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Fluoroquinolones for treating tuberculosis (presumed drug-sensitive)

  1. Lilia E Ziganshina1,*,
  2. Albina F Titarenko1,
  3. Geraint R Davies2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 4 MAR 2013

DOI: 10.1002/14651858.CD004795.pub4


How to Cite

Ziganshina LE, Titarenko AF, Davies GR. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD004795. DOI: 10.1002/14651858.CD004795.pub4.

Author Information

  1. 1

    Kazan (Volga region) Federal University, Department of Basic and Clinical Pharmacology, Kazan, Tatarstan, Russian Federation

  2. 2

    University of Liverpool, Institute of Infection and Global Health, Liverpool, Merseyside, UK

*Lilia E Ziganshina, Department of Basic and Clinical Pharmacology, Kazan (Volga region) Federal University, 18 Kremlevskaya Street, 420008, 14-15 Malaya Krasnaya Street, 420015, Kazan, Tatarstan, Russian Federation. lezign@mail.ru. lezign@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 6 JUN 2013

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Characteristics of included studies [ordered by study ID]
Burman 2006

MethodsTrial design: multicentre RCT

Follow-up: 8 weeks

Adverse event monitoring: not described

Inclusion of all randomized participants in the final analysis: 59/336 (17.6%) excluded from final analysis


ParticipantsNumber: 336 randomized; 277 evaluated

Inclusion criteria: aged 18 years or older with suspected pulmonary TB and acid-fast bacilli in an expectorated sputum sample

Exclusion criteria: history of > 7 days of a fluoroquinolone antibiotic or TB treatment within the previous 6 months; pregnancy or breastfeeding; initial sputum cultures negative for M. tuberculosis or resistance to rifampicin, fluoroquinolones, or pyrazinamide (patients whose isolates were resistant to isoniazid were included)


InterventionsFluoroquinolone (moxifloxacin) substituted into regimen (replacing ethambutol) for 2 months (8 weeks), initial 2 weeks of daily therapy under "supervision"

1. Moxifloxacin (400 mg daily) orally plus basic regimen (5 days a week or thrice a week for both dosing regimens) for 2 months
2. Ethambutol (0.8 g - 40 to 55 kg; 1.2 g - 56 to 75 kg; 1.6 g - 76 to 90 kg) daily orally 5 days a week or (1.2 g - 40 to 55 kg; 2 g - 56 to 75 kg; 2.4g - 76 to 90 kg) thrice weekly for 2 months plus basic regimen

Basic regimen:
Isoniazid (300 mg), rifampicin (450 mg if ≤ 45 kg; 600 mg if > 45 kg), and pyrazinamide (1 g - 40 to 55 kg; 1.5 g - 56 to 75 kg; 2 g - 76 to 90 kg) given orally 5 days a week for 2 months; or
isoniazid (15 mg/kg, max dose 900 mg), rifampicin (450 mg if ≤ 45 kg; 600 mg if > 45 kg), and pyrazinamide (1.5 g - 40 to 55 kg; 2.5 g - 56 to 75 kg; 3 g - 76 to 90 kg) given thrice weekly orally for 2 months


Outcomes1. Death from any cause: 1/169 versus 0/167

2. Sputum culture conversion at 8 weeks: 99/169 versus 98/167
3. Serious adverse events: 10/169 versus 8/167


NotesLocation: North America and Africa

Setting: not described

HIV status: HIV-positive participants (30/169 - fluoroquinolones + HRZ group, 30/167 - control HRZE group)

Resistance: isoniazid resistance (15/169 - fluoroquinolones + HRZ group, 10/167 - control HRZE group); 11 participants with resistance to rifampicin, fluoroquinolone or pyrazinamide - excluded from analysis

Dates: no mention in the trial report

Funding: the US CDC. Bayer Pharmaceuticals donated moxifloxacin and moxifloxacin placebo tablets. Two of 12 authors had a financial relationship with the commercial entity that had an interest in the subject of the manuscript.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"randomised in a factorial design"; "Randomisation was stratified by continent of enrolment and presence of pulmonary cavitation".

Allocation concealment (selection bias)Unclear riskMethod of concealment not described.

Blinding of participants/personnel (efficacy outcomes);performance bias
All outcomes
Low riskNot described in study report. However the trial was double-dummy placebo controlled. Review authors judged that the efficacy outcomes were not likely to be influenced by lack of blinding.

Blinding of participants/personnel (safety outcomes);performance bias
All outcomes
Low riskNot described in study report. However the trial was double-dummy placebo controlled. Review authors judged that the safety outcomes were not likely to be influenced by lack of blinding.

Blinding of outcome assessment (efficacy outcomes);detection bias
All outcomes
Low riskNot described in the study report. However the trial was double-dummy placebo controlled and outcome assessment for bacteriological outcomes was independent and almost certainly blinded.

Blinding of outcome assessment (safety outcomes);detection biasLow riskNot described in the study report. However the trial was double-dummy placebo controlled so safety outcomes were not likely to have been influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes
High risk59/336 (17.6%) excluded from final analysis.

Quote: "we excluded (1) patients who took non study therapy or required more than 70 days to complete the intensive phase, (2) patients who died during the intensive phase of therapy, and (3) patients whose sputum cultures were overgrown with bacteria or yeast. Patients who received at least one dose of study drug were included in the safety analysis".

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskTwo of 12 authors had a financial conflict of interest. Bayer Pharmaceuticals donated moxifloxacin and moxifloxacin placebo tablets.

Conde 2009

MethodsTrial design: single-centre randomized double-blind double-dummy controlled trial

Follow-up: 18 months

Adverse event monitoring: at weekly clinic visits. Liver enzymes, serum creatinine levels and complete blood counts performed monthly.

ECG obtained at weeks 2, 4, 6, and 8 of treatment.

Inclusion of all randomized participants in the final analysis: 45/170 (26.5%) excluded from final analysis


ParticipantsNumber: 170 randomized; 125 evaluated

Inclusion criteria: aged 18 years or older with sputum smear-positive pulmonary TB and abnormal chest radiograph, and at least one acid-fast bacilli in an expectorated sputum sample with no previous history of treatment.

Exclusion criteria: haemoglobin < 70 g/L; AST or ALT > 3 times the upper limit of normal value; serum creatinine > twice the upper limit of normal; an ECG with a QTc interval more than 450 ms; pregnancy; breastfeeding; silico-TB; a history of severe adverse reactions to fluoroquinolones or any other study agent; seropositivity for HIV with CD4-cell count < 200 cells per μL. 

Randomized patients were excluded if culture-negative or culture resistant to isoniazid, rifampicin, or ethambutol.  


InterventionsFluoroquinolone (moxifloxacin) substituted into regimen (replacing ethambutol) for 2 months (8 weeks) under direct supervision

1. Moxifloxacin (400 mg daily) with an ethambutol placebo orally plus basic regimen (5 days a week) for 2 months (8 weeks)
2. Ethambutol (15 to 20 mg/kg) plus moxifloxacin placebo daily orally 5 days a week for 2 months (8 weeks) plus basic regimen

Basic regimen:
isoniazid (300 mg), rifampicin (450 mg if < 50 kg; 600 mg if > 50 kg), and pyrazinamide (20 to 25mg/kg) given orally 5 days a week for 2 months


Outcomes1. Relapse (within a year after treatment completion) 1/85 versus 2/85

2. Death (from any cause) 3/85 versus 5/85

3. TB-related death 0/85 versus 1/85

4. Sputum culture negative at 8 weeks: 59/85 versus 45/85.

5. Time to culture conversion: no numerical data

6. Serious adverse events: 6/85 versus 6/85   


NotesLocation: Brazil, Rio de Janeiro

Setting: Hospital Clementino Fraga Filho

HIV status: HIV negative participants, HIV-seropositivity was used as an exclusion criterion

Resistance: 11 participants with isoniazid, rifampicin, or ethambutol resistance excluded from authors' analysis

Dates: October 2004 to March 2007

Funding: Office of Orphan Product Development, USA FDA, Fogarty International Center of the NIH, career development grant supported Dr. Chaisson's participation. Bayer Healthcare donated moxifloxacin and matching placebo.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"permuted block randomisation with blocks of four".

Allocation concealment (selection bias)Low riskAdequate: "allocation slips sealed in opaque envelopes opened after enrolment".

Blinding of participants/personnel (efficacy outcomes);performance bias
All outcomes
Low riskDouble dummy placebo control was used. Patients, study clinicians, and study staff were unaware of the treatment assignments of patients with the exception of the pharmacist who dispensed medication packets.

Blinding of participants/personnel (safety outcomes);performance bias
All outcomes
Low riskDouble dummy placebo control was used. Patients, study clinicians, and study staff were unaware of the treatment assignments of patients with the exception of the pharmacist who dispensed medication packets.

Blinding of outcome assessment (efficacy outcomes);detection bias
All outcomes
Low riskDouble dummy placebo control was used. Though not specifically stated in the study report laboratory staff were likely blinded to treatment assignment.

Blinding of outcome assessment (safety outcomes);detection biasLow riskDouble dummy placebo control was used. Patients, study clinicians and study staff were unaware of the treatment assignments of patients with the exception of the pharmacist who dispensed medication packets.

Incomplete outcome data (attrition bias)
All outcomes
High risk45/170 (26.5%) excluded from final analysis.

Quote: "Randomised patients were excluded if their baseline culture did not grow M. tuberculosis or grew a strain of M. tuberculosis that was resistant to isoniazid, rifampicin, or ethambutol".

