Scolaris Content Display Scolaris Content Display

Logic diagram of relationship between the use of fixed‐dose combinations (FDCs) and expected improvement of reported outcomes.
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Figure 1

Logic diagram of relationship between the use of fixed‐dose combinations (FDCs) and expected improvement of reported outcomes.

Flow diagram of the trial selection process.
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Figure 2

Flow diagram of the trial selection process.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.
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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.
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Figure 4

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.

Funnel plot of comparison: 1 Fixed‐dose combinations versus single‐drug formulations as available data, outcome: 1.4 Sputum smear or culture conversion at two months of starting treatment.
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Figure 5

Funnel plot of comparison: 1 Fixed‐dose combinations versus single‐drug formulations as available data, outcome: 1.4 Sputum smear or culture conversion at two months of starting treatment.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 1 Treatment failure.
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Analysis 1.1

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 1 Treatment failure.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 2 Relapse.
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Analysis 1.2

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 2 Relapse.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 3 Death.
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Analysis 1.3

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 3 Death.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 1.4

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 5 Sputum smear or culture conversion at end of treatment (EOT).
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Analysis 1.5

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 5 Sputum smear or culture conversion at end of treatment (EOT).

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 6 Treatment adherence at 8 weeks of starting treatment.
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Analysis 1.6

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 6 Treatment adherence at 8 weeks of starting treatment.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 7 Treatment adherence at EOT.
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Analysis 1.7

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 7 Treatment adherence at EOT.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 8 Acquisition of drug resistance.
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Analysis 1.8

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 8 Acquisition of drug resistance.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 9 Patient satisfaction.
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Analysis 1.9

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 9 Patient satisfaction.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 10 Serious adverse events.
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Analysis 1.10

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 10 Serious adverse events.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 11 Adverse events leading to discontinuation of therapy.
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Analysis 1.11

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 11 Adverse events leading to discontinuation of therapy.

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 12 Other adverse events.
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Analysis 1.12

Comparison 1 Fixed‐dose combinations versus single‐drug formulations as available data, Outcome 12 Other adverse events.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 1 Treatment failure.
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Analysis 2.1

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 1 Treatment failure.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 2 Relapse.
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Analysis 2.2

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 2 Relapse.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 3 Death.
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Analysis 2.3

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 3 Death.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 2.4

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 5 Sputum smear or culture conversion at EOT.
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Analysis 2.5

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 5 Sputum smear or culture conversion at EOT.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 6 Acquisition of drug resistance.
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Analysis 2.6

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 6 Acquisition of drug resistance.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 7 Serious adverse events.
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Analysis 2.7

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 7 Serious adverse events.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 8 Adverse events leading to discontinuation of therapy.
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Analysis 2.8

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 8 Adverse events leading to discontinuation of therapy.

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 9 Other adverse events.
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Analysis 2.9

Comparison 2 Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias, Outcome 9 Other adverse events.

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 1 Treatment failure (ITT analysis and all losses to follow‐up judged as failure).
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Analysis 3.1

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 1 Treatment failure (ITT analysis and all losses to follow‐up judged as failure).

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 2 Relapse (ITT analysis and all losses to follow‐up judged as relapse).
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Analysis 3.2

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 2 Relapse (ITT analysis and all losses to follow‐up judged as relapse).

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 3 Sputum smear or culture conversion at 2 months of starting treatment (ITT analysis and all losses to follow‐up judged as conversion failure).
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Analysis 3.3

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 3 Sputum smear or culture conversion at 2 months of starting treatment (ITT analysis and all losses to follow‐up judged as conversion failure).

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 4 Sputum smear or culture conversion at EOT (ITT analysis and all losses to follow‐up judged as conversion failure).
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Analysis 3.4

Comparison 3 Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT), Outcome 4 Sputum smear or culture conversion at EOT (ITT analysis and all losses to follow‐up judged as conversion failure).

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 1 Treatment failure.
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Analysis 4.1

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 1 Treatment failure.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 2 Relapse.
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Analysis 4.2

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 2 Relapse.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 3 Death.
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Analysis 4.3

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 3 Death.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 4.4

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 5 Acquisition of drug resistance.
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Analysis 4.5

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 5 Acquisition of drug resistance.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 6 Adverse events leading to discontinuation of therapy.
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Analysis 4.6

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 6 Adverse events leading to discontinuation of therapy.

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 7 Other adverse events.
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Analysis 4.7

Comparison 4 Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment, Outcome 7 Other adverse events.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 1 Treatment failure.
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Analysis 5.1

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 1 Treatment failure.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 2 Relapse.
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Analysis 5.2

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 2 Relapse.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 3 Death.
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Analysis 5.3

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 3 Death.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 5.4

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 5 Sputum smear or culture conversion at EOT.
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Analysis 5.5

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 5 Sputum smear or culture conversion at EOT.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 6 Acquisition of drug resistance.
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Analysis 5.6

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 6 Acquisition of drug resistance.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 7 Serious adverse events.
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Analysis 5.7

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 7 Serious adverse events.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 8 Adverse events leading to discontinuation of therapy.
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Analysis 5.8

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 8 Adverse events leading to discontinuation of therapy.

