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

NCT03100786 | Completed Phase 3 DMC

• 2 other identifiers: 27TB110179/Z/15/Z
• Study Type: interventional
• Target: 702
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Tuberculosis; Tuberculous Meningitis; Drug-Induced Liver Injury

Keywords

Tuberculosis; tuberculous meningitis; drug induced liver injury; dexamethasone; LTA4H; host genotype; personalized medicine

Outcome Measures

Primary Outcomes (1)

• All-cause mortality or new neurological event

  The primary endpoint is all cause mortality or new neurological event (defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the onset of any of the following clinical adverse events: cerebellar symptoms, focal neurological signs, or new onset of seizures) during 12 months from randomisation. Survivors without a new neurological event known to be alive at 12 months will be censored at that time-point and subjects who withdrew or were lost to follow-up before 12 months will be censored at the date they were last known to be alive.

  12 months from randomisation

Secondary Outcomes (4)

• Overall survival until 12 months after randomization

  12 months after randomization

• Neurological disability at 12 months (modified Rankin score)

  at 12 months

• Severe (grade 3 and 4) and serious adverse events by 12 months

  by 12 months

• Requirement for 'rescue' corticosteroids

  during the 12 month follow-up

Study Arms (2)

Dexamethasone

ACTIVE COMPARATOR

standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks

Drug: Dexamethasone

Identical placebo

PLACEBO COMPARATOR

standard anti-tuberculosis drugs plus placebo for 6-8 weeks

Other: Placebo

Interventions

Dexamethasone DRUG

Active treatment with dexamethasone from randomisation (IV followed by oral according to disease severity at the start of treatment): Dexamethasone for intravenous injection and dexamethasone for oral ingestion

Dexamethasone

Placebo OTHER

Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose

Identical placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (18 years or older)
• HIV-uninfected
• Clinical diagnosis of TBM (≥5 days of meningitis symptoms, and CSF abnormalities) and anti-tuberculosis chemotherapy either planned or started by the attending physician
• Note: Published diagnostic criteria will be applied to all enrolled participants at the end of the study when all mycobacterial culture results are available. The criteria will sub-divide all cases into definite, probable and possible TBM, and those with an alternative diagnosis.

You may not qualify if:

• An additional brain infection (other than TBM) confirmed or suspected: positive CSF Gram or India Ink stain; positive blood or CSF Cryptococcal antigen test
• More than 6 consecutive days of two or more drugs active against M. tuberculosis immediately before screening
• More than 3 consecutive days of any type of orally or intravenously administered corticosteroid immediately before randomisation
• Dexamethasone considered mandatory for any reason by the attending physician
• Dexamethasone considered to be contraindicated for any reason by the attending physician
• Previously been randomised into the trial for a prior episode of TBM
• Lack of consent from the participant or family member (if the participant is incapacitated by the disease)

Sponsors & Collaborators

• Oxford University Clinical Research Unit, Vietnam: lead
• Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam: collaborator
• Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam: collaborator

Study Sites (3)

Hospital for Tropical Diseases

Ho Chi Minh City, Vietnam

Location

Oxford University Clinical Research Unit

Ho Chi Minh City, Vietnam

Location

Pham Ngoc Thach Hospital

Ho Chi Minh City, Vietnam

Location

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• Donovan J, Oanh PKN, Dobbs N, Phu NH, Nghia HDT, Summers D, Thuong NTT, Thwaites GE; Vietnam ICU Translational Applications Laboratory (VITAL) Investigators. Optic Nerve Sheath Ultrasound for the Detection and Monitoring of Raised Intracranial Pressure in Tuberculous Meningitis. Clin Infect Dis. 2021 Nov 2;73(9):e3536-e3544. doi: 10.1093/cid/ciaa1823.

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MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Meningeal; Chemical and Drug Induced Liver Injury

Interventions

Dexamethasone

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases; Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Guy Thwaites, MD

  University of Oxford, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2017
• First Posted: April 4, 2017
• Study Start: February 12, 2018
• Primary Completion: March 9, 2023
• Study Completion: March 9, 2024
• Last Updated: June 17, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

VN (3)