"The primary endpoint of the trial, culture conversion, was assessed by modified ITT analysis; patients whose baseline cultures were negative, contaminated, or contained drug-resistant M. tuberculosis were excluded and all missing 8 week results were deemed treatment failures".

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Other biasUnclear riskThe authors declared no conflict of interest. Bayer Healthcare donated moxifloxacin and matching placebo, but had no input into the study design, execution, or analysis. Authors described the role of the funding source in the trial from design to publication of report.

Dorman 2009

MethodsTrial design: multicentre randomized placebo-controlled double-blind phase 2 clinical trial

Follow-up: 2 months

Adverse event monitoring: assessed at baseline and weeks 2, 4, 6, and 8 of treatment: symptoms, blood tests for AST, bilirubin, creatinine, and complete blood count.

Inclusion of all randomized participants in the final analysis: 105/433 (24.3%) excluded from final analysis


ParticipantsNumber: 433 randomized; 328 evaluated

Inclusion criteria: adults (age not specified) with suspected pulmonary TB and acid-fast bacilli in a sputum specimen

Exclusion criteria: history of > 7 days of antituberculous treatment within the previous 6 months or of fluoroquinolone treatment within the previous 3 months; pregnancy, or breastfeeding; initial sputum cultures negative for M. tuberculosis or resistance to isoniazid, fluoroquinolones, rifampicin, or pyrazinamide.


InterventionsFluoroquinolone (moxifloxacin) substituted into regimen (replacing isoniazid) for 2 months (8 weeks) under direct observation

1. Moxifloxacin (400 mg daily) with an isoniazid placebo orally plus basic regimen (5 days a week or 7 days per week during the first two weeks) for 2 months (8 weeks)
2. Isoniazid (300 mg) plus moxifloxacin placebo daily orally 5 days a week (or 7 days per week during the first two weeks) for 2 months (8 weeks) plus basic regimen

Basic regimen: rifampicin, pyrazinamide, ethambutol, and pyridoxine in accordance with published guidelines (Blumberg 2003)


Outcomes1. Death from any cause: 3/219 versus 4/214 (intensive versus continuation phase)

2. TB-related death: 2/219 versus 1/214

3. Sputum culture negative at 8 weeks: 99/219 versus 90/214

2. Time to sputum culture conversion (no numeric data provided)

3. Serious adverse events: 9/219 versus 8/214


NotesLocation: North America, Brazil, South Africa, Spain, and Uganda

Setting: 26 Tuberculosis Trials Consortium (TBTC) sites

HIV status: HIV-positive participants (17/219 in study group fluoroquinolones + RZE, 18/214 in control group HRZE)

Resistance: 13/219 in fluoroquinolones + RZE group, 14/214 in HRZE group); full susceptibility not confirmed: 13/219 in fluoroquinolones + RZE group, 6/214 in HRZE group

Dates: no mention in the trial report

Funding: CDC and the Global Alliance for Tuberculosis Drug Development. Bayer Pharmaceuticals provided moxifloxacin and moxifloxacin placebo tablets. Three out of 19 authors had a financial relationship with a commercial entity that had an interest in the subject of the manuscript.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy report specified "randomly assigned" but did not mention the method of randomization. "Randomisation was stratified by the presence of cavitation on baseline chest radiograph and continent of enrolment (Africa or not Africa); randomisation was not restricted within strata".

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants/personnel (efficacy outcomes);performance bias
All outcomes
Low riskDouble dummy placebo control was used. Review authors judged that efficacy outcomes were unlikely to have been influenced by a lack of blinding.

Blinding of participants/personnel (safety outcomes);performance bias
All outcomes
Low riskDouble dummy placebo control was used. Review authors judged that safety outcomes were unlikely to have been influenced by a lack of blinding.

Blinding of outcome assessment (efficacy outcomes);detection bias
All outcomes
Low riskDouble dummy placebo control was used. Laboratory staff assessing bacteriological outcomes were likely blinded to the treatment assignment.

Blinding of outcome assessment (safety outcomes);detection biasLow riskDouble dummy placebo control was used. Review authors judged that safety outcomes were unlikely to have been influenced by a lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes
High risk105/433 (24.3%) excluded from final analysis.

Quote: "Two efficacy analysis groups were prespecified. A modified ITT group excluded participants whose enrolment specimen failed to grow M. tuberculosis or had proven resistance to isoniazid, rifampin, pyrazinamide, ciprofloxacin, or ofloxacin; and enrollees whose treatment was incorrectly allocated. A protocol-correct (PC) group excluded participants whose enrolment specimen failed to grow M. tuberculosis or was not proven susceptible to isoniazid, rifampin, pyrazinamide, ciprofloxacin, and ofloxacin; whose treatment was incorrectly allocated; who had contaminated week-8 cultures; who died during intensive phase; who required more than 700 days to complete the study intensive-phase treatment; or who took non study therapy for more than 14 days during the intensive phase. For safety analyses, all participants who received at least one dose of study treatment were included".

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Other biasUnclear riskThree out of 19 authors had a financial conflict of interest. Bayer Pharmaceuticals provided moxifloxacin and moxifloxacin placebo tablets.

El-Sadr 1998

MethodsTrial design: multicentre open label RCT

Follow-up: 12 months

Adverse event monitoring: regularly with two week intervals during receipt of study medication and for 8 weeks after its discontinuation, graded on a five-point scale

Inclusion of all randomized participants in the final analysis: 73/174 (42%) excluded at 8 weeks analysis; 39% lost to follow-up in continuation phase


ParticipantsNumber: 174 randomized; 101 evaluated

Inclusion criteria: suspected human immunodeficiency virus (HIV) and pulmonary TB; age > 18 years in resistant areas or > 13 years in other areas; aspartate aminotransferase (AST) ≤ 10 times upper limit; serum bilirubin < 2.5 times upper limit; serum creatinine ≤ 3 times upper limit or creatinine clearance rate ≥ 50 mL/min

Exclusion criteria: history of MDR-TB or close contact with an MDR-TB patient; > 3 weeks continuous antituberculous treatment immediately prior to enrolment; > 12 weeks antituberculous therapy in the past 2 years; pregnancy; exclusively extrapulmonary TB.


InterventionsFluoroquinolone (levofloxacin) added to regimen:

1. Levofloxacin plus standard regimen
500 mg levofloxacin daily for 2 weeks (induction phase); then 750 mg levofloxacin three times weekly for 6 weeks; then standard regimen only (continuation phase)
2. Standard regimen
Induction phase (2 weeks daily): isoniazid (300 mg), vitamin B6 (50 mg), rifampicin (450 mg to 600 mg; < 50 kg to > 50 kg), pyrazinamide (1.5 g to 2.0 g; < 50 kg to > 50 kg), ethambutol (20 mg/kg; rounded to the nearest 400 mg)

6 weeks (thrice weekly): isoniazid (600 to 900 mg; < 50 kg to > 50 kg), vitamin B6 (50 mg), rifampicin (600 mg), pyrazinamide (2.0 g to 2.5 g; < 50 kg to > 50 kg), ethambutol (30 mg/kg; rounded to the nearest 400 mg)
Continuation phase lasting 6 or 9 months (18 or 31 weeks of total therapy) (twice weekly): isoniazid (600 mg to 900 mg; < 50 kg to > 50 kg), vitamin B6 (50 mg), rifampicin (600 mg)

Study report states that "the protocol strongly recommended directly observed therapy: all units had access to such programs"


Outcomes1. Death from any cause: 1/87 versus 3/87 - best case analysis ; 1/50 versus 3/40 - complete case analysis
2. TB-related death: 1/87 versus 1/87
5. Sputum culture negative at 8 weeks: 46/87 versus 36/87

6. Serious adverse events: 11/87 versus 13/87


NotesLocation: New York city area and Hawaii, USA

Setting: 21 clinics across the USA

HIV status: HIV positive and suspected HIV positive participants

Resistance: > 80% M. tuberculosis strains susceptible to both isoniazid and rifampin.

Dates: 1993-95 to August 1997

Funding: National Institute for Allergy and Infectious Disease. Drugs were supplied by manufacturers.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Stratified permuted block randomisation was used in both phases of this study, with the research unit being the stratification factor". However, the specific method of randomization was not mentioned.

Allocation concealment (selection bias)Unclear riskAllocation concealment not described.

Blinding of participants/personnel (efficacy outcomes);performance bias
All outcomes
Unclear riskStudy report gave no information on blinding but study was open-labelled.

Blinding of participants/personnel (safety outcomes);performance bias
All outcomes
Unclear riskStudy report gave no information on blinding but study was open-labelled.

Blinding of outcome assessment (efficacy outcomes);detection bias
All outcomes
Low riskStudy report gave no information on blinding but laboratory staff were likely blinded to treatment allocation and "all TB endpoints were reviewed by an independent clinical events committee blinded to treatment group".

Blinding of outcome assessment (safety outcomes);detection biasUnclear riskStudy report gave no information on blinding but study was open-labelled.

Incomplete outcome data (attrition bias)
All outcomes
High risk73/174 (42%) excluded at 8 weeks analysis; 39% lost to follow-up in continuation phase.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Other biasHigh riskNo conflict of interest statement. Drugs were supplied by manufacturers.

Rustomjee 2008a

MethodsTrial design: four-arm, open label RCT

Follow-up: 2 months

Adverse event monitoring: not described

Inclusion of all randomized participants in the final analysis: 18 participants (8.3%) excluded


ParticipantsNumber: 217 randomized / 199 analyzed

Inclusion criteria: newly diagnosed patients with pulmonary TB, with two consecutive sputum smears positive for acid-fast bacilli, aged between 18 to 65 years, weighing between 38 to 80 kg, and willing to co-operate in the intensive study were eligible. The medical findings for haematology, chemistry, liver enzymes, and cardiovascular function were not to exceed grade 2 of the Division of Microbiology and Infectious Disease.