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 9 Other adverse events.
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Analysis 5.9

Comparison 5 Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase, Outcome 9 Other adverse events.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 1 Treatment failure.
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Analysis 6.1

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 1 Treatment failure.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 2 Relapse.
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Analysis 6.2

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 2 Relapse.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 3 Death.
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Analysis 6.3

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 3 Death.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 6.4

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 4 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 5 Sputum smear or culture conversion at EOT.
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Analysis 6.5

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 5 Sputum smear or culture conversion at EOT.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 6 Treatment adherence at 8 weeks of starting treatment.
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Analysis 6.6

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 6 Treatment adherence at 8 weeks of starting treatment.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 7 Treatment adherence at EOT.
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Analysis 6.7

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 7 Treatment adherence at EOT.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 8 Serious adverse events.
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Analysis 6.8

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 8 Serious adverse events.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 9 Adverse events leading to discontinuation of therapy.
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Analysis 6.9

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 9 Adverse events leading to discontinuation of therapy.

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 10 Other adverse events.
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Analysis 6.10

Comparison 6 Supervised treatment versus self‐administered treatment during the intensive phase, Outcome 10 Other adverse events.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 1 Treatment failure.
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Analysis 7.1

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 1 Treatment failure.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 2 Relapse.
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Analysis 7.2

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 2 Relapse.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 3 Death.
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Analysis 7.3

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 3 Death.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 4 Adverse events leading to discontinuation of therapy.
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Analysis 7.4

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 4 Adverse events leading to discontinuation of therapy.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 5 Sputum smear or culture conversion at EOT.
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Analysis 7.5

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 5 Sputum smear or culture conversion at EOT.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 6 Acquisition of drug resistance.
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Analysis 7.6

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 6 Acquisition of drug resistance.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 7 Serious adverse events.
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Analysis 7.7

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 7 Serious adverse events.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 8 Sputum smear or culture conversion at 2 months of starting treatment.
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Analysis 7.8

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 8 Sputum smear or culture conversion at 2 months of starting treatment.

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 9 Other adverse events.
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Analysis 7.9

Comparison 7 Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase, Outcome 9 Other adverse events.

Summary of findings for the main comparison. 'Summary of findings' table 1

Fixed‐dose combinations compared to single‐drug formulations for treating newly diagnosed pulmonary tuberculosis (TB)

Participant or population: treating pulmonary TB
Setting: hospitals and health centres for TB treatment
Intervention: fixed‐dose combinations
Comparison: single‐drug formulations

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

single‐drug formulations

Corresponding risk

FDCs

Treatment failure

19 per 1000

24 per 1000
(15 to 37)

RR 1.28
(0.82 to 2.00)

3606
(7 RCTs)

⊕⊕⊕⊝
moderate1,2,3,4

Relapse

55 per 1000

71 per 1000
(55 to 91)

RR 1.28
(1.00 to 1.64)

3621
(10 RCTs)

⊕⊕⊝⊝
low2,3,4,5

Death

25 per 1000

24 per 1000
(17 to 34)

RR 0.96
(0.67 to 1.39)

4800
(11 RCTs)

⊕⊕⊕⊝
moderate1,3,6,7

Sputum smear or culture conversion at end of treatment

892 per 1000

883 per 1000
(857 to 910)

RR 0.99
(0.96 to 1.02)

2319
(7 RCTs)

⊕⊕⊕⊕
high1,2,3,8

Serious adverse events

16 per 1000

23 per 1000
(14 to 37)

RR 1.45
(0.90 to 2.33)

3388
(6 RCTs)

⊕⊕⊕⊝
moderate1,2,3,7

Adverse events leading to discontinuation of therapy

40 per 1000

38 per 1000
(22 to 67)

RR 0.96
(0.56 to 1.66)

5530
(13 RCTs)

⊕⊕⊝⊝
low3,4,5,9

Combined endpoint of treatment failure, relapse, or death**

(0 RCTs)

*The risk in the intervention group (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).
**Outcome not reported.
Abbreviations: CI: confidence interval; RR: risk ratio; TB: tuberculosis; FDCs: fixed‐dose combinations; RCTs: randomized controlled trial.

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

1 We did not downgrade the quality of the evidence due to limitations in design and execution. Analysis of studies at low risk of bias does not change the effect estimate.
2Quality not downgraded for inconsistency (I² statistic = 0%).
3Quality not downgraded for indirectness. Differences in dosages probably do not affect the comparability of groups
4We downgraded by 1 for imprecision. The optimal information size considering an absolute > 0.5% non‐inferiority margin as clinically meaningful, is not reached. In addition 1 side of the 95% CI does not exclude potential harm associated to FDCs.
5We downgraded by 1 for methodological limitations. Exclusion of studies at highest risk of bias heavily affects the pooled estimate of effect.
6Quality not downgraded for inconsistency (I² statistic = 26%).
7We downgraded by 1 for imprecision. The optimal information size considering an absolute > 0.1% non‐inferiority margin as clinically meaningful, is not reached.
8Quality not downgraded for imprecision. Although the optimal information size (considering an absolute > 0.5% non‐inferiority margin as clinically meaningful) is not reached, the total sample size and number of events are very large.
9Quality not downgraded for inconsistency. Studies of highest risk of bias contribute to explain the large heterogeneity (I² statistic = 57%).

