A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT
Authors: Gao Jingtao , Gao Mengqiu , Du Jian , Pang Yu , Mao Gary , Lounis Nacer , Bakare Nyasha , Jiang Yanxin , Zhan Ying , Liu Yuhong , Li Liang ,   on behalf of the Trial Team, Rongmei Liu , Juan Du , Guihui Wu , Yi Pei , Wei Sha , Lian Shi , Hua Wang , Long Jin , Yuqing Wu , Yu Xiong , Xiaofeng Yan , Xiaohong Chen , Zhongfeng Huang , Fei Ren , Xiujie Li , Huiru An , Junwei Cui 
Published: April 2024

AbstractIntroductionThe lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China.MethodsThis phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ)versusan all-oral SCR without BDQ for adult MDR-TB patients (18–65 years) in China. The trial design mainly mirrors that of the “Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB” (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants withMycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. Theprimary outcomemeasures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is thesecondary outcome. Assuming anα = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority.DiscussionPROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16.Trial registrationClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 athttps://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1{2}.