High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Wellcome Open Research

article

Darma Imran¹  Suzaan Marais²  Fiona V Cresswell³  Raph L. Hamers⁶  Lindsey H.M. te Brake⁸  Ahmad R. Ganiem⁹  Ananta Bangdiwala^1,11  Emily Martyn³  John Kasibante³  Enock Kagimu³  Abdu Musubire³  Kartika Maharani¹  Riwanti Estiasari¹  Ardiana Kusumaningrum^1,12  Nadytia Kusumadjayanti^1,10  Vycke Yunivita⁹  Kogieleum Naidoo^1,13  Richard Lessells^1,13  Yunus Moosa^1,16  Elin M. Svensson⁸  Katherine Huppler Hullsiek^1,11  Rob E. Aarnoutse⁸  David R. Boulware^1,18  Reinout van Crevel⁷  Rovina Ruslami^1,10  David B. Meya³ 

[1] Department of Neurology, Faculty of Medicine, Universitas Indonesia, Dr Cipto Mangukusumo Hospital;Department of Neurology, Inkosi Albert Luthuli Central Hospital;Infectious Diseases Institute, Mulago College of Health Sciences;Clinical Research Department, London School of Hygiene & Tropical Medicine;MRC-UVRI, London School of Hygiene & Tropical Medicine Uganda Research Unit;Eijkman-Oxford Clinical Research Unit;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford;Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre;Department of Neurology, Faculty of Medicine, Universitas Padjadjaran/ Hasan Sadikin Hospital;Infectious Disease Research Centre, Faculty of Medicine, Universitas Padjadaran;Division of Biostatistics, School of Public Health, University of Minnesota;Department of Microbiology, Faculty of Medicine, Universitas Indonesia, Dr Cipto Mangukusumo Hospital;Centre for the AIDS programme of research in South Africa ,(CAPRISA), Doris Duke Medical Research Institute;CAPRISA-MRC HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu Natal;KwaZulu-Natal Research Innovation and Sequencing Platform, Nelson R Mandela School of Medicine, University of KwaZulu-Natal;Department of Infectious Diseases, Division of Internal Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal;Department of Pharmaceutical Biosciences, Uppsala University;Division of Medicine, University of Minnesota;Department of Internal Medicine, Radboud University Nijmegen Medical Centre;Department of Biomedical Sciences, Division of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran

关键词: Tuberculous Meningitis;    TB;    rifampicin;    Xpert Ultra;    HIV;    treatment;    RCT;   

DOI  :  10.12688/wellcomeopenres.15565.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: 50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events.Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment.Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia.

【 授权许可】

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