Figures and Tables -
Summary of findings for the main comparison. 'Summary of findings' table 1
Table 1. Suggested definitions of main outcomes according to the authors of included trials

Trial1

Outcomes2

Definitions

Notes

Bartacek 2009

Treatment failure

“sputum smear still or again positive after 4 and/or 6 months of treatment”

Treatment efficacy based on bacteriological response rate (sputum smear conversion rate) on 2 smears

Relapse

“patient cured at end of treatment (EOT) and sputum smear again positive at months 9 or 12”

Chaulet 1995

Treatment failure

“two positive cultures with or without radiological deterioration at EOT (treatment failure) or during the follow‐up (relapse) and consequently resulting in a new course of treatment”

Treatment efficacy based on bacteriological criteria (2 negative cultures)

Relapse

Treatment adherence

Not defined

Determined by testing urine for isoniazid metabolites by biochemical methods

Acquisition of drug resistance

Determined by drug sensitivity test for isoniazid, rifampicin and streptomycin

Geiter 1987

Treatment adherence

Not defined

Asking patients for missed doses, by pill counts and by testing urine for isoniazid metabolites

Lienhardt 2011

Treatment failure

“One culture of at least 20 colonies` growth or 2 cultures of 10 or more colonies growth at EOT not identified as a reinfection”

Treatment efficacy based on bacteriological results: 2 sputum smears and cultures. One case of relapse was reported based only in radiologic deterioration

Relapse

“One culture of at least 20 colonies` growth or 2 cultures of 10 or more colonies growth in the follow‐phase not identified as reinfection”

Acquisition of drug resistance

Not defined

Determined by drug sensitivity test for isoniazid, rifampicin, streptomycin and ethambutol

RCTAI 1989

Relapse

Not defined

Efficacy based on bacteriological results (sputum smear and culture)

Treatment adherence

Not defined

Assessed by delay in drug collection and surprise pill counting

Su 2002

Treatment failure

Not defined

Treatment efficacy based on clinical, bacteriological (3 sputum smears and cultures) and radiographic criteria

Relapse

Efficacy based on bacteriological results (3 sputum smears and cultures)

Treatment adherence

Assessed by “cases lost to follow‐up and cases who changed to another regimen during treatment”

Suryanto 2008

Treatment failure

"Smear positive at 5 months or later"3

Efficacy based on bacteriological results (sputum smear)

Relapse

  1. “Definite TB relapse: a patient previously declared cured with a new episode of bacteriologically positive TB by sputum smear microscopy or culture.

  2. Possible TB relapse, based on interviews, proxy interviews or verbal autopsies: a patient previously declared cured with a history of recurrent signs and symptoms of TB, a history of sputum examination after cure and a history of being treated for TB after cure, or a patient previously declared cured who died with signs and symptoms consistent with or suspected of TB”.

Efficacy based on bacteriological results (1 smear sputum and culture) and information from interviews and verbal autopsies

Teo 1999

Treatment failure

Not defined

Treatment efficacy based on bacteriological results (sputum smear and culture)

Relapse

“Bacteriological relapse after chemotherapy was defined as a positive culture with a growth of 10 or more colonies in 2 different months during any 3‐month period up to 30 months, and during any 6‐month period up to 60 months”

Efficacy based on bacteriological results (sputum smear and culture). One case of relapse was reported based on radiological deterioration

Acquisition of drug resistance

Not defined

Determined by drug sensitivity test for isoniazid, rifampicin, and streptomycin

Zaka‐Ur‐Rehman 2008

Relapse

Not defined

Efficacy based on bacteriological results (sputum smear)

Zhang 1996

Relapse

Not defined

Efficacy based on bacteriological results (sputum smear and culture)

Zhu 1998

Treatment adherence

Not defined

There were 3 kinds of treatment management (whole‐course hospitalization; hospitalization only during intensive phase and outpatient treatment), combined with 3 supervision model respectively (supervision by medical staff; supervision by no‐medical staff who had been trained by the medical staff [relatives, colleagues] and supervision by medical staff in the intensive phase but non‐medical staff in the continuation phase). Treatment and supervision were established according to participants economic status

Abbreviations: EOT: end of treatment; TB: tuberculosis.

1Munteanu 2004 did not report the outcomes included in this table and Semenova 2003 was not included in quantitative analysis.
2Outcomes reported in each clinical trial.
3Treatment failure was defined in the preliminary publication (Gravendeel 2003).

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Table 1. Suggested definitions of main outcomes according to the authors of included trials
Table 2. Numbers of randomized participants and treatment regimens of trials included in the meta‐analysis

Trial

Number of participants

Treatment regimens

Bartacek 2009

1159

2HRZE/4HR

Chaulet 1995

250

2HRZ/4HR

Geiter 1987

701

2HRZ/4HR

Lienhardt 2011

1585

2HRZE/4HR1

Munteanu 2004

40

2HRZE/4HR

RCTAI 1989

229

2HRZ/4HR1

Su 2002

105

2HRZE/4HRE

Suryanto 2008

434

2HRZE/3HR

Teo 1999

310

3 different regimes were given2

Wu 2015

161

2HRZE/4HRE

Zaka‐Ur‐Rehman 2008

293

2HRZE/4HRE

Zhang 1996

209

2HRZ/4HR

Zhu 1998

348

2HRZ/4HR

Abbreviations: H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin.
1In Lienhardt 2011 and RCTAI 1989 the treatment regimen was 8 weeks for intensive phase and 18 weeks for continuation phase.
2Intensive phase: Regimen 1: 2SHRZ, Regimen 2: 1SHRZ or Regimen 3: 2HRZ and continuation phase: H and R to complete 6 months of treatment (4HR or 5HR).

