Methods

Study design: multi‐centre, randomized, parallel‐group, double‐blind (participant, care provider, investigator, outcomes assessor), 3‐armed, placebo‐controlled, non‐inferiority trial

Study period: January 2008 to February 2014

Recruitment sites: 47 sites in 9 countries

Countries where the trial was undertaken: South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, Mexico

Length of follow‐up: 18 months after randomization (1 year after treatment completion)

Participants

No. of participants randomized: 1931

Interventions: 1291 (636 to ethambutol group; 655 to isoniazid group)

Control: 640 .

Age: > 35 years, 37% in isoniazid group, 39% in ethambutol group, and 40% in control group

Gender: male 70% in ethambutol group, 68% in isoniazid group, 70% in control group

Inclusion criteria:

• 2 sputum specimens positive for tubercle bacilli on direct smear microscopy, of which 1 was confirmed by the REMoxTB study laboratory at the local laboratory

• No history of previous anti‐tuberculosis chemotherapy

• Aged 18 years and older

• Firm home address that is readily accessible for visiting and willingness to inform the study team of any change in address and follow‐up period

• Agreement to participate in the study and to give a sample of blood for HIV testing

• Negative pregnancy test (women of childbearing potential)

• Pre‐menopausal women must be using a barrier form of contraception or must be surgically sterilized or have an IUCD in place

• Laboratory parameters performed at least 14 days before enrolment

  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 times upper limit of normal

  • Serum total bilirubin level less than 2.5 times upper limit of normal

  • Creatinine clearance (CrCl) level greater than 30 mL/min

  • Haemoglobin level at least 7.0 g/dL

  • Platelet count at least 50 x 10⁹ cells/L

  • Serum potassium greater than 3.5 mmol/L

Exclusion criteria:

• Patients unable to take oral medication

• Previously enrolled in this study

• Receiving any investigational drug in the past 3 months or an antibiotic active against M tuberculosis

• Pregnancy or breastfeeding

• Any condition that may prove fatal during the first 2 months of the study period

• Severe tuberculosis with high risk of a poor outcome (e.g. meningitis)

• Pre‐existing condition likely to prejudice the response to, or assessment of, treatment; a condition likely to lead to uncooperative behaviour

• Contraindication to any medications in the study regimens

• Congenital or sporadic cardiac syndrome or taking medications that could result in QTc prolongation

• Patients already receiving antiretroviral therapy

• Weight less than 35 kg

• HIV infection with CD4 count less than 250 cells/μL

• End‐stage liver failure (class Child‐Pugh C)

• Patients whose initial isolate was shown to be multiple drug resistant or monoresistant to rifampicin, or to any fluoroquinolone

Proportion with HIV seropositivity: 7% overall (and in intervention and control groups)

Proportion with cavitation: 71% overall (69% and 70% in intervention groups and 72% in control groups)

Baseline drug resistance: isoniazid: 7% overall (6% in control arm and 7% in each intervention arm); pyrazinamide: 2% overall (1% in each intervention arm)

Interventions

Interventions: 4‐month (17‐week) ATT regimen

Isoniazid group (moxifloxacin for 17 weeks substituting ethambutol): N = 655; 568 eligible, 514 completed (78% of those randomized; 91% of those eligible)

8 weeks of moxifloxacin, isoniazid, rifampicin, pyrazinamide, + ethambutol placebo administered daily, followed by

9 weeks of moxifloxacin, isoniazid, and rifampicin, followed by 9 weeks of isoniazid and rifampicin placebo

Ethambutol group (moxifloxacin for 17 weeks substituting isoniazid): N = 636; 551 eligible, 524 completed (82% of those randomized; 91% of those eligible)

8 weeks of moxifloxacin, ethambutol, rifampicin, pyrazinamide + isoniazid placebo administered daily, followed by

9 weeks of moxifloxacin and rifampicin + isoniazid placebo daily, followed by

9 weeks of isoniazid and rifampicin placebo

Control: 6‐month (26‐week) ATT regimen: N = 640; 555 eligible, 510 completed (80% of those randomized; 92% of those eligible)

8 weeks of isoniazid, rifampicin, ethambutol, pyrazinamide, and moxifloxacin placebo given daily, followed by

9 weeks of isoniazid, rifampicin, and moxifloxacin placebo given daily, followed by

9 weeks of isoniazid and rifampicin

Dosage: Moxifloxacin 400 mg, isoniazid 300 mg; rifampicin, ethambutol, and pyrazinamide were dosed based on weight

Outcomes

Outcomes reported and used in this review:

