A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis

Trials

Study Protocol

M Rassool¹  X Gong²  PPJ Phillips²  R Aarnoutse³  M Boeree³  L Te Brake³  EM Svensson⁴  TD McHugh⁵  LM Wildner⁵  L Hoffmann⁶  A Dierig⁶  M Hoelscher⁶  S Schultz⁶  N Heinrich⁶  A Jarchow-MacDonald⁷  B Mbeya⁸  FA Mhimbira⁸  S Mpagama⁹  A Liyoyo⁹  YL Cho^1,10  L Geiter^1,10  N Ntinginya^1,11  LT Minja^1,11  RS Wallis^1,12  M Sebe^1,12 

[1] Clinical HIV Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, Helen Joseph Hospital, University of the Witwatersrand, Johannesburg, South Africa;Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of California San Francisco, San Francisco, USA;Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands;Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands;Department of Pharmacy, Uppsala University, Uppsala, Sweden;Division of Infection & Immunity, UCL Centre for Clinical Microbiology, University College of London, London, UK;Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, Munich, Germany;German Center for Infection Research (DZIF), Munich partner site, Munich, Germany;Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, Munich, Germany;German Center for Infection Research (DZIF), Munich partner site, Munich, Germany;Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK;Ifakara Health Institute, Dar es Salaam, Tanzania;Kilimanjaro Clinical Research Institute, Kilimanjaro, Tanzania;LegoChem Biosciences, Daejeon, South Korea;National Institute for Medical Research, Mbeya Medical Research Centre (NIMR-MMRC), Mbeya, Tanzania;The Aurum Institute, Tembisa, South Africa;

关键词: Uncomplicated pulmonary tuberculosis;    Treatment;    Delpazolid;    Randomized controlled trial;    Phase IIb;    Oxazolidinone;   

DOI  :  10.1186/s13063-023-07354-5

 received in 2022-09-01, accepted in 2023-05-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLinezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure–response and exposure–toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.MethodsSeventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response.Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.DiscussionDECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.Trial registrationDECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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