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Table 2. Numbers of randomized participants and treatment regimens of trials included in the meta‐analysis
Table 3. Comparison of given dose between fixed‐dose combinations and single‐drug formulations during the intensive phase in the included studies

Trial

Regimen treatment

Directly observed therapy

Dosing

Dose simulation during intensive phase

Comment

45 kg participant

60 kg participant

Fixed‐dose

Single‐dose

Fixed‐dose

Single‐dose

Bartacek 2009

2HRZE/4HR

Mode of drugs administration: not reported

By weight categories

Unclear

Unclear

Unclear

Unclear

The trial authors state: "The mean daily doses of INH, PZA and EMB administered during the initiation phase in the 4‐FDC group were significantly lower than those administered in the ST group; RMP doses were similar in both groups".

Chaulet 1995

2HRZ/4HR

At the beginning of intensive phase

By weight categories

H: 250 mg

R: 600 mg

Z: 1500 mg

H: 300 mg

R: 450 mg

Z: 1500 mg

H: 300 mg

R: 720 mg

Z: 1800 mg

H: 300 mg

R: 600 mg

Z: 2000 mg

During directly observed treatment (DOT), "health personal" supervised treatment. Time with DOT is unclear.

Geiter 1987

2HRZ/4HR

No

By weight categories only for FDCs

H: 225 mg

R: 450 mg

Z: 1200 mg

Not reported

H: 300 mg

R: 600 mg

Z: 1600 mg

Not reported

Self‐administered treatment was done during the whole treatment. Dose used for single‐drug formulations: not reported.

Lienhardt 2011

2HRZE/4HR1

During 6 days a week

By weight categories

H: 225 mg

R: 450 mg

Z: 1200 mg

E: 825 mg

H: 250 mg

R: 450 mg

Z: 1200 mg

E: 800 mg

H: 300 mg

R: 600 mg

Z: 1600 mg

E: 1100 mg

H: 300 mg

R: 600 mg

Z: 1600 mg

E: 1200 mg

The trial authors state: "In the majority of the trial centers, treatment was fully supervised for a minimum of 6 days a week". Every treatment dose was taken under the supervision of the medical staff.

Munteanu 2004

2HRZE/4HR

During the intensive phase

Not reported

Not reported

Not reported

Not reported

Not reported

The supervision mechanism during DOT is unclear, and only mention "strictly supervised". Self‐administered treatment was done during the continuation phase.

RCTAI 1989

2HRZ/4HR2

No

By weight categories

H: 320 mg

R: 480 mg

Z: 1000 mg

Unclear

H: 400 mg

R: 600 mg

Z: 1250 mg

Unclear

Self‐administered treatment during the whole treatment.

Semenova 2003

4HRZE

Mode of drugs administration: not reported

By weight categories

Mairin‐P: 4 tablets +

H: 225 mg

H: 450 mg

R: 450 mg

Z: 900 mg

E: 1125 mg

Mairin‐P: 5 tablets +

H: 300 mg

H: 600 mg

R: 600 mg

Z: 1200 mg

E: 1500 mg

Streptomycin was added in 2 of the 4 randomized groups3.

Su 2002

2HRZE/4HRE

No

By weight categories

H: 200 mg

R: 480 mg

Z: 1000 mg

E: not reported

H: 300 mg

R: 450 mg

Z: 1500 mg

E: 1200 mg

H: 250 mg

R: 600 mg

Z: 1250 mg

E: not reported

H: 300 mg

R: 600 mg

Z: 1500 mg

E: 1200 mg

Self‐administered treatment during the whole treatment.

Suryanto 2008

2HRZE/3HR

Once a weekly

By weight categories

Average dose

H: 225 mg

R: 450 mg

Z: 1200 mg

E: 825 mg

Average

dose

H: 300 mg

R: 450 mg

Z: 1500 mg

E: 750 mg

Average dose

H: 225 mg

R: 450 mg

Z: 1200 mg

E: 825 mg

Average dose

H: 300 mg

R: 450 mg

Z: 1500 mg

E: 750 mg

The study authors state: "The loose drug regimen contained higher dosages of H and Z and lower dosage for E compared to the FDCs".

Drugs "were given under supervision at health facilities" during DOT.

Self‐administered treatment was done the remaining days.

Teo 1999

Three different regimes were given4

During the whole treatment

By weight categories

H: 250 mg

R: 600 mg

Z: 1500 mg

S: 750 mg

H: 300 mg

R: 600 mg

Z: 1500 mg

S: 750 mg

H: 300 mg

R: 720 mg

Z: 1800 mg

S: 750 mg

H: 300 mg

R: 600 mg

Z: 2000 mg

S: 750 mg

The supervision mechanism during DOT is not clear. And only mention: DOT was given "at the community health clinic".

Wu 2015

2HRZE/4HRE

Treatment was given as TDO 5 days per week and self‐administered during weekends

By weight categories

H: 320 mg

R: 480 mg

Z: 1000 mg

H: 300 mg

R: 450 mg

Z: 1125 mg

E: 900 mg

H: 400 mg

R: 600 mg

Z: 1250 mg

H: 300 mg

R: 600 mg

Z: 1500 mg

E: 1200 mg

DOT was supervised by "health workers". The ethambutol dose in FDCs groups was not reported.

Zaka‐Ur‐Rehman 2008

2HRZE/4HRE

During the intensive phase

By weight categories

5H: 300 mg

R: 480 mg

Z: 1400 mg

E: 1000 mg

H: 300 mg

R: 450 mg

Z: 1500 mg

E: 1200 mg

5H: 375 mg

R: 600 mg

Z: 1750 mg

E: 1250 mg

H: 400 mg

R: 600 mg

Z: 2000 mg

E: 1600 mg

The supervision mechanism during DOT is unclear and only mention: "directly observed therapy was followed for each patient on a daily basis".

