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

• Status: Recruiting
• Trial end date: 2022-10-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Oxford University Clinical Research Unit, Vietnam
• Collaborators: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
• Treatments: BB 1101; Dexamethasone; Dexamethasone 21-phosphate; Dexamethasone acetate

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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)