Clinical Trial Division, International Union Against Tuberculosis and Lung Disease, Paris, France.
JAMA. 2011 Apr 13;305(14):1415-23. doi: 10.1001/jama.2011.436.
Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance.
To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis.
DESIGN, SETTING, AND PATIENTS: 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. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis.
Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n = 798 patients) or separately (n = 787) in the 8-week intensive phase of treatment.
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%.
In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC 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 patients (83.3%) had a favorable outcome in the FDC 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 patients (89.8%) in the FDC 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.
Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis 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.
clinicaltrials.gov Identifier: NCT00216333.
固定剂量组合（FDCs）药物已被提倡用于治疗结核病，以防止耐药性的出现。
评估一种 4 药物 FDC 治疗结核病的疗效和安全性。
设计、地点和患者：Study C 试验是一项平行组、开放标签、非劣效性、随机对照试验，于 2003 年至 2008 年在非洲、亚洲和拉丁美洲的 11 个地点进行。患者为 1585 名新诊断为痰涂片阳性的肺结核成人。
患者随机接受每日治疗，用 4 种药物（利福平、异烟肼、吡嗪酰胺、乙胺丁醇）作为 FDC（n = 798 例）或单独（n = 787 例）治疗，在强化治疗的 8 周内。
有利的治疗结果定义为随机分组后 18 个月培养阴性且未被归类为不利的结果。非劣效性取决于方案和改良意向治疗分析的一致性结果，后一种分析使用了两种不同的模型，将所有治疗改变或拒绝继续治疗（例如，细菌学失败/复发、不良事件、失访、耐药性）归类为不利（模型 1），并根据其 18 个月的细菌学结果对治疗改变的原因进行归类（事后模型 2）。预设的非劣效性边界为 4%。
在方案分析中，591 例患者（93.9%）中有 555 例（FDC 组）有良好的结果，579 例患者（94.6%）中有 548 例（单独药物组）有良好的结果（风险差异，-0.7%[90%可信区间（CI），-3.0%至 1.5%]）。在模型 1 分析中，684 例患者中有 570 例（83.3%）有良好的结果，664 例患者中有 563 例（84.8%）有良好的结果（风险差异，-1.5%[90%CI，-4.7%至 1.8%]）。在后序模型 2 分析中，658 例患者中有 591 例（89.8%），647 例患者中有 589 例（91.0%）有良好的结果（风险差异，-1.2%[90%CI，-3.9%至 1.5%]）。与试验药物相关的不良事件在治疗组中分布相似。
与分别给予药物的方案相比，4 种药物 FDC 方案治疗结核病在 3 项分析中的 2 项中满足预设的非劣效性标准。尽管与严格应用于本试验的单独药物相比，结果未显示 FDC 与单独药物相比具有完全的非劣效性，但由于与单独药物制剂相比，使用 FDC 具有潜在的优势，因此仍优先使用 FDC。
clinicaltrials.gov 标识符：NCT00216333。