• Relapse within 18 months after randomization (relapse strains were those shown to be identical on 24‐locus MIRU analysis)

• Death from any cause

• Rates of treatment discontinuation

• Sputum smear/culture positivity at 8 weeks

• Proportion with bacteriologically or clinically defined failure

• Serious adverse events

• Other adverse events

Outcomes sought but not reported:

• Development of secondary drug resistance to anti‐tuberculosis drugs, identified by drug susceptibility testing

Outcomes reported but not used in this review:

• Composite unfavourable outcome (clinical or bacteriologic failure or relapse within 18 months after randomization) (non‐inferiority was defined as a between‐group difference of less than 6 percentage points in the upper boundary of the 2‐sided 97.5% Wald confidence interval for the difference in proportion of patients with an unfavourable outcome)

• Re‐treated for tuberculosis

• Time to first culture‐negative sputum

• Pharmakokinetic data (substudy reported separately)

Notes

Funding: Global Alliance for TB Drug Development (supported by multiple international donor agencies and local agencies and institutions in participating countries). Bayer Healthcare donated moxifloxacin and Sanofi donated rifampicin

Treatment supervision: treatment was given daily and was observed according to guidelines at the study site

Follow‐up method: following screening and baseline visits, there were 8 weekly visits followed by 8 visits until 18 months after randomization. Safety analysis was performed at the screening visit and thereafter at weeks 2, 8, 12, and 17

Trial registration ID: NCT00864383 (retrospectively registered: registered March 2009; study start January 2008)

Acronym: REMoxTB

Comment: data from both moxifloxacin‐containing shorter regimens were combined and compared with data from the standard treatment regimen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from report: "Randomization was performed with the use of lists with blocks of variable sizes that were stratified according to the patient weight group and study centre"

Allocation concealment (selection bias)

Low risk

Quote from report: "During randomization, patients were assigned a unique study number selected sequentially from the appropriate randomization list that corresponded to the treatment pack allocated"

Quote from report: "Only statisticians who were responsible for preparing the reports for the independent data and safety monitoring committee and essential manufacturing and distribution staff members had access to the list of identifiers matched to the intervention"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote from study protocol: "This will be a blinded study with matching placebo for each of the study medicines except for pyrazinamide"

Quote from trial registration document: "Masking: quadruple (participant, care provider, investigator, outcomes assessor)"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from trial registration document: "Masking: quadruple (participant, care provider, investigator, outcomes assessor)"

Incomplete outcome data (attrition bias): At the end of ATT (Treatment failure, positive sputum culture, treatment discontinuation, adverse events)

Low risk

Quote from report: "Of the 1931 patients who underwent randomization, 89% in the isoniazid group, 92% in the ethambutol group, and 89% in the control group met the requirements for treatment adherence, which was based on receipt of approximately 80% of the assigned regimen"

Comment: the modified‐intention‐to‐treat analysis used included 87% of those randomized to the combined moxifloxacin‐containing ATT regimens and 87% of those randomized to standard regimens. A sensitivity analysis included 94% of those randomized to both regimens

Incomplete outcome data (attrition bias): At the end of follow‐up (Relapse, deaths)

Low risk

Of those randomized, 91% of those allotted to the 2 moxifloxacin combination therapy arms and 92% allotted to control treatment were included in the modified intention‐to‐treat analyses. Results of the per‐protocol and modified intention‐to‐treat analyses were consistent

Selective reporting (reporting bias)

Low risk

Although the trial was retrospectively registered, all pre‐stated outcomes listed in the trial registration document and protocol were published with no evidence of selective reporting

Other bias

Low risk

Quote from report: "Bayer Healthcare donated moxifloxacin, and Sanofi donated rifampin. Neither company had any role in the study design, data accrual, data analysis, or manuscript preparation. Representatives of Bayer Healthcare reviewed the manuscript but did not suggest revisions"

Methods

Study design: randomized, open‐label, parallel‐group, 3‐armed, active comparator, equivalence trial

Study period: started May 2004 for an anticipated duration of 5 years; terminated early (between February and October 2006) due to high recurrence rates in the shorter treatment arms

Recruitment sites: Chennai and Madurai

Country where the trial was undertaken: India

Length of follow‐up: 24 months after treatment completion

Participants

No. of participants randomized: 429 (of 1200 anticipated)

Intervention groups: 259 (gatifloxacin regimen 141; moxifloxacin regimen 118)

Control group: 170

Age: < 40 years 72% (gatifloxacin 66%; moxifloxacin 77%; control 73%)