Exclusion criteria: resistance to RMP of the pre-treatment strain of M. tuberculosis, extra-pulmonary TB, pregnancy, WHO stage 4 of HIV infection, prolongation of the cardiological QT interval 480 msec, bradycardia, any condition causing delay in drug absorption, metabolism or elimination, or other serious illness.


InterventionsFluroquinolone (ofloxacin, or moxifloxacin, or gatifloxacin) substituted into regimen (replacing ethambutol in standard first-line regimen - HRZE).

Control:

Akurit-4 (Lupin, Mumbai, India) containing 275 mg E, 75 mg H, 150 mg R, and 400 mg Z - HRZE regimen. Patients weighing between 38 to 50 kg received three tablets and those weighing between 50 to 80 kg received four tablets.

Fluroquinolone:

Ofloxacin 800 mg daily orally for 2 months

Moxifloxacin 400 mg daily orally for 2 months

Gatifloxacin 400 mg daily orally for 2 months

plus AKurit-Z (Lupin) containing the same first-line drugs without ethambutol (E) - HRZ.


Outcomes1. Death from any cause

2. TB-related death

3. Sputum culture conversion at 8 weeks

4. Serious adverse events

5. Rate of late phase elimination of organisms as measured by serial sputum viable colony counting

6. Hazard ratio of culture conversion in Cox regression


NotesLocation: KwaZulu Natal, South Africa

Setting: four clinics in KwaZulu Natal

HIV status: 53% - 63% HIV positive participants

Resistance: all patients confirmed not resistant to rifampicin; 1 participant was isoniazid resistant

Dates: June 2004 to June 2005
Funding: European Commission, Framework 5, WHO/UNDP/UNISEF Special programme on Tropical Disease Research (TDR)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described. Quote: "Patients were randomly allocated in successive blocks of 20 equally to one of four regimens for the first 8 weeks of treatment".

Allocation concealment (selection bias)Unclear riskNot described. Quote: "Patients were randomly allocated in successive blocks of 20 equally to one of four regimens for the first 8 weeks of treatment".

Blinding of participants/personnel (efficacy outcomes);performance bias
All outcomes
High riskNot described. Study was open-labelled. Review authors judged that study procedures could have been affected by a lack of blinding.

Blinding of participants/personnel (safety outcomes);performance bias
All outcomes
High riskNot described. Study was open-labelled. Review authors judged that assessment of safety outcomes could have been affected by a lack of blinding.

Blinding of outcome assessment (efficacy outcomes);detection bias
All outcomes
Unclear riskNot described. Study was open-labelled but laboratory staff were likely blinded to treatment assignment. Review authors judged that bacteriological efficacy outcomes were unlikely to have been at high risk of bias.

Blinding of outcome assessment (safety outcomes);detection biasHigh riskNot described. Study was open-labelled.

Incomplete outcome data (attrition bias)
All outcomes
High risk18 participants (8.3%) excluded; however the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; quote: "Of these, eight were excluded from the SSCC analysis, two due to initial resistance to RMP but no other drug, two due to severe acquired immunodeficiency syndrome (AIDS) and super-infections during treatment caused by pan-resistant strains, one due to death on day 2, one had no sputum cultures after day 0 (included in the culture results), one withdrew voluntarily from the study and one had only two widely different bacillary counts." "For the analysis of sputum culture results at 8 weeks, a further five patients were excluded, one due to early death, one due to heavy ethanol consumption, two had treatment changed due to drug reactions and one voluntary withdrawal".

Selective reporting (reporting bias)High riskAuthors did not present data on the most frequent adverse events by study group or on cause of death by study group, or time of death. Presentation of adverse events in the text and in the table was confusing.

This obscured the data.

Quote: "The most frequent adverse events were raised amylase (in 41% of patients due to HIV infection), raised transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and vomiting (5%). Serious adverse events occurred in 18 patients. Deaths were due to progression of AIDS in two patients, and to haemoptysis and to epileptic seizure in two other patients. Of the remaining 14 patients, two had elevated liver enzymes, three had arthralgia and the remaining nine developed one of the following events: renal failure, pancytopaenia, thrombocytopaenia, deep vein thrombosis, gastroenteritis, gastritis, Pneumocystis carinii infection, spontaneous pneumothorax or worsening pulmonary TB with AIDS. There were no serious glycaemic events in any arm. Minor grades of hypoglycaemia or hyperglycaemia were no more evident during therapy than at baseline, nor were they more common in the Gati arm. There was no evidence of prolongation of the QTc interval in electrocardiograms".

Other biasHigh riskNo conflict of interest statement.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abdullah 1997Reported as an abstract only, MDR-TB, not in review.

Abdullah 1998Reported as an abstract only, MDR-TB, not in review.

Agarwal 2007Reported as an abstract only. No randomization.

Andries 2005Experimental animal study, plus a small section in healthy human volunteers (tolerability); not a trial report.

Anonymous 1997No randomization or control group.

Barmina 2009Not relevant research question: roncoleukin versus basic regimen.

Bartacek 2009Not relevant research question: fixed-dose combination versus single tablets treatment, fluoroquinolones not used.

Carroll 2012A case report, XDR-NB, another drug - linezolide, not in review.

Chambers 1998The outcome, early bactericidal activity, not in review.

Chang 2008Not relevant research question: hepatotoxicity of pyrazinamide. No randomization, cohort and case-control analysis.

Chang 2009Not relevant research question: participants with community acquired pneumonia or exacerbation of bronchiectasis.

Chen 2003No randomization and the intervention was a combination of levofloxacin plus capreomycin.

Chigutsa 2012Not a RCT, MDR-TB, not in review.

Chukanov 2006Mixed intervention of ciprofloxacin, ofloxacin, or levofloxacin plus kanamycin or amikacin added to the basic regimen in study group versus streptomycin added to the basic regimen in control group.

Diacon 2009Not relevant comparison/research question: study drug TMC207 (investigational diarylquinoline compound), ofloxacin used in the study and control groups.

Diacon 2012aNot relevant study drug TMC207 - bedaquiline, MDR-TB, not in review.

Diacon 2012bThe outcome, bactericidal activity, not in review.

Estebanez 1992Exclusively urogenital TB.

Fouad 2011Review paper, not RCT.

Gosling 2003The outcome, early bactericidal activity, not in review.

Grishin 1998No randomization; cohort study.

Heemskerk 2011Protocol for TB meningitis. International Standard Randomized Controlled Trial Number ISRCTN61649292.

Ho 2007Reported as an abstract only, not a trial report.

Huang 2000Participants with MDR-TB, not in review.

Jenkins 2008Not relevant comparison/research question: ciprofloxacin compared with clarithromycin in patients with pulmonary disease caused by M. avium-intracellulare (MAC).

Ji 2001Participants: MDR-TB, not in review.

Johnson 2006The outcome, early bactericidal activity, not in review.

Kang 2009Mixed intervention of 3RFT AM Ofx Pto PAS-INH/5RFT Ofx Pto PAS-INH in study group versus 3 H3R3Z3E3S3/5 H3R3E3 in control group, that is comparison groups differed not only by fluoroquinolone use.

Kawahara 1992No randomization.

Kennedy 1993Intervention: ciprofloxacin substituted for pyrazinamide and ethambutol, not in review.

Kennedy 1996Intervention: ciprofloxacin substituted for pyrazinamide and ethambutol, not in review.

Kohno 1992Intervention: ofloxacin substituted for ethambutol in drug-sensitive disease, basic regimen without pyrazinamide, not in review.

Kumar 2004Study in healthy volunteers, not a trial report, in which the outcome was uric acid concentration in urine samples excreted over 0 to 8 hours.

Lee 2011A retrospective study, not a RCT.

Li 2008Mixed intervention of 3RFT AM Ofx Pto PAS-INH/5RFT Ofx Pto PAS-INH regimen, including rifapentine (RFT), amikacin (Am), ofloxacin (Ofx), protionamide (Pto), para-aminosalicylic acid-isoniazid (PAS-INH) for three months and then RFT, Ofx, Pto, and PAS-INH for five months in study group versus 3 H3R3Z3E3S3/5 H3R3E3, including isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) for three months and then H, R, and E for five months in control group, that is comparison groups differed not only by fluoroquinolone use.

Lu 2000Participants: presumed MDR-TB, re-treatment; basic regimen without rifampicin, not in review.

Marra 2005Retrospective safety study; not a trial report.

Merle 2012Discussion of OFLOTUB project, not a trial report.

Moadebi 2007Review paper, not a trial report.

Mohanty 1993Intervention: ciprofloxacin substituted for rifampicin, not in review.

Moulding 2008Correspondence paper, not a trial report.

Nakamura 2007Not relevant research question: comparison of five day short-course therapies for secondary infection in patients with chronic respiratory disease using gatifloxacin and levofloxacin.

Nosova 2008Not relevant research question: study of fluoroquinolone resistance in TB patients; not a RCT.

O'Brien 1994Communication to the Editor of Chest; not a trial report.

Peloquin 2008Not relevant research question: population pharmacokinetics of three fluoroquinolones - levofloxacin, gatifloxacin and moxifloxacin.

Pletz 2004The outcome, early bactericidal activity, not in review.

Ruslami 2013TB meningitis, not in review.

Rustomjee 2008bThe outcome, early bactericidal activity, not in review.

Saigal 2001Intervention: ofloxacin + pyrazinamide substituted for rifampicin, not in review.

Sirgel 1997The outcome, early bactericidal activity, not in review.

Sirgel 2000The outcome, early bactericidal activity, not in review.

Sokolova 1998No randomization; cohort study.

Sun 2000Participants: all proven MDR-TB, not in review.

Suo 1996No randomization; not a controlled study.

Thwaites 2011Participants: TB meningitis, not in review.

TRC 2002No control arm, that is, a group treated without the studied fluoroquinolone (ofloxacin), a different fluoroquinolone, or different dose.

Valerio 2003No randomization and outcomes not reported.

Venter 2006The outcome, indices of adrenocortical function, not in review; none of the included outcomes reported, too small (20 participants).

Wang 2006Retrospective study; not a trial report.

Wolbers 2011TB meningitis, not in review. Current Controlled Trials ISRCTN61649292.

Yoon 2005Retrospective case-control study; not a trial report.

Yoon 2012Not a RCT report, fluoroquinolone substitution for rifampicin, not in review.

Zhang 1997The efficacy of bronchofibrescope and catheter intervention with ofloxacin and amikacin studied in comparison with traditional chemotherapy.

Zhang 2006The efficacy of rifabutin versus rifapentine containing antituberculous regimens studied, both regimens included levofloxacin; study question not in review.

Zhao 2003No randomization.

Zheng 2004Mixed intervention of levofloxacin plus pasiniazide plus M. vaccae.

Zhu 2006The efficacy of rifabutin versus rifapentine containing antituberculous regimens studied, both regimens included levofloxacin; study question not in review.

Zhu 2012A review paper, not a RCT report.

Zvada 2012Not a RCT report.

 
Characteristics of ongoing studies [ordered by study ID]
CTRI/2012/10/003060

Trial name or titleThrice weekly 4- months moxifloxacin or gatifloxacin regimens for pulmonary TB

MethodsRandomized, parallel group, active controlled trial
Method of generating randomization sequence: stratified block randomization. Method of allocation concealment: sequentially numbered, sealed, opaque envelopes. Blinding and masking: open label

ParticipantsInclusion criteria: patients aged 18 years and above, residing in or around Chennai or Madurai will be eligible for enrolment to the study. They should not have had anti-TB treatment in the past or should have had less than one month of treatment (but less than one week in the preceding one month before enrolment in the study).
They should have sputum culture-positive pulmonary TB (at least two cultures should be positive). Patients will be enrolled to the study when two sputum smears are positive and will be retained for analysis only if two cultures are positive.
They should consent to attend the treatment centre for supervised treatment for 6 months and for home visits by the staff of the centre. They should give written informed consent.

Exclusion criteria: body weight less than 30 kg; hepatic or renal disease as evidenced by clinical or biochemical abnormalities; diabetes mellitus; a history of seizures; psychiatric illness; an abnormal electrocardiogram or those on anti-arrhythmic medication; those in a moribund state;
those sero-positive for HIV antibodies; pregnant or lactating women.

InterventionsIntervention 1: 2GHRZ thrice weekly/ 2GHR thrice weekly: gatifloxacin, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by gatifloxacin, isoniazid, and rifampicin thrice weekly for 2 months (total duration 4 months).
Intervention 2: 2MHRZ thrice weekly/ 2MHR thrice weekly: moxifloxacin, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by moxifloxacin, isoniazid, and rifampicin thrice weekly for 2 months (total duration 4 months).
Intervention 3: Regimen 1:
2MHRZ thrice weekly/2 MHR thrice-weekly.
Regimen 2:
2 GHRZ thrice weekly/ 2 GHR thrice weekly.
Regimen 1:
2 MHRZ thrice weekly/ 2 MHR thrice weekly: moxifloxacin, isoniazid, rifampicin, and pyrazinamide thrice-weekly for 2 months followed by moxifloxacin, isoniazid, and rifampicin thrice-weekly for 2 months (duration 4 months).
Regimen 2:
2 GHRZ thrice weekly/ 2 GHR thrice weekly: gatifloxacin, isoniazid, rifampicin, and pyrazinamide thrice-weekly for 2 months followed by gatifloxacin, isoniazid, and rifampicin thrice-weekly for 2 months (duration 4 months).
Intervention 4: Regimen 2:
2 GHRZ thrice weekly/ 2 GHR thrice weekly: Regimen 2: gatifloxacin, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by gatifloxacin, isoniazid, and rifampicin thrice weekly for 2 months (total duration 4 months).
Control Intervention 1: 2EHRZ thrice weekly/ 4HR thrice weekly: ethambutol, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by isoniazid and rifampicin thrice weekly for 4 months (total duration 6 months).
Control Intervention 2: 2EHRZ thrice weekly/ 4HR thrice weekly: ethambutol, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by isoniazid and rifampicin thrice weekly for 4 months (total duration 6 months).
Control Intervention 3: Regimen 3:
2EHRZ thrice weekly/ 4HR thrice weekly: ethambutol, isoniazid, rifampicin, and pyrazinamide thrice weekly for 2 months followed by isoniazid and rifampicin thrice weekly.

OutcomesTB recurrence rate timepoint: up to 24 months post-treatment; secondary outcomes: a) sputum culture conversion at 2 months; b) status at end of treatment; c) treatment related adverse reaction timepoint: up to 24 months post-treatment.

Starting date14-05-2004

Contact informationNational Institute for Research in TB, Indian Council of Medical Research, No:1, Mayor Sathyamoorthy Road, Chetpet, Chennai-31 600 031Chennai, TAMIL NADUIndia; shaheedjawahar@gmail.com; 04428369500

NotesLocation: India

Source of funding: ICMR, National Institute for Research in TB, Indian Council of Medical Research, No:1, Mayor Sathyamoorthy Road, Chetpet, Chennai-31

ISRCTN44153044 RIFAQUIN

Trial name or titleAn international multi centre controlled clinical trial to evaluate high dose RIFApentine and a QUINolone in the treatment of pulmonary TB - RIFAQUIN

Methods

ParticipantsInclusion criteria: newly diagnosed pulmonary TB; 2 sputum specimens positive for tubercle bacilli on direct smear microscopy; either no previous antituberculous chemotherapy, or < 2 weeks of previous chemotherapy; aged 18 years and over; firm home address that is readily accessible for visiting and be intending to remain there during 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.

Exclusion criteria: any condition (except HIV infection) that may prove fatal during the study period; tuberculous meningitis; pre-existing nontuberculous 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; suffering from a condition likely to lead to uncooperative behaviour such as psychiatric illness or alcoholism; contraindications to any medications in the study regimens; requires antiretroviral treatment (ART) at diagnosis; history of prolonged QTc syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of antituberculous therapy; haemoglobin < 7g/L; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper range; creatinine clearance < 30 mL/min; history of seizures; HIV positive with a CD4 count < 200/mm3; weight < 35 kg.

Interventions1. 2 months of daily ethambutol (E), moxifloxacin (M), rifampicin (R), and pyrazinamide (Z) followed by 2 months of twice weekly moxifloxacin and rifapentine (2EMRZ/2P2M2).
2. 2 months of daily ethambutol, moxifloxacin, rifampicin, and pyrazinamide followed by 4 months of once weekly moxifloxacin and rifapentine (2EMRZ/4P1M1).
3. 2 months of daily ethambutol (E), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR).

Outcomes1. Combined rate of failure at the end of treatment and relapse, measured at 18 months.
2. Presence of rifamycin mono-resistance (RMR) in relapse cultures of HIV-infected patients, measured at 5, 6, 7, 8, 9, 10, 11, 12, 15, 18 months on the 4-month arm and 7, 8, 9, 10, 11, 12, 15, 18 months on the 6-month arm, plus at any unscheduled visit.
3. Occurrence of serious adverse events at any time during chemotherapy, recorded as they present themselves throughout the course of the trial.
4. Sputum culture results at 2 months after the initiation of chemotherapy, measured at all visits.
5. Rate of completion of chemotherapy according to the protocol, measured at all visits.
6. Number of observed doses of chemotherapy ingested, measured at all visits.
7. Any adverse events, recorded as they present themselves throughout the course of the trial.

Starting date31 July 2007

Contact informationDr Amina Jindani (ajindani@sgul.ac.uk), Centre for Infection

Department of Cellular and Molecular Medicine

St. George’s University of London, UK

NotesLocation: South Africa, Mozambique, Zimbabwe, Zambia

Registration number: ISRCTN44153044

Source of funding: European and Developing Countries Clinical Trials Partnership (EDCTP) (The Netherlands)

NCT00216385

Trial name or titleA controlled trial of a 4-month quinolone-containing regimen for the treatment of pulmonary TB OFLOTUB III

Methods

ParticipantsInclusion criteria: male or female; aged 18 to 65 years; currently suffering from recently diagnosed microscopically proven pulmonary TB and providing informed consent for inclusion in the study.

Exclusion criteria: history of TB treatment within the last 3 years; history of diabetes mellitus or non-insulin dependent diabetes mellitus requiring treatment; concomitant infection requiring additional anti-infective treatment (especially antiretroviral therapy); HIV- infected patients with WHO stage 3 infection - except those presenting with only the "loss of weight > 10% body weight" criterion - and all HIV infected patients at WHO stage 4.

Interventions1. 4-month gatifloxacin-containing antituberculous regimen
2. Standard antituberculous regimen

Outcomes1. Percentage of relapses by 24 months following treatment cure.
2. Percentage of adverse events.
3. Time to relapse.
4. Percentage of smear and culture conversion at 8 weeks.
5. Percentage of patient cured at the end 6. of treatment.
7. Time to a composite "unsatisfactory" endpoint.
8. Distribution of type and grading of adverse events.

