Leukotriene A4 Hydrolase Stratified Trial Of Adjunctive Corticosteroids For HIV-Uninfected Adults With Tuberculous Meningitis (The LAST ACT Trial)


2016 – 2023

Clinical Trial Registration
Registration number: NCT03100786

Principal Investigator: 
Professor Guy Thwaites

The LAST ACT Trial is 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.


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.

How dexamethasone, as an adjunctive anti-inflammatory treatment, can improve survival in TBM patients, especially in HIV-uninfected individuals, and whether they do so in all patients remain uncertain and is the focus of this trial.


Our primary aim is to determine whether LTA4H genotype, defined at randomisation, determines dexamethasone’s clinical effectiveness when added to the first 6–8 weeks of anti-tuberculosis treatment of TBM.

In making this assessment, we not only determine whether placebo is non-inferior to dexamethasone in patients having LTA4H CT or CC-genotype, in terms of:

  • Survival rate;
  • Incidence of new neurological events;
  • Disability, as assessed by the modified Rankin scale;
  • Frequency of severe and serious adverse events;
  • Need for rescue corticosteroids.

Our secondary aim is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible.


Peter J. Dodd, Muhammad Osman,Fiona V. Cresswell, Anna M. Stadelman, Nguyen Huu Lan, Nguyen Thuy Thuong Thuong, Morris Muzyamba, Lisa Glaser, Sicelo S. Dlamini, James A. Seddon
Lancet Glob Health
December 8, 2021
DOI: 10.1371/journal.pgph.0000069
Fiona V Cresswell, Angharad G Davis, Kusum Sharma, Robindra Basu Roy, Ahmad Rizal Ganiem, Enock Kagimu, Regan Solomons, Robert J Wilkinson, Nathan C Bahr, Nguyen Thuy Thuong Thuong, Tuberculous Meningitis International Research Consortium
Wellcome Open Res
January 28, 2021
DOI: 10.12688/wellcomeopenres.15506.3


Joseph Donovan

Dr Joseph Donovan

HTD-updated logo

Hospital For Tropical Diseases


Pham Ngoc Thach Hospital

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