Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial

Wellcome Open Research

article

Nguyen Duc Bang¹  Do Chau Giang¹  Dang Thi Minh Ha¹  Jeremy Day²  Nguyen TT Thuong²  Nguyen Nang Vien¹  Ronald B. Geskus²  Tran Tinh Hien²  Evelyne Kestelyn²  Marcel Wolbers²  Nguyen Van Vinh Chau⁴  Guy E. Thwaites²  Joseph Donovan²  Nguyen Hoan Phu⁴  Le Thi Phuong Thao²  Nguyen Huu Lan¹  Nguyen Thi Hoang Mai⁴  Nguyen Thi Mai Trang¹  Nguyen Thi Thu Hiep²  Tran Bao Nhu⁴  Bui Thi Bich Hanh⁴  Vu Thi Phuong Mai² 

[1] Pham Ngoc Thach Hospital;Oxford University Clinical Research Unit;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford;Hospital for Tropical Diseases

关键词: Tuberculous meningitis;    HIV-uninfected;    Dexamethasone;    Drug induced liver injury;    LTA4H;    Adrenal suppression;    Hyponatraemia;   

DOI  :  10.12688/wellcomeopenres.14007.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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.

【 授权许可】

CC BY