Gender: male 74% (gatifloxacin 76%; moxifloxacin 72%; control 72%)

Inclusion criteria:

• Adult patients 18 years or older with newly diagnosed pulmonary tuberculosis with at least 2 positive sputum cultures

• Resident within a designated study area and permitted home visits

Exclusion criteria:

• Those with previous treatment for tuberculosis exceeding 30 days, weighing < 30 kg, pregnant or lactating women

• Those with concomitant diabetes mellitus, severe systemic hypertension, epilepsy, serious forms of extrapulmonary tuberculosis, or HIV infection

Proportion with HIV seropositivity: nil (excluded)

Proportion with cavitation: not reported

Baseline drug resistance: isoniazid 7% overall (gatifloxacin 4%; moxifloxacin 1.2%; control 12%); rifampicin 0.2% overall (moxifloxacin 1%); ofloxacin 1.7% overall (gatifloxacin 2%; control 3%); isoniazid and ethambutol 0.4% overall (1% in each intervention arm); isoniazid and ofloxacin 0.2% overall (control 1%)

Interventions

Interventions: 4‐month ATT regimens

Gatifloxacin regimen (gatifloxacin replacing ethambutol): N = 141; 136 eligible, 131 completed (93% of those randomized; 96% of those eligible)

2 months of gatifloxacin, isoniazid, rifampicin, and pyrazinamide thrice weekly, followed by

2 months of gatifloxacin, isoniazid, and rifampicin thrice weekly

Moxifloxacin regimen (moxifloxacin replacing ethambutol): N = 118; 115 eligible, 113 completed (96% of those randomized; 98% of those eligible)

2 months of moxifloxacin, isoniazid, rifampicin, and pyrazinamide thrice weekly, followed by

2 months of moxifloxacin, isoniazid, and rifampicin thrice weekly

Control: 6‐month ATT regimen: N = 170; 165 eligible, 159 completed (94% of those randomized; 96% of those eligible)

2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide thrice weekly, followed by

4 months of isoniazid and rifampicin thrice weekly

Dosage: gatifloxacin or moxifloxacin 400 mg, rifampicin 450 or 600 mg, depending on body weight (< 60 kg or ≥ 60 kg), pyrazinamide 1500 mg, and isoniazid 600 mg

Outcomes

Outcomes reported and used in this review:

• Recurrence of tuberculosis among those with a favourable response at the end of treatment

• Death from any cause

• Rates of treatment discontinuation

• Sputum smear/culture positivity at 8 weeks

• Proportion with bacteriologically or clinically defined failure

• Serious adverse events

• Other adverse events

• Development of secondary drug resistance to anti‐tuberculosis drugs, identified by drug susceptibility testing

Notes

Funding: Tuberculosis Research Centre of the Indian Council of Medical Research

Follow‐up method: a physician examined the patient every month and recorded adherence to treatment, any adverse drug reactions, and the clinical response. Sputum specimens were examined every month by microscopy and culture: 2 (2 overnight and 1 spot) during the treatment phase, and 2 (1 overnight and 1 spot) during the follow‐up phase

Treatment supervision: directly observed, thrice‐weekly treatment in all arms

Trial registration ID: CTRI/2012/10/003060; retrospectively registered (trial commenced May 2004; trial registered 15/10/2012, after termination)

Comment: the data safety monitoring board recommended termination of both intervention arms in 2006 due to high tuberculosis recurrence rates in the 2 arms compared to the standard 6‐month regimen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from report: "Restricted random allocation sequences were generated by a biostatistician using random number tables, separately for the two strata and sealed envelopes were used to assign regimens"

Quote from trial registration document: "Stratified block randomization"

Allocation concealment (selection bias)

High risk

Quote from report: "Patients were enrolled by the physicians, and when ready for allocation, the biostatistician drew the regimen from sealed envelopes. Allocation was stratified on sputum smear grading and extent of lesions in chest x ray"

Quote from report: "The study design envisaged enrolling 400 patients in each arm in a 1∶1:1 ratio. However, due to the non‐availability of one of the test drugs (M), patients were enrolled initially in a 1∶1 ratio in the G and control regimen arms commencing in May 2004. Subsequently, when M became available (May 2005), patients were enrolled to the G, M, and control regimen arms in a 1∶2:1 ratio to compensate for the delay in recruiting to the moxifloxacin arm at the onset"

Quotes from correspondence with study authors: "When the first patient on Moxifloxacin was allocated, there were 110 patients randomised to the Gatifloxacin regimen and 110 to the Control regimen. The last patient was allocated to the Gatifloxacin regimen on 3 February 2006"

