Harrison Linda J, Velásquez Gustavo E, Kempker Russell R, Imperial Marjorie Z, Nuermberger Eric, Dorman Susan E, Ignatius Elisa, Granche Janeway, Phillips Patrick P J, Furin Jennifer, Yang Eunsol, Foley Colleen, Chiambah Shawn, Rogers Rochelle, Van Grack Austin, Roa Jhoanna, Shenje Justin, Nerette Sandy, Kanyama Cecilia, Kyeyune Rachel Bakyayita, Mendoza-Ticona Alberto, Murtaugh William, Foraida Salah, Goth Melanie, Vernon Andrew, Dooley Kelly E, Savic Radojka M
Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, USA.
Trials. 2025 Aug 15;26(1):291. doi: 10.1186/s13063-025-08973-w.
The standard of care (SOC) treatment for drug-susceptible pulmonary tuberculosis (DS-TB) consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). New treatment regimen options for DS-TB are needed as HRZE is long in duration (6 months), associated with frequent adverse events, unforgiving of adherence lapses, and complicated by rifamycin-based drug-drug interactions. The recent resurgence of TB drug development, particularly in the context of drug-resistant TB, offers promise for additional regimens for persons with DS-TB, provided they are sufficiently effective and well-tolerated. We spotlight wave 1 of the RAD-TB platform trial (ACTG A5409, NCT06192160) that will investigate new chemical entities for the treatment of DS-TB.
In wave 1 of the RAD-TB platform, adult participants initiating treatment for DS-TB will be randomized to SOC (HRZE, Arm 1) or one of five experimental arms for the 8-week intensive phase. The experimental treatment arms will consist of a bedaquiline and pretomanid backbone (BPa) in combination with one of three oxazolidinones. Arm 2 will study linezolid (BPaL) at a dose of 600 mg daily, Arms 3A and 3B will study TBI-223 at 1200 mg and 2400 mg daily, respectively, and Arms 4A and 4B will study sutezolid at 800 mg and 1600 mg daily, respectively. The primary efficacy objective is to compare sputum culture time to positivity (TTP) slope over the first 6 weeks of treatment for each experimental treatment arm to SOC. The primary safety objective is to compare new Grade 3 or higher adverse events over the first 8 weeks of treatment for each experimental treatment arm to SOC. After the intensive phase, all participants will receive the standard isoniazid and rifampicin (HR) continuation phase for 18 weeks. Participants will be followed for 52 weeks after TB treatment initiation to assess long-term outcomes.
Wave 1 of the RAD-TB platform aims to identify the optimal oxazolidinone(s), with regard to both efficacy and safety, to combine with the BPa backbone for the treatment of DS-TB. Subsequent waves of this platform trial may add a fourth drug to the regimen, study new diarylquinolines to substitute for bedaquiline, or study novel agents from other TB drug classes.
ClinicalTrials.gov NCT06192160 . Registered on January 5, 2024.
药物敏感型肺结核（DS-TB）的标准治疗方案（SOC）包括异烟肼、利福平、吡嗪酰胺和乙胺丁醇（HRZE）。由于HRZE疗程长达6个月，不良反应频发，对依从性不佳难以容忍，且存在基于利福霉素的药物相互作用，因此需要新的DS-TB治疗方案。近期结核病药物研发的复兴，特别是在耐药结核病背景下，为DS-TB患者提供了更多治疗方案的希望，前提是这些方案足够有效且耐受性良好。我们重点介绍RAD-TB平台试验的第1阶段（ACTG A5409，NCT06192160），该试验将研究用于治疗DS-TB的新化学实体。
在RAD-TB平台的第1阶段，开始接受DS-TB治疗的成年参与者将被随机分配至SOC组（HRZE，第1组）或五个试验组之一，进行为期8周的强化期治疗。试验治疗组将由贝达喹啉和pretomanid主干（BPa）与三种恶唑烷酮之一联合组成。第2组将研究每日剂量为600 mg的利奈唑胺（BPaL），第3A组和第3B组将分别研究每日剂量为1200 mg和2400 mg的TBI-223，第4A组和第4B组将分别研究每日剂量为800 mg和1600 mg的舒替唑胺。主要疗效目标是比较每个试验治疗组与SOC组在治疗的前6周内痰培养转阴时间（TTP）斜率。主要安全性目标是比较每个试验治疗组与SOC组在治疗的前8周内新出现的3级或更高等级不良事件。强化期结束后，所有参与者将接受标准的异烟肼和利福平（HR）继续治疗阶段，为期18周。在开始结核病治疗后，将对参与者进行52周的随访，以评估长期结局。
RAD-TB平台的第1阶段旨在确定在疗效和安全性方面最佳的恶唑烷酮，与BPa主干联合用于治疗DS-TB。该平台试验的后续阶段可能会在方案中添加第四种药物，研究新的二芳基喹啉以替代贝达喹啉，或研究其他结核病药物类别的新型药物。
ClinicalTrials.gov NCT06192160。于2024年1月5日注册。
