretion (e.g. probenecid, cimetidine, ranitidine) Pregnant or lactating women Patients with congenital QT interval prolongation > 480 ms Patients with clinically significant bradycardia (40 beats/min) Baseline laboratory values exceeding grade 2 using the Division of Microbiology and Infectious Disease grading system (DMID) except glycaemia value as previously stated, haemoglobin, and hypokalaemia for which the limit values are as follows: potassium < 3.0 mEq/L (> grade 1), haemoglobin < 6.5 g/dL Any other finding considered by the investigator as compromising the participation of the patient in the trial Any condition rendering the patient unable to understand the nature, scope, and possible consequences of the study and to provide consent Participation in another drug trial within the 3 months before the screening visit Proportion with HIV seropositivity: 19% in the control regimen and 18% in the 4‐month regimen Proportion with cavitation: 50% in the control regimen and 52% in the 4‐month regimen Baseline drug resistance: excluded people with rifampicin resistance and MDR‐TB; isoniazid resistance: (gatifloxacin 8.5%; control 6.6%)
Interventions	Intervention: 4‐month ATT regimen Gatifloxacin: gatifloxacin replacing ethambutol in intensive and continuation phases: N = 917 randomized; 791 eligible, 651 included in per‐protocol analysis (71% of those randomized, 82% of those eligible) 2 months of gatifloxacin, isoniazid, rifampicin, and pyrazinamide given daily, followed by 2 months of gatifloxacin, isoniazid, and rifampicin Control: 6‐month ATT regimen (N = 919 randomized; 784 eligible, 601 included in per‐protocol analysis (65% of those randomized; 77% of those eligible) 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide, followed by 4 months of isoniazid and rifampicin Dosage: Fixed‐dose combination tablets of isoniazid–rifampin, isoniazid–rifampin–pyrazinamide, or isoniazid–rifampin–pyrazinamide–ethambutol were used wherever needed. Gatifloxacin was given at a dose of 400 mg. Other drugs were given in weight‐based doses (< 50 kg, ≥ 50 kg)
Outcomes	Outcomes reported and used in this review: Recurrence (relapse or reinfection) Death from any cause Treatment failure (at 4 months or 6 months) Sputum positive smear/culture at 8 weeks Treatment discontinuation Serious adverse events Other adverse events (hyperglycaemia during treatment phase, prolongation of QT interval) Outcomes sought for this review but not reported: Acquired drug resistance Outcomes reported and not used in this review: Unfavourable outcome by 24 months after treatment (composite of treatment failure, recurrence, death, or withdrawal) Unfavourable outcome at 18 months after randomization Time to an unfavourable outcome after treatment Pharmacokinetic/pharmacodynamic data (published separately)
Notes	Funding: Institut de Recherche pour le Développement (IRD) (on behalf of the OFLOTUB Consortium), World Health Organization (WHO). Lupin Pharmaceuticals provided study medicines Follow‐up method: trial drugs were administered orally under supervision 6 days a week during the intensive phase and were provided every 2 weeks in the continuation phase. Two sputum samples were obtained for smear examination, solid culture, and drug sensitivity tests at baseline and at all subsequent visits. Electrocardiograms (ECGs) were done at baseline, between 1 and 5 hours after drug intake, at 4 weeks, at 8 weeks, and at end of treatment Treatment supervision: trial drugs were given orally, 6 days a week under direct observation supervision during intensive phase and were provided every 2 weeks in the continuation phase to a supervisor who ensured treatment was taken. Adherence was assessed by pill count that remained in the weekly treatment boxes Trial Registration ID: NCT00216385 (retrospectively registered: September 2005) Acronym: OFLOTUB/gatifloxacin
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from report: "Patients were randomly assigned, in a 1:1 ratio with stratification according to country, to either a gatifloxacin‐containing regimen (experimental group) or the 6‐month standard treatment (control group)" Quote from protocol: "Randomization lists, stratified by study site and indicating a randomization number and which treatment is to be given, will be produced prior to the start of the trial by the medical statistician in London"
Allocation concealment (selection bias)	Low risk	Quote from protocol:"The Code for each individual will be provided in separate sealed envelopes and assigned to individuals in the order in which they are enrolled in the study"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote from protocol: "It must be noted that management of patients cannot be blinded, because of the difference in treatment length, but steps will be taken to ensure equal management and follow‐up of both treatment arms"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote from protocol: "Lastly, when patients recruited in the trial come to the clinic with a suspicion of relapse, the treatment they received will be blinded to the physician examining them" Quote from protocol: "Laboratory technicians will be blinded to the origin of each sample, ensuring unbiased assessment of endpoints"
Incomplete outcome data (attrition bias): At the end of ATT (Treatment failure, positive sputum culture, treatment discontinuation, adverse events)	Low risk	Althought 35% of those eligible after randomization in the control arm and 29% in the intervention arm were excluded from the per‐protocol analyses, modified intention‐to‐treat analyses included 86% of those randomized to each arm. Results of modified intention‐to treat analyses and per‐protocol analyses were consistent and did not suggest that differential attrition significantly biased the relative estimates of effects
Incomplete outcome data (attrition bias): At the end of follow‐up (Relapse, deaths)	Low risk	Quote from report: "The cumulative percentage of patients retained in the experimental and control groups, respectively, was 93.5% and 93.4% by 52 weeks, 91.0% and 89.6% by 78 weeks, and 87.5% and 82.7% by 94 weeks" Comment: there was differential attrition over 24 months, but results of the per‐protocol and intention‐to‐treat analyses were consistent
Selective reporting (reporting bias)	Low risk	The trial was retrospectively registered. However all outcomes in the registration documents and changes in the protocol were documented and reported adequately, and did not indicate selective reporting
Other bias	Low risk	Quote from report: "Lupin Pharmaceuticals had no role in the conduct of the trial, the analysis of the data, or the preparation of the manuscript"