Comment: alteration of recruitment ratios raises serious concerns that allocation concealment was compromised. Even though biostatisticians implemented allocation after clinicians confirmed eligibility, by the time the first patient was recruited to the moxifloxacin regimen in May 2005, 110 allocated to the gatifloxacin regimen (80% of 136 eligible among those finally recruited), and 110 allocated to the control regimen (67% of the 165 eligible) had already been recruited. This would have alerted investigators that most of those to be recruited over the following year would be allocated to the moxifloxacin regimen. In addition, premature termination of the trial, combined with the alteration in allocation ratios, appears to have led to imbalance in the numbers recruited to the gatifloxacin (141), moxifloxacin (118), and control (170) regimens that is not explained, given that block randomization was used. There were also baseline imbalances in proportions resistant at baseline to any of the anti‐tuberculosis drugs tested (6%, 3%, and 16% respectively)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

This was an open‐label trial; given the likelihood that allocation concealment was compromised, treating personnel may have had knowledge of allocation. However, it is unlikely that this led to performance bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from report: "Sputum specimens were given identification laboratory numbers, and bacteriological investigations were carried out by technicians who were blinded to the clinical status of the patient and the regimen. ECG was done every month"

Comment: although bacteriologic outcomes were done blind to treatment allocation, clinical efficacy and safety outcomes were undertaken by study personnel. But results at the time of termination favouring the standard and not experimental interventions suggest that detection bias was unlikely

Incomplete outcome data (attrition bias): At the end of ATT (Treatment failure, positive sputum culture, treatment discontinuation, adverse events)

Low risk

In the combined fluoroquinolone arms, 228 of 259 (88%) completed treatment compared to 152 of 170 (89%) in the control arms. Study results did not differ between per‐protocol and modified intention‐to‐treat analyses (that excluded only late‐screening failures). The modified‐ITT analysis included 97%, 98%, and 97% of those in the gatifloxacin, moxifloxacin, and standard ATT arms, respectively. The results of both analyses were consistent

Incomplete outcome data (attrition bias): At the end of follow‐up (Relapse, deaths)

Low risk

In the combined fluoroquinolone arms, 230 of 259 (89%) were assessed for tuberculosis recurrence compared to 154 of 170 (91%) in the control arm. Per‐protocol and modified intention‐to‐treat analyses did not significantly alter the results. Early termination led to recruitment of only a third of the estimated 1200 participants required to prove equivalence, but although this reduces the power of the trial to detect equivalence, lack of differential attrition, with similar reasons for exclusion, is unlikely to affect the reported relative effect estimates

Selective reporting (reporting bias)

Low risk

Although the trial was retrospectively registered, stated outcomes in trial registry documents and in the online study protocol were available in the trial report and do not suggest selective reporting

Other bias

Low risk

The trial was terminated early at the recommendation of the Data Safety Monitoring Board after an interim analysis showed high recurrence rates in the fluoroquinolone arms compared to the control arm. Because this was a planned interim analysis, it is unlikely to have introduced bias, other than that discussed under allocation concealment

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"

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"

Methods

Study design: randomized, open‐label, parallel‐group, 5‐arm, active‐controlled trial

Study period: patient recruitment commenced in May 2007 (interim results of an ongoing trial)

Recruitment sites: Chennai, Madurai

Country where the trial was undertaken: India

Length of follow‐up: 24 months after treatment completion

Participants

No. of participants randomized: 801 (of the 1650 anticipated)

Combined intervention arms: 3 to 4 months moxifloxacin: N = 629

Control: 6 months ATT: N = 172

Age: < 35 years: moxifloxacin 52%; control 52%

Gender: male: moxifloxacin 74%; control 77%

Inclusion criteria:

• Adult patients, 18 years or older, with newly diagnosed sputum smear positive pulmonary tuberculosis

• Resident within a designated study area and permitted home visits.

