The Safety and Efficacy of BDL(Bedaquiline Plus Delamanid Plus Linezolid) Regimen in Subjects With Pulmonary Infection of Multi-drug Resistant Tuberculosis (MDR-TB) or Rifampicin-Resistant Tuberculosis (RR-TB)

Summary

The goal of this investigator initiated trial (IIT) is to learn if a 6-9months BDL regimen (bedaquiline plus delamanid plus linezolid）works to treat adults with multi-drug resistant tuberculosis or rifampicin-resistant pulmonary tuberculosis, in the context of Pretomanid not available in China. It will also learn about the safety of BDL regimen. The main questions it aims to answer are: 1. What is the percentage of participants with favorable treatment outcome at the end of treatment? 2. What are the frequency and degree of AE and SAE associated with BDL regimen? Participants will take Bedaquiline +Delamanid+ Linezolid for 6 months, option for 9 months for subjects who remain culture positive at month 4 to 6. Safety and efficacy data will be monitored and collected during treatment. A 12 month follow-up will be conducted after treatment completion.

Timeline

Start

2024-06

Primary completion

2025-06

Completion

2026-06

Publications

• Background Dooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, Lama JR, Shenje J, De Los Rios J, Comins K, Morganroth J, Diacon AH, Cramer YS, Donahue K, Maartens G; AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021 Jul;21(7):975-983. doi: 10.1016/S1473-3099(20)30770-2. Epub 2021 Feb 12.
• Background Lachatre M, Rioux C, Le Du D, Frechet-Jachym M, Veziris N, Bouvet E, Yazdanpanah Y. Bedaquiline plus delamanid for XDR tuberculosis. Lancet Infect Dis. 2016 Mar;16(3):294. doi: 10.1016/S1473-3099(16)00047-5. No abstract available.
• Background Kim CT, Kim TO, Shin HJ, Ko YC, Hun Choe Y, Kim HR, Kwon YS. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur Respir J. 2018 Mar 22;51(3):1702467. doi: 10.1183/13993003.02467-2017. Print 2018 Mar.
• Background Gao JT, Du J, Wu GH, Pei Y, Gao MQ, Martinez L, Fan L, Chen W, Xie L, Chen Y, Wang H, Jin L, Li GB, Zong PL, Xiong Y, Wu QH, Li MW, Yan XF, Miao YF, Cai QS, Li XJ, Bai DP, Geng SJ, Yang GL, Tang PJ, Zeng Y, Chen XH, Li TX, Cai C, Zhou Y, Zhuo M, Wang JY, Guan WL, Xu L, Shi JC, Shu W, Cheng LL, Teng F, Ning YJ, Xie SH, Sun YX, Zhang LJ, Liu YH. Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety. Infect Dis Poverty. 2021 Mar 19;10(1):32. doi: 10.1186/s40249-021-00819-2.
• Background Blair HA, Scott LJ. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs. 2015 Jan;75(1):91-100. doi: 10.1007/s40265-014-0331-4.
• Background Pieterman ED, Keutzer L, van der Meijden A, van den Berg S, Wang H, Zimmerman MD, Simonsson USH, Bax HI, de Steenwinkel JEM. Superior Efficacy of a Bedaquiline, Delamanid, and Linezolid Combination Regimen in a Mouse Tuberculosis Model. J Infect Dis. 2021 Sep 17;224(6):1039-1047. doi: 10.1093/infdis/jiab043.
• Background Tasneen R, Williams K, Amoabeng O, Minkowski A, Mdluli KE, Upton AM, Nuermberger EL. Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):129-35. doi: 10.1128/AAC.03822-14. Epub 2014 Oct 20.
• Background Upton AM, Cho S, Yang TJ, Kim Y, Wang Y, Lu Y, Wang B, Xu J, Mdluli K, Ma Z, Franzblau SG. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. doi: 10.1128/AAC.03823-14. Epub 2014 Oct 20.
• Background Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H, Shimokawa Y, Komatsu M. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 2006 Nov;3(11):e466. doi: 10.1371/journal.pmed.0030466.
• Background Zhang F, Li S, Wen S, Zhang T, Shang Y, Huo F, Xue Y, Li L, Pang Y. Comparison of in vitro Susceptibility of Mycobacteria Against PA-824 to Identify Key Residues of Ddn, the Deazoflavin-Dependent Nitroreductase from Mycobacterium tuberculosis. Infect Drug Resist. 2020 Mar 11;13:815-822. doi: 10.2147/IDR.S240716. eCollection 2020.
• Background Stinson K, Kurepina N, Venter A, Fujiwara M, Kawasaki M, Timm J, Shashkina E, Kreiswirth BN, Liu Y, Matsumoto M, Geiter L. MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration. Antimicrob Agents Chemother. 2016 May 23;60(6):3316-22. doi: 10.1128/AAC.03014-15. Print 2016 Jun.
• Background Keller PM, Homke R, Ritter C, Valsesia G, Bloemberg GV, Bottger EC. Determination of MIC distribution and epidemiological cutoff values for bedaquiline and delamanid in Mycobacterium tuberculosis using the MGIT 960 system equipped with TB eXiST. Antimicrob Agents Chemother. 2015 Jul;59(7):4352-5. doi: 10.1128/AAC.00614-15. Epub 2015 May 4.
• Background Liu Y, Matsumoto M, Ishida H, Ohguro K, Yoshitake M, Gupta R, Geiter L, Hafkin J. Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis (Edinb). 2018 Jul;111:20-30. doi: 10.1016/j.tube.2018.04.008. Epub 2018 May 3.
• Background Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M; Nix-TB Trial Team. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.
• Background Trebucq A, Schwoebel V, Kashongwe Z, Bakayoko A, Kuaban C, Noeske J, Hassane S, Souleymane B, Piubello A, Ciza F, Fikouma V, Gasana M, Ouedraogo M, Gninafon M, Van Deun A, Cirillo DM, Koura KG, Rieder HL. Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries. Int J Tuberc Lung Dis. 2018 Jan 1;22(1):17-25. doi: 10.5588/ijtld.17.0498. Epub 2017 Nov 17.

Drugs

Indications