Background: Tuberculosis kills more people than any other
bacterial infection worldwide. In
tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding
leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to
dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive
dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop
drug induced liver injury (DILI) that will enable the safe continuation of
rifampicin and
isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, multi-centre Phase III non-inferiority trial, comparing
dexamethasone versus placebo for 6-8 weeks in addition to standard anti-
tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either
dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care
dexamethasone. We will also perform a randomised comparison of three management strategies for anti-
tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of
dexamethasone in HIV-infected adults with TBM (ACT HIV). Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of
inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify
dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory
therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of
rifampicin and
isoniazid.