Exclusion criteria:

• Those with previous treatment for tuberculosis exceeding 30 days, weighing over 30 kg, pregnant or lactating women

• Those with concomitant diabetes mellitus, severe systemic hypertension, epilepsy, serious forms of extrapulmonary tuberculosis, or HIV infection

Proportion with HIV seropositivity: nil (excluded)

Proportion with cavitation: moxifloxacin 36%; control 41%

Baseline drug resistance: isoniazid (moxifloxacin 7%; control 8%); ofloxacin (moxifloxacin 5%; control 7%); rifampicin, ethambutol, isoniazid, and ethambutol; isoniazid and ofloxacin (< 1% in both groups)

Interventions

Interventions: 3‐ and 4‐month moxifloxacin regimens: moxifloxacin added to standard ATT drugs

N = 629 randomized; 13 exclusions; 616 (98%) evaluated of those randomized

• Rifampicin, isoniazid, pyrazinamide, ethambutol, and moxifloxacin daily for 3 months

• Rifampicin, isoniazid, pyrazinamide, ethambutol, and moxifloxacin daily for 2 months, followed by rifampicin, isoniazid, and moxifloxacin daily for 2 months

• Rifampicin, isoniazid, pyrazinamide, ethambutol, and moxifloxacin daily for 2 months, followed by rifampicin, isoniazid, and moxifloxacin thrice weekly for 2 months

• Rifampicin, isoniazid, pyrazinamide, ethambutol, and moxifloxacin daily for 2 months, followed by rifampicin, isoniazid, ethambutol, and moxifloxacin thrice weekly for 2 months

Control (6‐month regimen): N = 172 randomized: 8 exclusions; 164 (95%) evaluated of those randomized

• Rifampicin, isoniazid, pyrazinamide, and ethambutol thrice weekly for 2 months, followed by rifampicin and isoniazid thrice weekly for 4 months

Dosage: rifampicin 450 (< 60 kg) or 600 mg (> 60 kg); isoniazid 300 mg (daily) and 600 mg (thrice weekly); pyrazinamide 1500 mg; ethambutol 800 mg (daily) and 1200 mg (thrice weekly); moxifloxacin 400 mg

Outcomes

Outcomes reported and used in this review:

• Sputum culture conversion at 2 months of treatment (assessed at 5 months)

• Adverse reactions while on anti‐tuberculosis drugs

Outcomes sought for the review but not reported:

• Relapse rates 24 months after treatment among those with a favourable or doubtful bacteriologic response at end of treatment (primary outcome for the ongoing trial)

• Death from any cause

• Failure to complete treatment

• Treatment failure (bacteriologic response at end of treatment is an outcome in the ongoing trial)

• Acquired drug resistance

Notes

Funding: Indian Council of Medical Research

Follow‐up method: over the 24‐month follow‐up period, participants had monthly clinical examination and adherence and adverse events recording; monthly sputum microscopy and culture (and on days 15 and 45) and monthly drug susceptibility testing for 1 positive culture; monthly ECG, haemogram, liver and kidney functions, random blood sugars, and HIV ELISA tests. Chest X‐ray after the 2‐month intensive phase. Adverse events were assessed monthly for the duration of treatment (3 to 6 months)

Treatment supervision: during the daily phase, treatment was under direct observation on 5 of 7 days of the week, whereas 2 doses were self‐administered. All thrice‐weekly phase doses were directly observed. Patients who missed treatment visits were visited at home and were motivated to attend the clinic for treatment

Trial registration ID: CTRI 2008/091/000024 (retrospectively registered on 09/05/2008)

Comment: results for sputum conversion at 2 months presented are the combined results of the 4 moxifloxacin regimens. Results for adverse events include up to the end of the 3‐ or 4‐month moxifloxacin regimens and over 6 months in the control regimen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from report: "Restricted random allocation sequences generated using random number tables,separately for the 6 strata, were used to assign the regimens"

Allocation concealment (selection bias)

Low risk

Quote from trial registration document: "Sequentially numbered, sealed, opaque envelopes"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

This was an open‐label study but all treatment arms had supervised treatment and scheduled assessments for efficacy and safety outcomes

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The outcomes reported are sputum culture results at 2 months and drug adverse events that were assessed for all participants at specified time points. Sputum culture results and ECG reports are objective outcomes, and the likelihood of detection bias influencing the reporting of other adverse events is low

Incomplete outcome data (attrition bias): At the end of ATT (Treatment failure, positive sputum culture, treatment discontinuation, adverse events)

Low risk

590 of 616 (96%) on moxifloxacin regimens and 151 of 162 (93%) on the control regimen had sputum cultures reported at 2 months. The 3% differential attrition is unlikely to have influenced the difference in proportions with negative sputum cultures at 2 months of 14.6% (95% CI 8.8% to 21.8%)

Incomplete outcome data (attrition bias): At the end of follow‐up (Relapse, deaths)

Low risk

Not reported, as the trial is ongoing and this report includes only interim outcomes

Selective reporting (reporting bias)

Low risk

This is an interim report of an ongoing trial. The outcomes presented were pre‐stated in the trial registration document

Other bias

Low risk

No other sources of bias were detected