Zhang 1996

2HRZ/4HR

During the

intensive phase

By weight categories

H: 320 mg

R: 400 mg

Z: 1000 mg

H: 300 mg

R: 450 mg

Z: 1500 mg

H: 400 mg

R: 600 mg

Z: 1250 mg

H: 300 mg

R: 600 mg

Z: 1500 mg

The trial authors state: "All drugs were taken under close supervision of a health care provider".

Zhu 1998

2HRZ/4HR

Only for a part of participants6

By weight categories

H: 320 mg

R: 480 mg

Z: 1000 mg

H: 300 mg

R: 450 mg

Z: 1500 mg

H: 320 mg

R: 480 mg

Z: 1000 mg

H: 300 mg

R: 600 mg

Z: 1500 mg

There were 3 kinds of treatment management combined with 3 supervision models.

Abbreviations: kg: kilograms of body weight; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; FDCs: fixed‐dose combinations; SDF: single‐dose formulations; mg: milligrams; DOT: directly‐observed treatment.

1In Lienhardt 2011 the treatment regimen was 8 weeks for intensive phase and 18 weeks for continuation phase.
2In RCTAI 1989 the treatment regimen was 8 weeks for intensive phase and 18 weeks for continuation phase.
3 Data and dosage simulation done only for the groups 1 and 3. (In Semenova 2003 there were another two regimens for the intensive phase: 2 and 4).
4Data extracted and dose simulation done only for the regimen 1: 2SHRZ. (In Teo 1999 there were another two regimens for the intensive phase: 1SHRZ and 2HRZ).
5In the FDCs group, data and dosage similation presented for the regimen A. (In Zaka‐Ur‐Rehman 2008 there was another FDCs regimen: regimen B).
6In Zhu 1998 there were 3 modes of treatment supervision.

Figures and Tables -
Table 3. Comparison of given dose between fixed‐dose combinations and single‐drug formulations during the intensive phase in the included studies
Table 4. 'Summary of findings' table 2

Fixed‐dose combinations (FDCs) compared to single‐drug formulations for treating newly diagnosed pulmonary tuberculosis (TB)

Participant or population: treating pulmonary TB
Setting: hospitals and health centres for TB treatment
Intervention: fixed‐dose combinations
Comparison: single‐drug formulations as available data: sensitivity analysis considering the global risk of bias

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

single‐drug formulations

Corresponding risk

FDCs

Combined endpoint of treatment failure, relapse, or death**

(0 RCTs)

Treatment failure

22 per 1000

25 per 1000
(15 to 42)

RR 1.17
(0.70 to 1.93)

2507
(2 RCTs)

⊕⊕⊕⊝
moderate1,2,3,4

Relapse

79 per 1000

88 per 1000
(68 to 115)

RR 1.12
(0.86 to 1.46)

2293
(2 RCTs)

⊕⊕⊕⊝
moderate1,2,3,4

Death

9 per 1000

12 per 1000
(6 to 26)

RR 1.35
(0.63 to 2.93)

2470
(2 RCTs)

⊕⊕⊕⊝
moderate2,4,5,6

Sputum smear or culture conversion at end of treatment

827 per 1000

802 per 1000
(761 to 851)

RR 0.97
(0.92 to 1.03)

1159
(1 RCT)

⊕⊕⊕⊕
high2,4,7,8

Serious adverse events

17 per 1000

25 per 1000
(15 to 42)

RR 1.44
(0.86 to 2.44)

2703
(2 RCTs)

⊕⊕⊕⊝
moderate1,2,3,4

Adverse events leading to discontinuation of therapy

18 per 1000

30 per 1000
(19 to 50)

RR 1.71
(1.04 to 2.81)

2703
(2 RCTs)

⊕⊕⊕⊝
moderate1,2,3,4

*The risk in the intervention group (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).
**Outcome not reported.
Abbreviations: CI: confidence interval; RR: risk ratio; TB: tuberculosis; FDCs: fixed‐dose combinations; RCTs: randomized controlled trial.

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

1We did not downgrade the quality due to inconsistency. I² statistic = 0%.
2We did not downgrade the quality for risk of bias. There were no limitations in the design and execution of the trials.
3Downgraded by 1 for imprecision. The optimal information size, considering an absolute > 0.5% non‐inferiority margin as clinically meaningful, is not reached. In addition, 1 side of the 95% CI does not exclude potential harm associated to FDCs.
4We did not downgrade quality for indirectness. Differences in dosages probably do not affect the comparability of groups.
5We did not downgrade quality due to inconsistency. Large heterogeneity (I² statistic = 72%) can be explained by the limited number of events and the effect of chance.
6Downgraded by 1 for imprecision. The optimal information size, considering an absolute > 0.1% non‐inferiority margin as clinically meaningful, is not reached. In addition, the number of events is very limited.
7We did not downgrade the quality due to inconsistency. There was only a single included trial.
8We did not downgrade the quality due to imprecision. Although the optimal information size considering an absolute > 0.5% non‐inferiority margin as clinically meaningful is not reached, the total sample size and number of events are very large.

Figures and Tables -
Table 4. 'Summary of findings' table 2
Table 5. Optimal information size calculations: fixed‐dose combinations versus single‐drug formulations (Comparison 1)

Outcomes

Assumed risk

Clinically important reduction

Optimal sample size 1,2

Single‐drug formulations

Absolute

Relative

Treatment failure

2.2 %

0.5%

25%

6092

Relapse

2.3 %

0.5%

25%

4718

Death3

0.9 %

0.1%

4.5%

737,340

Sputum/culture conversion at end of treatment

88.7%

0.5%

0.6%

95,044

Serious adverse events

1.5 %

0.1%

6.7%

12,356

Adverse events leading to discontinuation of therapy

4.1 %

0.5%

24.4%

325,024

1We based all calculations are based on: 1‐sided tests, with a ratio of 1:1, power of 0.9, and confidence level of 0.05.
2We performed all calculations using: http://www.sealedenvelope.com/power/binary‐noninferior/.
3 If there is truly no difference between the standard and experimental treatment, then 737,340 participants are required to be 90% sure that the upper limit of a 1‐sided 95% confidence interval (CI) (or equivalently a 90% 2‐sided CI) will exclude a difference in favour of the standard group of more than 0.1%.

Figures and Tables -
Table 5. Optimal information size calculations: fixed‐dose combinations versus single‐drug formulations (Comparison 1)
Comparison 1. Fixed‐dose combinations versus single‐drug formulations as available data

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

7

3606

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.82, 2.00]

2 Relapse Show forest plot

10

3621

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.00, 1.64]

3 Death Show forest plot

11

4800

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.67, 1.39]

4 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

13

4836

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

5 Sputum smear or culture conversion at end of treatment (EOT) Show forest plot

7

2319

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.96, 1.02]

6 Treatment adherence at 8 weeks of starting treatment Show forest plot

3

881

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.96, 1.12]

7 Treatment adherence at EOT Show forest plot

5

1229

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.97, 1.06]

8 Acquisition of drug resistance Show forest plot

3

491

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.15, 3.77]

9 Patient satisfaction Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

9.1 General satisfaction

1

222

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.97, 1.12]

9.2 No problems on swallowing

1

1023

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [1.00, 1.06]

9.3 Convenient number of tablets

1

1045

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [1.37, 1.64]

9.4 Acceptable taste

1

1044

Risk Ratio (M‐H, Fixed, 95% CI)

1.39 [1.27, 1.51]

10 Serious adverse events Show forest plot

6

3388

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.90, 2.33]

11 Adverse events leading to discontinuation of therapy Show forest plot

13

5530

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.56, 1.66]

12 Other adverse events Show forest plot

9

4639

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.72, 1.00]

Figures and Tables -
Comparison 1. Fixed‐dose combinations versus single‐drug formulations as available data
Comparison 2. Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

7

3606

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.82, 2.00]

1.1 High or unclear risk of selection bias

5

1099

Risk Ratio (M‐H, Fixed, 95% CI)

1.77 [0.67, 4.69]

1.2 Low risk of selection bias

2

2507

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.70, 1.93]

2 Relapse Show forest plot

10

3621

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.00, 1.64]

2.1 High or unclear risk of selection bias

8

1328

Risk Ratio (M‐H, Fixed, 95% CI)

2.84 [1.34, 6.00]

2.2 Low risk of selection bias

2

2293

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.86, 1.46]

3 Death Show forest plot

11

4800

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.67, 1.39]

3.1 High or unclear risk of selection bias

9

2330

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.57, 1.32]

3.2 Low risk of selection bias

2

2470

Risk Ratio (M‐H, Fixed, 95% CI)

1.35 [0.63, 2.93]

4 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

13

4836

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

4.1 High or unclear risk of selection bias

11

2507

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [1.01, 1.06]

4.2 Low risk of selection bias

2

2329

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.95, 1.02]

5 Sputum smear or culture conversion at EOT Show forest plot

7

2319

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.96, 1.02]

5.1 High or unclear risk of selection bias

6

1160

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.98, 1.03]

5.2 Low risk of selection bias

1

1159

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.92, 1.03]

6 Acquisition of drug resistance Show forest plot

3

491

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.15, 3.77]

6.1 High or unclear risk of selection bias

2

460

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.08, 4.79]

6.2 Low risk of selection bias

1

31

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.07, 15.57]

7 Serious adverse events Show forest plot

6

3388

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.90, 2.33]

7.1 High or unclear risk of selection bias

4

685

Risk Ratio (M‐H, Fixed, 95% CI)

1.47 [0.46, 4.71]

7.2 Low risk of selection bias

2

2703

Risk Ratio (M‐H, Fixed, 95% CI)

1.44 [0.86, 2.44]

8 Adverse events leading to discontinuation of therapy Show forest plot

13

5530

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.56, 1.66]

8.1 High or unclear risk of selection bias

11

2827

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.31, 1.43]

8.2 Low risk of selection bias

2

2703

Risk Ratio (M‐H, Random, 95% CI)

1.71 [1.04, 2.81]

9 Other adverse events Show forest plot

9

4639

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.72, 1.00]

9.1 High or unclear risk of selection bias

7

1936

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.71, 1.07]

9.2 Low risk of selection bias

2

2703

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.63, 1.07]

Figures and Tables -
Comparison 2. Fixed‐dose combinations versus single‐drug formulations as available data: sensitivity analysis by risk of bias
Comparison 3. Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure (ITT analysis and all losses to follow‐up judged as failure) Show forest plot

7

4004

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.93, 1.14]

2 Relapse (ITT analysis and all losses to follow‐up judged as relapse) Show forest plot

10

4716

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.95, 1.16]