Starting dateJanuary 2005

Contact informationChristian Lienhardt (Study Director), Institut de Recherche pour le Developpement, France

NotesLocation: Benin, Guinea, Kenya, Senegal, South Africa

Registration number: NCT00216385

Sponsors and collaborators: Institut de Recherche pour le Developpement; WHO;
European Commission

NCT00396084

Trial name or titleRandomized, open label, multiple dose Phase I study of the early bactericidal activity of linezolid, gatifloxacin, levofloxacin, and moxifloxacin in HIV-non-infected adults with Initial episodes of sputum smear-positive pulmonary TB (DMID 01-553)

Methods

ParticipantsInclusion criteria: adults, male or female, aged 18 to 65 years; women with child-bearing potential (not surgically sterilized or postmenopausal for < 1 year) must be using or agree to use an adequate method of birth control (condom: intravaginal spermicide (foams, jellies, sponge) and diaphragm: cervical cap or intrauterine device) during study drug treatment; newly diagnosed sputum smear-positive pulmonary TB as confirmed by sputum AFB smear and chest x-ray findings consistent with pulmonary TB; willing and able to provide informed consent; reasonably normal haemoglobin (≥ 8 gm/dL), renal function (serum creatinine < 2 mg/dL), hepatic function (serum AST < 1.5 times the upper limit of normal for the testing laboratory and total bilirubin < 1.3 mg/dL), and random blood glucose < 150 mg/dL.

Exclusion criteria: HIV infection; weight < 75% of ideal body weight; presence of significant haemoptysis; patients who cough up frank blood (more than blood streaked sputum); pregnant or breastfeeding women and those who are not practicing birth control; significant respiratory impairment (respiratory rate > 35/min); clinical suspicion of disseminated TB or TB meningitis; presence of serious underlying medical illness (e.g. such as liver failure, renal failure, diabetes mellitus, chronic alcoholism, decompensated heart failure, haematologic malignancy) or patients receiving myelosuppressive chemotherapy; patients receiving any of monoamine oxidase inhibitors (phenelzine, tranylcypromine), adrenergic/serotonergic agonists such as pseudoephedrine and phenylpropanolamine (frequently found in cold and cough remedies), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc), antipsychotics (e.g. chlorpromazine and buspirone), serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, etc), bupropion, agents known to prolong the QTc interval [erythromycin, clarithromycin, astemizole, type Ia (quinidine, procainamide, disopyramide) and III (amiodarone, sotalol) anti-arrhythmics, carbamazepine, insulin, sulphonylureas, and meperidine; presence of QTc prolongation (> 450 msec) on baseline EKG; allergy or contraindication to use of study drugs; treatment with antituberculous medications or other antibiotics with known activity against M. tuberculosis during the preceding 6 months; inability to provide informed consent; total white blood cell count < 3000/mm3; platelet count < 150,000/mm3; patients with suspected drug-resistant TB (e.g. contact to source patient with drug-resistant TB, patients who have relapsed after previous treatment for TB); patients likely, in the opinion of the local investigator, to be unable to comply with the requirements of the study protocol.

InterventionsParticipants will be randomized to receive gatifloxacin, levofloxacin, moxifloxacin, or isoniazid (control), and after these arms are enrolled, they will be randomized to receive either linezolid (600 mg once daily) or linezolid (600 mg twice daily) or isoniazid (control). After the initial treatment, all participants will receive 6 months of standard antituberculous treatment outside of the hospital.

Outcomes1. Early bactericidal activity.
2. Extended early bactericidal activity.
3. Safety evaluations including clinical examination, complete blood counts, and serum total bilirubin, aspartate aminotransferase, and creatinine, and urinalysis will be followed to monitor for drug toxicity.

Starting dateFebruary 2004

Contact informationJohn Johnson (jlj@po.cwru.edu)

NotesLocation: University of Espírito Santo, Vitória, Brazil

Registration number: NCT00396084

Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)

NCT00728507

Trial name or titleA Phase II randomized, open-label trial of a rifapentine plus moxifloxacin-based regimen for intensive phase treatment of smear-positive pulmonary TB

MethodsTreatment randomized, open label, parallel assignment, safety/efficacy study

ParticipantsInclusion criteria: presumptive diagnosis of sputum smear-positive pulmonary TB; age: > 18 years; seven or fewer days of multidrug therapy for TB disease in the preceding 6 months; seven or fewer days of fluoroquinolone therapy in the preceding 3 months; documentation of HIV infection status; for HIV seropositive individuals, a CD4 T lymphocyte count of greater than or equal to 200 cells/mm3; documentation of study baseline laboratory parameters done at, or 14 days prior to screening; AST less than or equal to 2.5 times upper limit of normal; total bilirubin level less than 2.5 times upper limit of normal; creatinine level less than 2 times upper limit of normal; haemoglobin level of at least 8.0 g/dL; platelet count of at least 75,000 mm3; potassium level of at least 3.5; negative pregnancy test (women of childbearing potential); Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs); male or nonpregnant, non-nursing female; provision of informed consent.

Exclusion criteria: CD4 count < 200 cells/cu mm; presence of active AIDS-related opportunistic infection (other than TB) or active AIDS-related malignancy; known intolerance to any of the study drugs; concomitant disorders or conditions for which any of the study drugs is contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis; inability to take oral medication;
central nervous system TB; pulmonary silicosis; current or planned therapy, during study phase (intensive phase of TB treatment) with any one or more of the following drugs: quinidine, procainamide, amiodarone,
sotalol, disopyramide, terfenadine, cisapride, erythromycin, clarithromycin, phenothiazines, haloperidol, olanzapine, ziprasidone, tricyclic antidepressants, chronic corticosteroids administered either orally or intravenously, chronic fluconazole, chronic itraconazole, chronic ketoconazole, oral or intravenous
tacrolimus, oral or intravenous cyclosporine, HIV protease inhibitor, HIV non-nucleoside reverse transcriptase inhibitor; concurrent severe and/or uncontrolled medical or psychiatric condition that, in the
opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol; unable or unwilling to receive directly observed therapy and/or adhere with follow-up
(e.g. due to residence remote from the study site); refusal of consent.

InterventionsDrug: rifapentine, moxifloxacin, pyrazinamide, isoniazid
Drug: isoniazid, rifampin, pyrazinamide, ethambutol

OutcomesPrimary: to compare, by treatment group, the proportions of patients with a negative sputum culture at the end of intensive phase therapy. Week 8: no.
To compare the safety and tolerability of the 2 intensive phase regimens. Weekly or more frequent: yes.

Secondary: to compare the time to respiratory culture conversion of the 2 intensive phase regimens, using data from weekly cultures. Weekly: no.
To compare, by treatment group, the proportions of subjects who experience treatment failure. Month 6: no.
To compare, by HIV serostatus, a) the safety of the 2 intensive phase regimens, b) the proportions of patients with negative sputum cultures at the end of intensive phase therapy, and c) the time to culture conversion using data from weekly cultures. Weekly or more frequently: yes.
To compare, in subjects with versus without cavitation on baseline chest x-ray, the proportions of patients with negative sputum cultures at the end of intensive phase therapy. Week 8: no.
To store serum for future assessment of hypersensitivity to study drugs, should it occur; to store plasma for future assessment of drug concentrations. Future: yes

Starting dateSeptember 2009

Contact informationSusan Dorman, MD
Tel: 410-955-1755
dsusan1@jhmi.edu

NotesNot yet recruiting. Location: Brazil, Hospital Universitario Clementio Fraga Filho
Rio de Janeiro; Hospital Escola Sao Francisco de Assis, Rio de Janeiro

NCT00864383 REMoxTB

Trial name or titleControlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary TB

CTRI/2011/05/001745 REMoxTB version 1.3  

MethodsA randomized placebo controlled double blind trial comparing two treatment shortening regimens with the standard regimen (two months ethambutol, isoniazid, rifampicin, and pyrazinamide followed by four months isoniazid and rifampicin) namely 1) two months moxifloxacin, isoniazid, rifampicin, and pyrazinamide followed by two months moxifloxacin, isoniazid, and rifampicin and 2) two months ethambutol, moxifloxacin, rifampicin, and pyrazinamide followed by two months moxifloxacin and rifampicin for the treatment of adults with pulmonary TB - REMoxTB.

Randomized, parallel group, placebo controlled trial.
Method of generating randomization sequence: random number table. Method of allocation concealment: pre-numbered or coded identical containers. Blinding and masking: participant, investigator, outcome assessor, and data-entry operator blinded.

ParticipantsTarget sample size: 1800

Inclusion criteria: signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial related activity; two sputum specimens positive for tubercle bacilli on direct smear microscopy at the local laboratory and confirmed at the study laboratory on a sample taken at screening; aged 18 years or over; no previous anti-TB chemotherapy; a firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during the treatment and follow-up period; agreement to participate in the study and to give a sample of blood for HIV testing
(see appendices 1 & 2); pre-menopausal women must be using a barrier form of contraception or be surgically sterilized or have an IUCD in place; laboratory parameters performed up to 14 days before enrolment (Serum aspartate transaminase (AST) activity less than 3 times the upper limit of normal. Serum total bilirubin level less than 2.5 times upper limit of normal. Creatinine clearance (CrCl) level greater than 30 mLs/min. Haemoglobin level of at least 7.0 g/dL. Platelet count of at least 50x109cells/L. Serum potassium greater than 3.5 mmol/L); negative pregnancy test (women of childbearing potential).

Exclusion criteria: unable to take oral medication; previously enrolled in this study; received any investigational drug in the past 3 months; received an antibiotic active against M. tuberculosis in the last 14 days (fluoroquinolones, macrolides, standard anti-TB drugs); any condition that may prove fatal during the first two months of the study period; TB meningitis or other forms of severe TB with high risk of a poor outcome; pre-existing non-TB disease likely to prejudice the response to, or assessment of, treatment e.g. insulin-dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhoeal disease; pregnant or breast feeding; suffering from a condition likely to lead to uncooperative behaviour e.g. psychiatric illness or alcoholism; contraindications to any medications in the study regimens; known to have congenital or sporadic syndromes of QTc prolongation or receiving concomitant medication reported to increase the QTc interval (e.g. amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine); known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated with quinolones; patients already receiving antiretroviral therapy; patients whose initial isolate is shown to be MDR-TB; weight less than 35 kg; HIV infection with CD4 count less than 250 cells/µL; end stage liver failure (class Child-Pugh C).

InterventionsIntervention 1: moxifloxacin in combination with ethambutol, pyrazinamide, and rifampicin: moxifloxacin, ethambutol, rifampicin, pyrazinamide for 2 months and moxifloxacin, rifampicin, and isoniazid placebo for 2 months and then isoniazid and rifampicin placebo for 2 months. Dose depend upon weight of the patient.
Intervention 2: moxifloxacin in combination with isoniazid, pyrazinamide, and rifampicin: moxifloxacin, isoniazid, rifampicin, pyrazinamide for 2 months and moxifloxacin, isoniazid, and rifampicin for 2 months.
Isoniazid and rifampicin placebo for 2 months. Dose depend upon weight of the patient.
Control intervention 1: standard anti-TB treatment: rifampicin, isoniazid, ethambutol, pyrazinamide for 2 months.
Rifampicin and isoniazid and placebo for 4 months. Dose depend upon the weight of the patient.

OutcomesPrimary:

1. Efficacy: combined failure of bacteriological cure and relapse within one year of completion of therapy as defined by culture using solid media.
2. Safety: both comparisons: proportion of patients with grade 3 or 4 adverse events.Timepoint: 1.5 years

Secondary:

Efficacy:
1. Combined failure of bacteriological cure and relapse within one year of completion of therapy as defined by culture using liquid media.
The following endpoints will be measured separately using both solid and liquid media.
2. Sensitivity analyses assuming all losses to follow-up and non-tuberculous deaths have an unfavourable outcome.
3. Sensitivity analyses assuming all losses to follow-up and non-tuberculous deaths have a favourable outcome.
4. Proportion of patients who are culture negative at eight weeks.
5. Time to first culture negative sputum sample.
6. Speed of decline of sputum viable count. Timepoint: 1.5 years.

Starting dateJanuary 2008

Contact informationStephen H Gillespie
Tel: +44 (0) 20 7794 0500 ext.: 33539
s.gillespie@medsch.ucl.ac.uk

Kapil Arora

579, Devli East Sainik Farms 110062New Delhi, DELHIIndia

011-24502551

Kapil. Arora@apothecaries.net

NotesRecruiting locations: Kenya, Centre for Respiratory Disease Research at KEMRI Nairobi; South Africa, Unit for Clinical & Biomedical TB Research, MRC Durban, South Africa, Tiervlei Trial Center and University of Stellenbosch, Cape Town, South Africa, Centre for TB Research and Innovation, UCT Lung Institute, Cape Town; Tanzania, Kilimanjaro Christian Medical Centre, Moshi; Tanzania, NIMR Mbeya Medical Research Programme, Mbeya; Zambia, University Teaching Hospital, Lusaka; China, India, Mexico, South Africa, Thailand,

Global Alliance for TB Drug Development, New York, USA

Primary sponsor: Apothecaries Private Limited

http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=2686

NCT01498419

Trial name or titleEvaluation of 8 weeks of treatment with the combination of moxifloxacin, PA-824, and pyrazinamide in patients with drug sensitive and multi drug-resistant pulmonary TB

NC-002-(M-Pa-Z)

MethodsA Phase II open-label partially randomized trial to evaluate the efficacy, safety and tolerability of the combination of moxifloxacin plus PA-824 plus pyrazinamide after 8 weeks of treatment in adult patients with newly diagnosed drug-sensitive or multi drug-resistant, smear-positive pulmonary TB.

ParticipantsTarget sample size: 230; Age: minimum: 18 years; Age maximum: 65 years;
Gender: both

Inclusion criteria: provide written, informed consent prior to all trial-related procedures including HIV
testing (if an HIV test was performed within 1 month prior to trial start, it should not be repeated as long as documentation can be provided (ELISA, or Western blot, or both); body weight (in light clothing and with no shoes) between 40 kg and 90 kg, inclusive; sputum smear-positive pulmonary TB (at trial appointed laboratory). For drug sensitive TB treatment arms, subjects should be newly diagnosed and previously untreated. Exception: participants can be included in the trial if they were diagnosed and treated for TB greater than 5 years prior to screening and can provide documentation of cure for that episode. Additionally, participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial. Drug-sensitive status to be confirmed with fluoroquinolone, rifampicin, and isoniazid susceptibility testing at screening using Hain Plus rapid sputum test.
For the MDR-TB treatment arm only: subjects with smear-positive MDR infection, defined as confirmed resistance to at least both R and H confirmed at screening for entry into this trial. Resistance to R and H will be determined using the rapid screen test (Hain Plus).
If the first spot sputum shows an indeterminate result, the test must be repeated on freshly collected spot sputum or overnight sputum and that result may be used.
Subjects with newly diagnosed MDR-TB are defined as a) subjects with MDR-TB who have never been treated for TB before, or b) subjects with MDR-TB who have previously been treated with only one course of first-line TB drugs (H, R, E, Z and/or S) and that treatment is/was discontinued at least 7 days prior to randomization into this trial. Additionally, MDR-TB participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial; a chest X-ray picture which in the opinion of the Investigator is compatible with TB; sputum positive (at site laboratory) on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale); ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production); females may participate if they are: 1) of non-childbearing potential (have had a bilateral oophorectomy, tubal ligation or hysterectomy or both, or have been postmenopausal for at least 12 consecutive months), 2) if they are using effective
birth control methods and are willing to continue practicing birth control methods throughout treatment, or 3) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either: 1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal-based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraceptive measures until one week after the last dose of study medication or one week after discontinuation from study medication in case of premature discontinuation. (Note: hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy); male participants who are having heterosexual intercourse with females of child-bearing potential are required to use one of the following birth control methods during their participation in the trial and for 12 weeks after their last dose of study medication to prevent pregnancy: a double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or a barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.
The use of the above mentioned birth control method does not apply if the male participant has been vasectomized or has had a bilateral orchidectomy minimally three months prior to screening, or is not heterosexually active, or practices sexual abstinence, or if the female sexual partner has had a bilateral oophorectomy, tubal ligation or hysterectomy or both, or has been postmenopausal for at least 12 consecutive months.

Exclusion criteria: evidence of clinically significant (as judged by the investigator), metabolic,
gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including myasthenia gravis and malaria; end stage liver failure (class Child Pugh C); poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator; clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator; history of allergy or hypersensitivity to any of the study IMP or related substances, including a known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifamycin antibiotics; resistance to fluoroquinolones (Hain plus rapid test), or pyrazinamide, or both; participants may be included in the study prior to receipt of the susceptibility test results for fluoroquinolones or pyrazinamide, however once these are received after a participant has entered into the study and if the results show the participant is resistant to fluoroquinolones, or pyrazinamide, or both, such a participant should be removed from the trial. DS participants will not be replaced, but MDR-TB participants taking part in the EBA sub-study could be replaced after consultation and written approval with the sponsor; known (positive urine drug screen) or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator sufficient to compromise the safety or cooperation of the participant;
For HIV infected participants:
having a CD4+ count < 200 cells/µL,
or having received intravenous antifungal medication within the last 90 days,
or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB), or having participated in other trials.

InterventionsDrug: M (400 mg) Pa (100 mg) Z (1500 mg)

Drug: M (400 mg) Pa (200 mg) Z (1500 mg)

Drug: rifafour

OutcomesPrimary: the rate of change in colony forming units (CFUs) using non-linear mixed effects modelling of the Serial Sputum Colony Counts (SSCC) over 8 weeks of treatment (time frame: over 8 weeks of treatment).

Secondary: proportion of participants with adverse events and proportion of participants who discontinue due to an adverse event in each experimental arm (time frame: over 8 weeks).

Proportion of patients with sputum culture conversion at 8 weeks (time frame: 8 weeks).

The rate of change in time to sputum culture positivity (TTP) through 8 weeks in the MGIT system in sputum over 8 weeks in participants which may be described with linear, bi-linear, or non-linear regression of TTP on time (time frame: over 8 weeks).

Time to sputum conversion using data from weekly cultures through 8 weeks (separately, on solid and liquid media) (time frame: over 8 weeks).

Starting dateFebruary 2012

Contact informationAlmari Conradie: Tel 27 (12) 844-0951; almari.conradie@tballiance.org

Rodney Dawson, MD University of Cape Town

http://clinicaltrials.gov/show/NCT01498419

NotesNot yet recruiting; location: Brazil, South Africa, Tanzania

Primary sponsor: Global Alliance for TB Drug Development

NCT01589497

Trial name or titleEarly bactericidal activity (EBA) study of TB regimens with and without INH and moxifloxacin

MethodsAllocation: randomized; endpoint classification: efficacy study; intervention model: parallel assignment; masking: open label; primary purpose: treatment

ParticipantsAge minimum: 18 years; age maximum: N/A; gender: both

Inclusion criteria: absence of HIV-1 infection within 30 days prior to study entry or
HIV-1 infection; confirmed sputum positive for acid fast bacilli (AFB) by smear-microscopy =1+ within 1 day prior to study entry; body weight: 40 kg to 90 kg, inclusive; age = 18 years at study entry; certain laboratory values, as defined in section 4.1.5 in the protocol, obtained within 30 days prior to entry.

