NCT03100786

Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis

Completed Phase 3 Last updated 17 June 2025

What this trial tests

Phase 3 trial testing Dexamethasone in Tuberculosis in 702 participants. Completed in 9 March 2024.

Timeline

12 February 2018

Primary endpoint
9 March 2023

9 March 2024

Quick facts

Lead sponsor	Oxford University Clinical Research Unit, Vietnam
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	702
Start date	12 February 2018
Primary completion	9 March 2023
Estimated completion	9 March 2024
Sites	3 locations across Vietnam

Drugs / interventions tested

• Dexamethasone (dexamethasone) — full drug profile →
• Placebo

Conditions studied

• Tuberculosis — all drugs for Tuberculosis →
• Tuberculous Meningitis — all drugs for Tuberculous Meningitis →
• Drug-Induced Liver Injury — all drugs for Drug-Induced Liver Injury →

Sponsor

Oxford University Clinical Research Unit, Vietnam

Who can join

18 and older, any sex, with Tuberculosis or Tuberculous Meningitis. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

The primary objective is to determine whether Leukotriene A4 hydrolase (LTA4H) genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. The investigators will conduct a LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III non-inferiority trial evaluating dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis drugs.

The investigators will take a hybrid trial-design approach which assumes a modest harm of dexamethasone and aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. Moreover, as it is possible that harm of dexamethasone only applies to the LTA4H CC genotype, the trial will allow dropping the CT group at an interim analysis but continue randomization of the CC group.

In making this assessment the investigators not only determine whether dexamethasone influences survival and the incidence of new neurological events (the primary endpoint), but also whether it influences disability assessed by the modified Rankin score 12 months after the start of treatment.

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Therapeutic host-directed strategies to improve outcome in tuberculosis.
   Young C, Walzl G, Du Plessis N. · · 2020 · cited 158× · PMID 31772320 · DOI 10.1038/s41385-019-0226-5
2. The pathogenesis of tuberculous meningitis.
   Davis AG, Rohlwink UK, Proust A, Figaji AA, et al · · 2019 · cited 133× · PMID 30645042 · DOI 10.1002/jlb.mr0318-102r
3. The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes.
   Seddon JA, Tugume L, Solomons R, Prasad K, et al · · 2019 · cited 86× · PMID 32118118 · DOI 10.12688/wellcomeopenres.15535.1
4. Corticosteroids as an adjunct to tuberculosis therapy.
   Schutz C, Davis AG, Sossen B, Lai RP, et al · · 2018 · cited 48× · PMID 30138039 · DOI 10.1080/17476348.2018.1515628
5. Tuberculous meningitis: where to from here?
   Donovan J, Thwaites GE, Huynh J. · · 2020 · cited 47× · PMID 32324614 · DOI 10.1097/qco.0000000000000648
6. Remembering the Host in Tuberculosis Drug Development.
   Frank DJ, Horne DJ, Dutta NK, Shaku MT, et al · · 2019 · cited 34× · PMID 30590592 · DOI 10.1093/infdis/jiy712
7. Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial.
   Donovan J, Phu NH, Mai NTH, Dung LT, et al · · 2018 · cited 34× · PMID 30320225 · DOI 10.12688/wellcomeopenres.14006.2
8. Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.
   Whitworth LJ, Troll R, Pagán AJ, Roca FJ, et al · · 2021 · cited 31× · PMID 33658385 · DOI 10.1073/pnas.2024852118