3 Sputum smear or culture conversion at 2 months of starting treatment (ITT analysis and all losses to follow‐up judged as conversion failure) Show forest plot

13

5731

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.97, 1.03]

4 Sputum smear or culture conversion at EOT (ITT analysis and all losses to follow‐up judged as conversion failure) Show forest plot

7

2552

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.95, 1.02]

Figures and Tables -
Comparison 3. Fixed‐dose combinations versus single‐drug formulations: sensitivity analysis by intention‐to‐treat (ITT)
Comparison 4. Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

7

3606

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.82, 2.00]

1.1 Fixed‐dose combinations (FDCs) only at intensive phase

1

307

Risk Ratio (M‐H, Fixed, 95% CI)

1.99 [0.18, 21.69]

1.2 FDCs during all treatment

6

3299

Risk Ratio (M‐H, Fixed, 95% CI)

1.26 [0.80, 1.99]

2 Relapse Show forest plot

10

3621

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.00, 1.64]

2.1 FDCs only at intensive phase

1

251

Risk Ratio (M‐H, Fixed, 95% CI)

3.94 [1.13, 13.78]

2.2 FDCs during all treatment

9

3370

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.93, 1.55]

3 Death Show forest plot

11

4800

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.67, 1.39]

3.1 FDCs only at intensive phase

1

271

Risk Ratio (M‐H, Fixed, 95% CI)

1.40 [0.50, 3.94]

3.2 FDCs during all treatment

10

4529

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.61, 1.35]

4 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

13

4836

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

4.1 FDCs only at intensive phase

1

269

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.96, 1.07]

4.2 FDCs during all treatment

12

4567

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

5 Acquisition of drug resistance Show forest plot

3

491

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.15, 3.77]

5.1 FDCs only at intensive phase

1

251

Risk Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 8.70]

5.2 FDCs during all treatment

2

240

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.15, 7.24]

6 Adverse events leading to discontinuation of therapy Show forest plot

13

5530

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.56, 1.66]

6.1 FDCs only at intensive phase

1

271

Risk Ratio (M‐H, Random, 95% CI)

1.84 [0.55, 6.15]

6.2 FDCs during all treatment

12

5259

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.48, 1.59]

7 Other adverse events Show forest plot

9

4639

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.72, 1.00]

7.1 FDCs only at intensive phase

1

271

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.75, 1.48]

7.2 FDCs during all treatment

8

4368

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.67, 0.97]

Figures and Tables -
Comparison 4. Fixed‐dose combinations (FDCs) administered only during intensive phase versus FDCs administered for the whole treatment
Comparison 5. Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

7

3606

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.82, 2.00]

1.1 Daily medication for the whole treatment

4

1517

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.63, 2.06]

1.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

3

2089

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [0.75, 2.96]

2 Relapse Show forest plot

10

3621

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.00, 1.64]

2.1 Daily medication for the whole treatment

7

1850

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.83, 1.50]

2.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

3

1771

Risk Ratio (M‐H, Fixed, 95% CI)

1.72 [1.07, 2.75]

3 Death Show forest plot

11

4800

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.67, 1.39]

3.1 Daily medication for the whole treatment

8

2859

Risk Ratio (M‐H, Fixed, 95% CI)

1.34 [0.79, 2.29]

3.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

3

1941

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.41, 1.16]

4 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

13

4836

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

4.1 Daily medication for the whole treatment

9

3001

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.98, 1.03]

4.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

4

1835

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.99, 1.05]

5 Sputum smear or culture conversion at EOT Show forest plot

7

2319

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.96, 1.02]

5.1 Daily medication for the whole treatment

6

1961

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.96, 1.02]

5.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

1

358

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.95, 1.05]

6 Acquisition of drug resistance Show forest plot

3

491

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.15, 3.77]

6.1 Daily medication for the whole treatment

1

209

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.07, 16.55]

6.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

2

282

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.09, 4.69]

7 Serious adverse events Show forest plot

6

3388

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.90, 2.33]

7.1 Daily medication for the whole treatment

4

1767

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [0.95, 2.68]

7.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

2

1621

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.21, 2.92]

8 Adverse events leading to discontinuation of therapy Show forest plot

13

5530

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.56, 1.66]

8.1 Daily medication for the whole treatment

9

3204

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.39, 1.59]

8.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

4

2326

Risk Ratio (M‐H, Random, 95% CI)

1.55 [0.74, 3.25]

9 Other adverse events Show forest plot

9

4639

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.72, 1.00]

9.1 Daily medication for the whole treatment

6

2747

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.70, 1.02]

9.2 Daily medication at intensive phase followed by intermittent treatment at continuation phase

3

1892

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.64, 1.18]

Figures and Tables -
Comparison 5. Daily regimen for the whole treatment versus daily regimen during the intensive phase followed by intermittent regimen during the continuation phase
Comparison 6. Supervised treatment versus self‐administered treatment during the intensive phase

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

6

2447

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.75, 2.84]

1.1 Supervised treatment during the intensive phase

4

1962

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [0.56, 2.89]

1.2 Self‐administered treatment during the intensive phase

2

485

Risk Ratio (M‐H, Fixed, 95% CI)

1.89 [0.59, 6.04]

2 Relapse Show forest plot

9

2676

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [1.09, 2.63]

2.1 Supervised treatment during the intensive phase

6

2318

Risk Ratio (M‐H, Fixed, 95% CI)

1.52 [0.94, 2.45]

