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 [version 1; referees: 2 approved]

Joseph Donovan, Nguyen Hoan Phu, Le Thi Phuong Thao, Nguyen Huu Lan, Nguyen Thi Hoang Mai, Nguyen Thi Mai Trang, Nguyen Thi Thu Hiep, Tran Bao Nhu, Bui Thi Bich Hanh, Vu Thi Phuong Mai, Nguyen Duc Bang, Do Chau Giang, Dang Thi Minh Ha, Jeremy Day, Nguyen T.T. Thuong, Nguyen Nang Vien, Ronald B. Geskus, Tran Tinh Hien, Evelyne Kestelyn, Marcel Wolbers & 2 others Nguyen Van Vinh Chau, Guy E. Thwaites

Research output: Contribution to journalArticleOtherpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number32
Number of pages21
JournalWellcome Open Research
Volume3
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

Keywords

  • Adrenal suppression
  • Dexamethasone
  • Drug induced liver injury
  • HIV-uninfected
  • Hyponatraemia
  • LTA4H
  • Tuberculous meningitis

Cite this

Donovan, Joseph ; Phu, Nguyen Hoan ; Thao, Le Thi Phuong ; Lan, Nguyen Huu ; Mai, Nguyen Thi Hoang ; Trang, Nguyen Thi Mai ; Hiep, Nguyen Thi Thu ; Nhu, Tran Bao ; Hanh, Bui Thi Bich ; Mai, Vu Thi Phuong ; Bang, Nguyen Duc ; Giang, Do Chau ; Ha, Dang Thi Minh ; Day, Jeremy ; Thuong, Nguyen T.T. ; Vien, Nguyen Nang ; Geskus, Ronald B. ; Hien, Tran Tinh ; Kestelyn, Evelyne ; Wolbers, Marcel ; Chau, Nguyen Van Vinh ; Thwaites, Guy E. / 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 [version 1; referees: 2 approved]. In: Wellcome Open Research. 2018 ; Vol. 3.
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title = "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 [version 1; referees: 2 approved]",
abstract = "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.",
keywords = "Adrenal suppression, Dexamethasone, Drug induced liver injury, HIV-uninfected, Hyponatraemia, LTA4H, Tuberculous meningitis",
author = "Joseph Donovan and Phu, {Nguyen Hoan} and Thao, {Le Thi Phuong} and Lan, {Nguyen Huu} and Mai, {Nguyen Thi Hoang} and Trang, {Nguyen Thi Mai} and Hiep, {Nguyen Thi Thu} and Nhu, {Tran Bao} and Hanh, {Bui Thi Bich} and Mai, {Vu Thi Phuong} and Bang, {Nguyen Duc} and Giang, {Do Chau} and Ha, {Dang Thi Minh} and Jeremy Day and Thuong, {Nguyen T.T.} and Vien, {Nguyen Nang} and Geskus, {Ronald B.} and Hien, {Tran Tinh} and Evelyne Kestelyn and Marcel Wolbers and Chau, {Nguyen Van Vinh} and Thwaites, {Guy E.}",
year = "2018",
month = "1",
day = "1",
doi = "10.12688/wellcomeopenres.14007.1",
language = "English",
volume = "3",
journal = "Wellcome Open Research",
issn = "2398-502X",
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}

Donovan, J, Phu, NH, Thao, LTP, Lan, NH, Mai, NTH, Trang, NTM, Hiep, NTT, Nhu, TB, Hanh, BTB, Mai, VTP, Bang, ND, Giang, DC, Ha, DTM, Day, J, Thuong, NTT, Vien, NN, Geskus, RB, Hien, TT, Kestelyn, E, Wolbers, M, Chau, NVV & Thwaites, GE 2018, '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 [version 1; referees: 2 approved]', Wellcome Open Research, vol. 3, 32. https://doi.org/10.12688/wellcomeopenres.14007.1

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 [version 1; referees: 2 approved]. / Donovan, Joseph; Phu, Nguyen Hoan; Thao, Le Thi Phuong; Lan, Nguyen Huu; Mai, Nguyen Thi Hoang; Trang, Nguyen Thi Mai; Hiep, Nguyen Thi Thu; Nhu, Tran Bao; Hanh, Bui Thi Bich; Mai, Vu Thi Phuong; Bang, Nguyen Duc; Giang, Do Chau; Ha, Dang Thi Minh; Day, Jeremy; Thuong, Nguyen T.T.; Vien, Nguyen Nang; Geskus, Ronald B.; Hien, Tran Tinh; Kestelyn, Evelyne; Wolbers, Marcel; Chau, Nguyen Van Vinh; Thwaites, Guy E.

In: Wellcome Open Research, Vol. 3, 32, 01.01.2018.

Research output: Contribution to journalArticleOtherpeer-review

TY - JOUR

T1 - Adjunctive dexamethasone for the treatment of hiv-uninfected adults with tuberculous meningitis stratified by leukotriene a4 hydrolase genotype (LAST ACT)

T2 - Study protocol for a randomised double blind placebo controlled non-inferiority trial [version 1; referees: 2 approved]

AU - Donovan, Joseph

AU - Phu, Nguyen Hoan

AU - Thao, Le Thi Phuong

AU - Lan, Nguyen Huu

AU - Mai, Nguyen Thi Hoang

AU - Trang, Nguyen Thi Mai

AU - Hiep, Nguyen Thi Thu

AU - Nhu, Tran Bao

AU - Hanh, Bui Thi Bich

AU - Mai, Vu Thi Phuong

AU - Bang, Nguyen Duc

AU - Giang, Do Chau

AU - Ha, Dang Thi Minh

AU - Day, Jeremy

AU - Thuong, Nguyen T.T.

AU - Vien, Nguyen Nang

AU - Geskus, Ronald B.

AU - Hien, Tran Tinh

AU - Kestelyn, Evelyne

AU - Wolbers, Marcel

AU - Chau, Nguyen Van Vinh

AU - Thwaites, Guy E.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Adrenal suppression

KW - Dexamethasone

KW - Drug induced liver injury

KW - HIV-uninfected

KW - Hyponatraemia

KW - LTA4H

KW - Tuberculous meningitis

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U2 - 10.12688/wellcomeopenres.14007.1

DO - 10.12688/wellcomeopenres.14007.1

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JO - Wellcome Open Research

JF - Wellcome Open Research

SN - 2398-502X

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