For HIV-positive candidates only: CD4+ cell count of > 100 cells/mm3, obtained within 7 days prior to study entry at a DAIDS approved laboratory.

For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to entry. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (condoms, with a spermicidal agent; a diaphragm, or cervical cap with spermicide; or an IUD) while receiving study medications.

If a chest x-ray has not been performed within 14 days prior to entry, or the results of such an x-ray are not available, then a chest x-ray must be performed as part of screening.
Ability and willingness of subject or legal guardian/representative to provide informed consent.
Willingness to be hospitalized for approximately 16 days.

Exclusion criteria: receipt of INH prophylaxis or TB therapy for more than 7 cumulative days in the last 6 months, or of any fluoroquinolone in the 1 month prior to entry; currently or within 30 days on antiretroviral treatment (ART) or expected to initiate ART within 2 weeks after study entry; breastfeeding; known intolerance to any of the study drugs; resistance to rifampicin determined by GeneXpert within 7 days prior to study entry; known history of resistance to isoniazid or rifampin or known close exposure (i.e., household exposure) to someone with MDR TB or known study candidate default on previous TB treatment (ie, the study candidate was diagnosed with TB, started TB treatment but did not complete that treatment); known allergy to any fluoroquinolone antibiotic; history of prolonged QT syndrome or a QTc of > 450 ms; current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the first 2 months of TB treatment; current or prior diagnosis of pulmonary silicosis; advanced disease as defined by Karnofsky score = 70 at entry; any of the following current comorbidities, complications, or underlying medical conditions:
- poorly controlled diabetes (definition: patients with random plasma glucose > 180 mg/dL within 2 days prior to study entry)
- uncontrolled hypertension (definition: requiring acute medical treatment or immediate hospitalization)
- miliary TB
- neurological TB (including TB of the spine, TB meningitis)
- peripheral neuropathy = Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity table, within 90 days prior to study entry
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- Estimated overnight sputum production of < 10 mL.
- Requirement for concomitant medications that may potentially interact with study drugs.

InterventionsDrug: ethambutol

Drug: isoniazid

Drug: moxifloxacin

Drug: pyrazinamide

Drug: rifampicin

OutcomesDaily decrease in log10 CFU/ml sputum between day 2 and 14 since study treatment initiation (time frame: 12 days)

Starting dateJanuary 2013

Contact informationWilliam Bishai, MD, PhD, KwaZulu-Natal Research Institute for TB and HIV (K-RITH); Susan Swindells, MBBS, University of Colorado Hospital CRS

NotesLocation: South Africa

Primary sponsor: AIDS Clinical Trials Group

SEcondary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

NCT01785186

Trial name or titleEvaluation of SQ109, high-dose rifampicin, and moxifloxacin in adults with smear-positive pulmonary TB in a MAMS design (PanACEA-MAMS-TB-01)

MethodsAllocation: randomized; endpoint classification: safety/efficacy study; intervention model: single group Assignment; masking: open label; primary purpose: treatment

ParticipantsAge minimum: 18 years; age maximum: N/A; gender: both

Inclusion criteria
1. The patient has given free, signed written or witnessed oral informed consent for study participation prior to all trial-related procedures, including HIV testing if HIV serostatus is not known or the last documented negative is more than four weeks ago.
2. The patient has a diagnosis of pulmonary TB from a health clinic established by sputum smear and/or GeneXpert MTB/RIF® and/or chest X-ray.
3. An adequate sputum bacterial load is confirmed by a Ziehl-Neelsen stained smear in the study laboratory, done from concentrated sputum found at least 1+ on the IUATLD/WHO scale.
4. The patient has a valid rapid test result (GeneXpert MTB/RIF®) from the sputum positive for M. tuberculosis complex, and indicating susceptibility to Rifampicin. This test must be done in the study laboratory.
5. The patient is aged at least 18 years at the day of informed consent.
6. The patient has a body weight in light clothing and without shoes of at least 35 kg, but not more than 90 kg.
7. Female patients of childbearing potential must have a negative serum pregnancy test, and consent to practise an effective method of birth control until week 26. Effective birth control for female patients has to include two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Female patients are considered not to be of childbearing potential if they are post-menopausal with no menses for the last 12 months, or surgically sterile (this condition is fulfilled by bilateral oophorectomy, hysterectomy, and by tubal ligation which is done at least 12 months prior to enrolment).
8. Male patients must consent to use an effective contraceptive method, if their sexual partner(s) is/are of childbearing potential, and if they are not surgically sterile (see 6). Contraception by male participants must be practised until at least week 24 to cover the period of spermatogenesis. Contraceptive methods used by male participants may include hormonal methods used by the partner(s).
9. The patient has a firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during trial participation, or will be compliant to study schedule, in the discretion of the investigator.

Exclusion criteria
1. Circumstances that raise doubt about free, uncoerced consent to study participation (e.g. in a prisoner or mentally handicapped person)
2. Poor general condition where delay in treatment cannot be tolerated or death within
three months is likely.
3. The patient is pregnant or breast-feeding.
4. The patient has an HIV infection and is receiving ART, or is likely to require ART during the twelve weeks of experimental study treatment as per local guidelines, or both.
5. The patient has a known intolerance to any of the study drugs, or concomitant disorders or conditions for which SQ109, rifampicin, moxifloxacin, or standard TB treatment are contraindicated.
6. The patient has an history or evidence of clinically relevant metabolic, gastrointestinal, neurological, psychiatric, or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:
clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis. Limited lymph node involvement will not lead to exclusion); serious lung conditions other than TB or severe respiratory impairment in the discretion of the investigator; neuropathy, epilepsy, or significant psychiatric disorder; uncontrolled and/or insulin-dependent diabetes; cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, uncontrolled hypertension (systolic blood pressure =160 mmHg, or diastolic blood pressure of =100 mmHg on two occasions, or both), arrhythmia, or tachyarrhythmia; long QT syndrome (see criterion 9), or family
history of long QT syndrome or sudden death of unknown or cardiac-related cause;
Plasmodium spp. parasitaemia as indicated by thick blood smear or a positive rapid test present at screening; alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage at the discretion of the investigator.
7. History of previous TB within the last five years.
8. Laboratory: at screening one or more of the following abnormalities were observed for the patient in screening laboratory: serum amino aspartate transferase (AST), or serum alanine aminotransferase (ALT) activity >3x the upper limit of normal, or both; Serum total bilirubin level > 2.5 times the upper limit of normal; creatinine clearance (CrCl) level lower than 30 mLs/min; complete blood count with haemoglobin level < 7.0 g/dL; platelet count < 50,000/mm3; Serum potassium below the lower level of normal.
9. ECG findings in the screening ECG: QTcB, or QTcF, or both, of > 0.450 s; atrioventricular (AV) block with PR interval > 0.20 s; prolongation of the QRS complex over 120 milliseconds; other changes in the ECG that are clinically relevant as per discretion of the investigator.
10. The patient has had treatment with any other investigational drug within 1 month prior to enrolment, or enrolment into other clinical (intervention) trials is planned during week 1 to 26.
11. Previous anti-TB treatment: the patient has had previous treatment with drugs active against M. tuberculosis within the last 3 months, including but not limited to INH, EMB, RIF, PZA, amikacin, cycloserine, rifabutin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, fluoroquinolones, thioamides.
12. QT prolonging medications: administration within 30 days prior to study start, anticipated administration during the study period, or during the 12 weeks of experimental treatment, of any QT-prolonging agents such as, but not limited to, azithromycin, bepridil chloroquine, chlorpromazine, cisapride, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, lumefantrine, mefloquine, mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, procainamide,
quinidine, quinine, roxithromycin, sotalol, sparfloxacin, terfenadine, thioridazine.
Exceptions may be made for participants who have received 3 days or less of one of
these drugs or substances, if there has been a wash-out period.

InterventionsDietary supplement: pyridoxine

Drug: ethambutol

Drug: isoniazid

Drug: moxifloxacin

Drug: pyrazinamide

Drug: rifampicin

Drug: SQ109

OutcomesPrimary outcome: sputum culture conversion (2 negative cultures) using liquid media (time frame: 0 to 12 weeks)

Secondary outcomes: changes in baseline laboratory safety parameters during treatment and follow-up (time frame: 0 to 12 weeks)

Frequency of adverse events (time frame: 0 to 12 weeks)

Mycobacteriology identification and characterization by PCR and MIC (time frame: 0 to 12 weeks)

Occurence of treatment failure (relapse or emergence of drug-resistance) (time frame: 0 to 12 weeks)

Pharmacodynamics including AUC0-24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) (time frame: 0 to 12 weeks)

Pharmacokinetics including AUC, Cl, t1/2, Vd, and protein binding (time frame: 0 to 12 weeks)

Proportion of negative sputum cultures (time frame: 0 to 12 weeks)

Rate of change in quantitative PCR during therapy (time frame: 0 to 12 weeks)

Rate of change in time to positivity (time frame: 0 to 12 weeks)

Time to first negative culture on liquid and solid media (time frame: 0 to 12 weeks)

Starting dateFebruary 2013

Contact informationMichael Hoelscher; Klinikum of the University of Munich; 0049 89 2180; hoelscher@lrz.uni-muenchen.de

NotesLocation: South Africa, Tanzania

Secondary sponsor:

European and Developing Countries Clinical Trials Partnership (EDCTP),

German Federal Ministry of Education and Research,

Medical Research Council,

Radboud University,

Sequella, Inc.

 
Comparison 1. Fluoroquinolones plus standard regimen (HRZE) versus standard regimen alone (HRZE)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death from any cause190Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.03, 2.47]

 2 TB-related death190Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.05, 12.40]

 3 Sputum culture conversion at 8 weeks185Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.91, 1.07]

 4 Serious adverse events1174Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.40, 1.78]

 5 Total number of people with adverse events1174Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.52, 1.92]

 
Comparison 2. Fluoroquinolone substitution for ethambutol (E) in a standard six month regimen (HRZE)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse1125Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.17, 3.06]

 2 Death from any cause3608Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.21, 1.32]

    2.1 Moxifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
3467Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.23, 2.09]

    2.2 Ofloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
170Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.02, 4.86]

    2.3 Gatifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
171Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.00, 2.56]

 3 TB-related death1125Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.82]

 4 Sputum culture conversion at 8 weeks3608Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.97, 1.19]

    4.1 Moxifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
3467Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.98, 1.22]

    4.2 Ofloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
170Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.53, 1.26]

    4.3 Gatifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
171Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.78, 1.68]

 5 Serious adverse events3723Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.53, 1.62]

    5.1 Ofloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
173Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.13, 3.28]

    5.2 Moxifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
3577Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.56, 1.99]

    5.3 Gatifloxacin (fluoroquinolones + HRZ) versus ethambutol (HRZE)
173Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.09, 2.71]

 
Comparison 3. Fluoroquinolone substitution for isoniazid (H) in a standard six month regimen (HRZE)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death from any cause1328Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.17, 3.30]

 2 TB-related death1328Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.18, 21.84]

 3 Sputum culture conversion at 8 weeks1328Risk Ratio (M-H, Fixed, 95% CI)1.1 [0.91, 1.33]

 4 Serious adverse events1433Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.43, 2.80]

 
Summary of findings for the main comparison. Fluoroquinolone plus standard regimen compared to standard regimen alone for presumed drug-sensitive TB

Fluoroquinolone plus standard regimen compared to standard regimen alone for drug-sensitive TB

Patient or population: Patients with presumed drug-sensitive TB
Settings: New York and Hawaii
Intervention: Fluoroquinolone plus standard regimen
Comparison: Standard regimen alone

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Standard regimen aloneFluoroquinolone plus standard regimen

Treatment failure---(0 studies)-Not reported

Relapse---(0 studies)-Not reported

Death from any cause75 per 100020 per 1000
(2 to 185)
RR 0.27
(0.03 to 2.47)
174
(1 study)
⊕⊝⊝⊝
very low1,2,3

TB-related death25 per 100020 per 1000
(1 to 310)
RR 0.80
(0.05 to 12.40)
174
(1 study)
⊕⊝⊝⊝
very low1,2,3

Sputum culture conversion at 8 weeks973 per 1000954 per 1000
(885 to 1041)
RR 0.98
(0.91 to 1.07)
174
(1 study)
⊕⊕⊝⊝
very low2,4,5

Serious adverse events149 per 1000127 per 1000
(60 to 265)
RR 0.85
(0.4 to 1.78)
174
(1 study)
⊕⊝⊝⊝
very low1,2,6

One or more adverse event172 per 1000172 per 1000
(89 to 330)
RR 1
(0.52 to 1.92)
174
(1 study)
⊕⊝⊝⊝
very low1,2,7

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by one for risk of bias: 73/174 (42%) of trial participants were excluded.
2 Downgraded by one for indirectness: This single trial was conducted in adults with and without HIV infection in New York and Hawaii over 15 years ago. The result may not be generalized to other situations. Levofloxacin was added to the standard regimen: 500 mg daily for two weeks (induction phase); then 750 mg levofloxacin thrice weekly for six weeks; then standard regimen only (continuation phase).
3 Downgraded by one for imprecision: This trial is underpowered to detect a statistically significant result. Only four deaths were reported: one in the intervention group and three in the controls. Of these only two were deemed to be due to TB; one in each group.
4 Downgraded by one for risk of bias: 73/174 (42%) of trial participants were excluded at eight weeks analysis.
5 Downgraded by one for imprecision: This trial remains underpowered to detect difference. The result is not statistically significant.
6 Downgraded by one for imprecision: This trial is underpowered to detect rare but important adverse effects. The adverse effects are described as: nausea, vomiting, peripheral neuropathy, dermatologic reactions with fever, haematological adverse events, renal or metabolic toxicity, and hepatic toxicity.
 
Summary of findings 2. Fluoroquinolone substitution for ethambutol in a standard six month regimen compared to standard regimen for presumed drug-sensitive TB

Fluoroquinolone substitution for ethambutol in a standard six month regimen compared to standard regimen for drug-sensitive TB

Patient or population: Patients with presumed drug-sensitive TB
Settings: Brazil, North America, Africa, and South Africa
Intervention: Fluoroquinolone substitution for ethambutol in a standard six month regimen (fluoroquinolones + HRZ)

Comparison: Standard regimen (HRZE)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Standard regimenFluoroquinolone substitution for ethambutol

Treatment failure---(0 studies)-Not reported

Relapse66 per 100047 per 1000
(11 to 202)
RR 0.71
(0.17 to 3.06)
170
(1 study)
⊕⊝⊝⊝
very low1,2,3

Death from any cause32 per 100017 per 1000
(7 to 42)
RR 0.52
(0.21 to 1.32)
723
(3 studies)
⊕⊕⊝⊝
very low1,4,5,6

TB-related death16 per 10005 per 1000
(0 to 129)
RR 0.33
(0.01 to 8.07)
170
(1 study)
⊕⊝⊝⊝
very low1,2,6

Sputum culture conversion at 8 weeks704 per 1000753 per 1000
(683 to 838)
RR 1.07
(0.97 to 1.19)
723
(3 studies)
⊕⊕⊝⊝
very low1,4,5,7

Serious adverse events65 per 100060 per 1000
(34 to 105)
RR 0.93
(0.53 to 1.62)
723
(3 studies)
⊕⊕⊝⊝
very low1,4,5,8

One or more adverse events---(0 studies)-Not reported

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by one for risk of bias. All three trials were considered at high risk of bias due to high levels of exclusions from the final analysis.
2 Downgraded by one for indirectness: Only a single trial comparing moxifloxacin with ethambutol assessed this outcome. It was conducted in adults in Brazil between 2004 and 2007 and is not easily generalized to other fluoroquinolones or populations.
3 Downgraded by one for imprecision: The result is not statistically significant and the 95% CI is wide. This study was underpowered to detect an effect.
4 No serious inconsistency: None of three trials found a statistically significant difference.
5 No serious indirectness. Moxifloxacin, gatifloxacin, and ofloxacin have been compared to ethambutol and moxifloxacin in three trials, and gatifloxacin and ofloxacin in one trial each. These were conducted in adults from Brazil (between 2004 and 2007), North America, and Africa (dates not given), and South Africa (between 2004 and 2005).
6 Downgraded by two for imprecision: Only 14 deaths were reported in the three trials. Only Conde 2009 reported on TB-related death and only one occurred. Much larger trials would be necessary to show an effect.
7 Downgraded by one for imprecision. CIs of two of three studies are wide and studies remain underpowered.
8 Downgraded by one for imprecision. All three trials were underpowered to detect difference and CIs are wide.
 
Summary of findings 3. Fluoroquinolone substitution for isoniazid in a standard six month regimen compared to standard regimen for presumed drug-sensitive TB

Fluoroquinolone substitution for isoniazid in a standard six month regimen compared to standard regimen for presumed drug-sensitive TB

Patient or population: Patients with presumed drug-sensitive TB
Settings: North America, Brazil, South Africa, Spain, Uganda
Intervention: Fluoroquinolone substitution for isoniazid in a standard six month regimen

Comparison: Standard regimen (HRZE)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Standard regimenFluoroquinolone substitution for isoniazid

Treatment failure---(0 studies)-not reported

Relapse---(0 studies)-not reported

Death from any cause24 per 100018 per 1000
(4 to 79)
RR 0.75
(0.17 to 3.30)
433
(1 study)
⊕⊕⊝⊝
low1,2

TB-related death6 per 100012 per 1000
(1 to 131)
RR 2
(0.18 to 21.84)
433
(1 study)
⊕⊕⊝⊝
low1,2

Sputum culture conversion at 8 weeks549 per 1000604 per 1000
(500 to 730)
RR 1.10
(0.91 to 1.33)
433
(1 study)
⊕⊕⊝⊝
low1,3

Serious adverse events37 per 100041 per 1000
(16 to 104)
RR 1.1
(0.43 to 2.8)
433
(1 study)
⊕⊕⊝⊝
low1,4

One or more adverse event---(0 studies)-not reported

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Downgraded by one for risk of bias. 105/433 (24.3%) participants were excluded from the final analysis.
2 Downgraded by one for imprecision: The result is not statistically significant and the 95% CI is wide. This study was underpowered to detect an effect. Only seven deaths occurred and three were deemed related to TB.
3 Downgraded by one for imprecision: this single trial remains underpowered to detect an effect. The result is not statistically significant and the 95% CI is wide.
4 Downgraded by one for imprecision: The result is not statistically significant and the 95% CI is wide. This single study was underpowered to detect an effect. Only 14 serious adverse events occurred and they were equally distributed between comparison groups.