Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial)

NCT03092817 | Completed Phase 3 DMC

• 1 other identifier: 26TB
• Study Type: interventional
• Target: 520
• Locations: 2 countries
• Sites: 6

Brief Summary

The investigators will conduct a randomized, double blind, placebo controlled trial of adjunctive dexamethasone in the initial (6-8 weeks) treatment of tuberculous meningitis in Vietnamese adults. The trial will address a primary hypothesis in all enrolled patients, and a secondary hypothesis in a sub-group of enrolled patients who develop anti-tuberculosis drug-induced liver injury (DILI). The primary hypothesis is adjunctive dexamethasone increases survival from TBM in HIV co-infected adults. The secondary hypothesis is current guidelines for the management of anti-tuberculosis drug-induced liver injury in those with TBM result in the premature interruption of rifampicin and isoniazid (the critical active drugs in early therapy) and are thereby placing participants at risk of poor outcomes.

Conditions

Tuberculosis; Tuberculous Meningitis; Drug-Induced Liver Injury; HIV; IRIS

Keywords

Tuberculosis; tuberculous meningitis; drug induced liver injury; HIV; IRIS; randomized controlled trial; dexamethasone

Outcome Measures

Primary Outcomes (1)

• Overall survival until 12 months after randomisation

  The primary endpoint is overall survival, i.e. the time from randomization to death, during a follow-up period of 12 months. Survivors 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 (11)

• Neurological disability at 12 months (modified Rankin score)

  at 12 months

• Time to new neurological event (defined as a fall in GCS of ≥2 points for ≥48 hours, new focal neurological sign, or new onset of seizures) or death by 12 months

  by 12 months

• Rate of neurological IRIS events up to 6 months from randomisation

  6 months from randomisation

• Time to new AIDS-defining illness or death by 12 months

  by 12 months

• Serious adverse events by 12 months

  by 12 months

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-infected
• 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; cerebral toxoplasmosis suspected and attending physician wants to give anti-toxoplasmosis treatment with anti-tuberculosis treatment
• 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
• Dr Cipto Mangunkusumo General Hospital: collaborator
• RSUP Persahabatan Hospital, Jakarta, Indonesia: collaborator
• Oxford University Clinical Research Unit Indonesia: collaborator

Study Sites (6)

Cipto Mangunkusumo Hospital

Jakarta, Indonesia

Location

Eijkman-Oxford Clinical Research Unit

Jakarta, Indonesia

Location

RSUP Persahabatan Hospital

Jakarta, Indonesia

Location

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

Related Publications (74)

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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 15, 2017
• First Posted: March 28, 2017
• Study Start: May 25, 2017
• Primary Completion: April 30, 2022
• Study Completion: April 26, 2023
• Last Updated: March 22, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share

Locations

ID (3); VN (3)