From the Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London (A.J.N, P.P.J.P., S.K.M., K.S.), and the Liverpool School of Tropical Medicine, Liverpool (S.B.S.) - both in the United Kingdom; International Union against Tuberculosis and Lung Disease (the Union), Paris (C.-Y.C., A.D., I.D.R.); the Department of Internal Medicine, Wanfang Hospital, and School of Medicine, Taipei Medical University (C.-Y.C.) - both in Taipei, Taiwan; the University of Witwatersrand, Faculty of Health Sciences, Johannesburg (F.C.), King Dinizulu Hospital Complex, Kwazulu Natal (I.M., N.N.), and Think TB and HIV Investigative Network, Durban (R.M.) - all in South Africa; National Center for Communicable Diseases (D.D.) and the Mongolian Tuberculosis Coalition (B.T.) - both in Ulaanbaatar, Mongolia; the Institute of Tropical Medicine, Antwerp, Belgium (A.D., G.T.); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (P.-T.D., N.L.); Armauer Hansen Research Institute (T.M.), and St. Peter's Tuberculosis Specialized Hospital and Global Health Committee (D.M.) - all in Addis Ababa, Ethiopia; the Division of Research and Development, Vital Strategies, New York (I.D.R.); and the Dalla Lana School of Public Health, University of Toronto, Toronto (I.D.R.).
N Engl J Med. 2019 Mar 28;380(13):1201-1213. doi: 10.1056/NEJMoa1811867. Epub 2019 Mar 13.
Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.
We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.
Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.
In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
在孟加拉国进行的队列研究显示，在接受世卫组织（WHO）2011 年推荐方案更短的药物治疗方案的耐多药结核病患者中，有较好的治愈率。
我们在对利福平耐药且对氟喹诺酮类和氨基糖苷类敏感的结核病患者中进行了一项非劣效性 3 期试验。参与者以 2:1 的比例随机分配，接受短疗程（9-11 个月）或长疗程（20 个月）治疗，短疗程方案包括高剂量莫西沙星，长疗程方案遵循 2011 年世卫组织指南。主要疗效结局为在第 132 周时的有利状态，定义为第 132 周和之前的培养物均为阴性，且无间隔性阳性培养物或之前的不利结局。两组之间的有利状态差异的上 95%置信限为 10 个百分点或更小，用于确定非劣效性。
在 424 名接受随机分组的参与者中，有 383 名参与者被纳入改良意向治疗人群。长疗程组中 79.8%的参与者和短疗程组中 78.8%的参与者报告了有利状态，调整人类免疫缺陷病毒状态后，差异为 1.0 个百分点（95%置信区间[CI]，-7.5 至 9.5）（非劣效性 P=0.02）。在 321 名符合方案人群中，非劣效性结果一致（调整差异，-0.7 个百分点；95%CI，-10.5 至 9.1）。长疗程组中 45.4%的参与者和短疗程组中 48.2%的参与者发生了 3 级或更高级别的不良事件。短疗程组中 11.0%的参与者出现 QT 间期或校正 QT 间期（用 Fridericia 公式计算）延长至 500 毫秒，而长疗程组中为 6.4%（P=0.14）；由于短疗程组中发生率较高，参与者接受了密切监测，部分人接受了药物调整。短疗程组中 8.5%的参与者死亡，长疗程组中为 6.4%，短疗程组中分别有 3.3%和 2.3%的参与者对氟喹诺酮类或氨基糖苷类药物产生耐药性。
在对氟喹诺酮类和氨基糖苷类敏感的利福平耐药结核病患者中，短疗程与长疗程相比，主要疗效结局非劣效，且安全性与长疗程相当。（由美国国际开发署和其他机构资助；当前对照试验编号，ISRCTN78372190；临床试验编号，NCT02409290）。