2.2 Self‐administered treatment during the intensive phase

3

358

Risk Ratio (M‐H, Fixed, 95% CI)

2.93 [0.89, 9.59]

3 Death Show forest plot

10

3678

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.55, 1.22]

3.1 Supervised treatment during the intensive phase

6

2503

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.50, 1.58]

3.2 Self‐administered treatment during the intensive phase

4

1175

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.44, 1.32]

4 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

12

3677

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [1.01, 1.05]

4.1 Supervised treatment during the intensive phase

8

2584

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.99, 1.05]

4.2 Self‐administered treatment during the intensive phase

4

1093

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [1.01, 1.11]

5 Sputum smear or culture conversion at EOT Show forest plot

6

1160

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.98, 1.03]

5.1 Supervised treatment during the intensive phase

2

513

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.04]

5.2 Self‐administered treatment during the intensive phase

4

647

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.97, 1.03]

6 Treatment adherence at 8 weeks of starting treatment Show forest plot

3

881

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.96, 1.12]

6.1 Supervised treatment during the intensive phase

1

142

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.97, 1.06]

6.2 Self‐administered treatment during the intensive phase

2

739

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.90, 1.31]

7 Treatment adherence at EOT Show forest plot

5

1229

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.97, 1.06]

7.1 Supervised treatment during the intensive phase

1

96

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.97, 1.11]

7.2 Self‐administered treatment during the intensive phase

4

1133

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.96, 1.06]

8 Serious adverse events Show forest plot

5

2266

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.46, 2.60]

8.1 Supervised treatment during the intensive phase

4

2056

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.40, 2.44]

8.2 Self‐administered treatment during the intensive phase

1

210

Risk Ratio (M‐H, Fixed, 95% CI)

3.17 [0.13, 77.05]

9 Adverse events leading to discontinuation of therapy Show forest plot

12

4408

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.43, 1.57]

9.1 Supervised treatment during the intensive phase

8

3121

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.11, 1.71]

9.2 Self‐administered treatment during the intensive phase

4

1287

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.55, 2.04]

10 Other adverse events Show forest plot

8

3517

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.68, 1.00]

10.1 Supervised treatment during the intensive phase

7

2979

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.64, 0.96]

10.2 Self‐administered treatment during the intensive phase

1

538

Risk Ratio (M‐H, Fixed, 95% CI)

2.56 [0.90, 7.23]

Figures and Tables -
Comparison 6. Supervised treatment versus self‐administered treatment during the intensive phase
Comparison 7. Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

7

3606

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.82, 2.00]

1.1 Four drugs as FDCs during the intensive phase

3

2941

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [0.80, 2.01]

1.2 Three or 2 drugs as FDCs during the intensive phase

4

665

Risk Ratio (M‐H, Fixed, 95% CI)

1.52 [0.26, 9.08]

2 Relapse Show forest plot

9

3523

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.00, 1.64]

2.1 Four drugs as FDCs during the intensive phase

4

2675

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.91, 1.54]

2.2 Three or 2 drugs as FDCs during the intensive phase

5

848

Risk Ratio (M‐H, Fixed, 95% CI)

2.55 [1.07, 6.06]

3 Death Show forest plot

11

4800

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.67, 1.39]

3.1 Four drugs as FDCs during the intensive phase

4

3002

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.48, 1.30]

3.2 Three or 2 drugs as FDCs during the intensive phase

7

1798

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [0.70, 2.10]

4 Adverse events leading to discontinuation of therapy Show forest plot

13

5530

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.56, 1.66]

4.1 Four drugs as FDCs during the intensive phase

4

3430

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.53, 2.78]

4.2 Three or 2 drugs as FDCs during the intensive phase

9

2100

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.37, 1.77]

5 Sputum smear or culture conversion at EOT Show forest plot

7

2319

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.96, 1.02]

5.1 Four drugs as FDCs during the intensive phase

2

1517

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.94, 1.02]

5.2 Three or 2 drugs as FDCs during the intensive phase

5

802

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.98, 1.03]

6 Acquisition of drug resistance Show forest plot

3

491

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.15, 3.77]

6.1 Four drugs as FDCs during the intensive phase

1

31

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.07, 15.57]

6.2 Three or 2 drugs as FDCs during the intensive phase

2

460

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.08, 4.79]

7 Serious adverse events Show forest plot

6

3388

Risk Ratio (M‐H, Fixed, 95% CI)

1.45 [0.90, 2.33]

7.1 Four drugs as FDCs during the intensive phase

3

2996

Risk Ratio (M‐H, Fixed, 95% CI)

1.34 [0.81, 2.23]

7.2 Three or 2 drugs as FDCs during the intensive phase

3

392

Risk Ratio (M‐H, Fixed, 95% CI)

2.59 [0.59, 11.34]

8 Sputum smear or culture conversion at 2 months of starting treatment Show forest plot

13

4836

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.99, 1.03]

8.1 Four drugs as FDCs during the intensive phase

4

2980

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.97, 1.03]

8.2 Three or 2 drugs as FDCs during the intensive phase

9

1856

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [1.01, 1.07]

9 Other adverse events Show forest plot

9

4639

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.72, 1.00]

9.1 Four drugs as FDCs during the intensive phase

3

2996

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.64, 1.02]

9.2 Three or 2 drugs as FDCs during the intensive phase

6

1643

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.71, 1.13]

Figures and Tables -
Comparison 7. Trials with four drugs as fixed‐dose combinations (FDCs) versus trials with three or two drugs as FDCs during the intensive phase