High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study)

Wellcome Open Research

article

Fiona V. Cresswell¹  Kenneth Ssebambulidde²  Daniel Grint³  Lindsey te Brake⁴  Abdul Musabire²  Rachel R. Atherton²  Lillian Tugume²  Conrad Muzoora⁵  Robert Lukande⁶  Mohammed Lamorde²  Rob Aarnoutse⁴  David Meya²  David R. Boulware²  Alison M. Elliott¹ 

[1] Clinical Research Department, London School of Hygiene and Tropical Medicine;Clinical Research, Infectious Diseases Institute;Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine;Department of Pharmacy, Radboud University Medical Centre;Mbarara University of Science and Technology;Department of Pathology, College of Health Sciences, Makerere University;Division of Infectious Diseases, University of Minnesota;MRC - UVRI - LSHTM Uganda Research Unit

关键词: TBM;    Tuberculous Meningitis;    TB;    rifampicin;    Ultra;    HIV;   

DOI  :  10.12688/wellcomeopenres.14691.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration.  With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration forM. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined.Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment.Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial.

【 授权许可】

CC BY