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

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ClinicalTrials.gov Identifier: NCT03092817
Recruitment Status : Recruiting
First Posted : March 28, 2017
Last Update Posted : July 17, 2018
Sponsor:
Collaborators:
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Cipto Mangunkusumo Hospital, Jakarta, Indonesia
RSUP Persahabatan Hospital, Jakarta, Indonesia
Eijkman Oxford Clinical Research Unit, Indonesia
Information provided by (Responsible Party):
Oxford University Clinical Research Unit, Vietnam

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Tuberculous Meningitis Drug-Induced Liver Injury HIV IRIS Drug: Dexamethasone Other: Placebo Phase 3

  Show Detailed Description

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Study Type : Interventional
Estimated Enrollment : 520 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: A Randomized Double Blind Placebo Controlled Trial of Adjunctive Dexamethasone for the Treatment of HIV-infected Adults With Tuberculous Meningitis
Actual Study Start Date : May 25, 2017
Estimated Primary Completion Date : April 1, 2020
Estimated Study Completion Date : April 1, 2022


Arm Intervention/treatment
Active Comparator: Dexamethasone
standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks
Drug: Dexamethasone
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

Placebo Comparator: Identical placebo
standard anti-tuberculosis drugs plus placebo for 6-8 weeks
Other: Placebo

Treatment with matched placebo:

Standard saline for intravenous injection and placebo oral tablets containing cellulose





Primary Outcome Measures :
  1. Overall survival until 12 months after randomisation [ Time Frame: 12 months from 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.


Secondary Outcome Measures :
  1. Neurological disability at 12 months (modified Rankin score) [ Time Frame: at 12 months ]

    Neurological disability will be assessed by the modified Rankin score (see below) on months 3, 6, 9, 12, 18 and 24 from randomisation. The main endpoint is the 12 month assessment and subjects who died before 12 months will be treated as having a score of 6 ('Dead').

    The Modified Rankin Scale Score Description 0 No symptoms

    1. Minor symptoms not interfering with lifestyle
    2. Symptoms that lead to some restriction in lifestyle, but do not interfere with the patients ability to look after themselves
    3. Symptoms that restrict lifestyle and prevent totally independent living
    4. Symptoms that clearly prevent independent living, although the patient does not need constant care and attention.
    5. Totally dependent, requiring constant help day and night.
    6. Death

  2. 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 [ Time Frame: by 12 months ]
    A neurological event is 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 onset of seizures.

  3. Rate of neurological IRIS events up to 6 months from randomisation [ Time Frame: 6 months from randomisation ]
    The rate is defined as the number of IRIS events divided by the observed person-time of follow-up in each treatment group.

  4. Time to new AIDS-defining illness or death by 12 months [ Time Frame: by 12 months ]
    AIDS-defining illnesses will be defined as per the WHO classification.

  5. Serious adverse events by 12 months [ Time Frame: by 12 months ]
    Comparison of the frequency of serious adverse events between treatment groups will form an important part of the study analysis.

  6. HIV-associated malignancy by 12 months [ Time Frame: by 12 months ]
    The three major HIV-associated malignancies are Kaposi sarcoma, high grade B-cell non-Hodgkin lymphoma and invasive cervical cancer.

  7. Overall survival [ Time Frame: by 24 months ]
    The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and overall survival will be reported once 24 month follow-up has been completed for all participants.

  8. Neurological disability [ Time Frame: by 24 months ]
    The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and neurological disability will be reported once 24 month follow-up has been completed for all participants.

  9. Time to new AIDS defining event or death [ Time Frame: by 24 months ]
    The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and this outcome will be reported once 24 month follow-up has been completed for all participants.

  10. Rate of HIV-related malignancy [ Time Frame: by 24 months ]
    The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and this outcome will be reported once 24 month follow-up has been completed for all participants.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

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; 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03092817


Contacts
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Contact: Guy Thwaites, MD (+84 8) 3923 7954 gthwaites@oucru.org
Contact: Clinical Trials Unit Oxford University Clinical Research Unit (+84 8) 3924 1983 CTU-Admin@oucru.org

Locations
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Indonesia
Cipto Mangunkusumo Hospital Active, not recruiting
Jakarta, Indonesia
Eijkman-Oxford Clinical Research Unit Active, not recruiting
Jakarta, Indonesia
RSUP Persahabatan Hospital Active, not recruiting
Jakarta, Indonesia
Vietnam
Hospital for Tropical Diseases Recruiting
Ho Chi Minh City, Vietnam
Principal Investigator: Phu Nguyen Hoan, MD PhD         
Sub-Investigator: Chau Nguyen Van Vinh, MD PhD         
Sub-Investigator: Mai Nguyen Thi Hoang, MD PhD         
Oxford University Clinical Research Unit Recruiting
Ho Chi Minh City, Vietnam
Sub-Investigator: Ronald Geskus, MD         
Sub-Investigator: Evelyne Kestelyn, MSc         
Sub-Investigator: Thao Le Thi Phuong, MSc         
Pham Ngoc Thach Hospital Active, not recruiting
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
Oxford University Clinical Research Unit, Vietnam
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Cipto Mangunkusumo Hospital, Jakarta, Indonesia
RSUP Persahabatan Hospital, Jakarta, Indonesia
Eijkman Oxford Clinical Research Unit, Indonesia
Investigators
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Principal Investigator: Guy Thwaites, MD University of Oxford, UK

Publications:

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Responsible Party: Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT03092817     History of Changes
Other Study ID Numbers: 26TB
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: July 17, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The Oxford University Clinical Research Unit recognizes the ethical obligation to ensure that optimal use is made of the data and specimens that the investigators collect for our research and the value of sharing individual level data. The investigators aim to ensure that data generated from all our research are collected, curated, managed and shared in a way that maximizes their benefit. When sharing data the investigators have an obligation to ensure that the interests of research participants, researchers and other stakeholders are appropriately protected. The Oxford University Clinical Research Unit data sharing policy and the data request form outline the default procedures for data sharing.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Oxford University Clinical Research Unit, Vietnam:
Tuberculosis
tuberculous meningitis
drug induced liver injury
HIV
IRIS
randomized controlled trial
dexamethasone

Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Meningeal
Chemical and Drug Induced Liver Injury
Meningitis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Diseases
Nervous System Diseases
Liver Diseases
Digestive System Diseases
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Poisoning
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Dexamethasone
Dexamethasone acetate
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones