Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of XXXX : the Study C randomized controlled trial.

@entity1 @entity3110 @entity5585 @entity5048 @entity3109 @entity1215 @entity378 @entity1907
CONTEXT: Fixed-dose combinations (FDCs) of drugs for treatment of @entity378 have been advocated to prevent the emergence of drug resistance. OBJECTIVE: To assess the efficacy and safety of a 4-drug @entity5048 for the treatment of @entity378 . DESIGN, SETTING, AND @entity1 : The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. @entity1 were 1585 adults with newly diagnosed smear-positive @entity1907 . INTERVENTIONS: @entity1 were randomized to receive daily treatment with 4 drugs ( @entity1215 , @entity3109 , @entity5585 , @entity3110 ) given as an @entity5048 (n = 798 @entity1 ) or separately (n = 787) in the 8-week intensive phase of treatment. MAIN OUTCOME MEASURE: Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%. RESULTS: In the per-protocol analysis, 555 of 591 @entity1 (93.9%) had a favorable outcome in the @entity5048 group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 @entity1 (83.3%) had a favorable outcome in the @entity5048 group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 @entity1 (89.8%) in the @entity5048 group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups. CONCLUSIONS: Compared with a regimen of separately administered drugs, a 4-drug @entity5048 regimen for treatment of @entity378 satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00216333.
