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

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ClinicalTrials.gov Identifier: NCT03100786
Recruitment Status : Recruiting
First Posted : April 4, 2017
Last Update Posted : April 10, 2018
Sponsor:
Collaborators:
Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Information provided by (Responsible Party):
Oxford University Clinical Research Unit, Vietnam

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.


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

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 640 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: A Randomized Double Blind Placebo Controlled Non-inferiority Trial of Adjunctive Dexamethasone for the Treatment of HIV-uninfected Adults With Tuberculous Meningitis Stratified by Leukotriene A4 Hydrolase Genotype
Actual Study Start Date : February 8, 2018
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : October 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. All-cause mortality or new neurological event [ Time Frame: 12 months from randomisation ]
    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.


Secondary Outcome Measures :
  1. Overall survival until 12 months after randomization [ Time Frame: 12 months after randomization ]
    Overall survival is defined as 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.

  2. Neurological disability at 12 months (modified Rankin score) [ Time Frame: at 12 months ]
    Neurological disability will be assessed by the modified Rankin score on months 3, 6, 9, and 12 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')

  3. Severe (grade 3 and 4) and serious adverse events by 12 months [ Time Frame: by 12 months ]
    Comparison of the frequency of severe (grade 3&4) and serious adverse events, respectively, between treatment groups will form an important part of the study analysis.

  4. Requirement for 'rescue' corticosteroids [ Time Frame: during the 12 month follow-up ]
    Neurological complications occurring after the start of anti-tuberculosis chemotherapy for TBM are common. The cause varies, but includes hydrocephalus, infarcts, tuberculoma formation and hyponatraemia. If the symptoms are thought to be caused by tuberculomas, many doctors will re-start or increase the dose of corticosteroids. In this trial, any re-start or dose increase of corticosteroids during the 12 month follow-up will be defined as 'rescue' corticosteroids.



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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-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)

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): NCT03100786


Contacts
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
Vietnam
Hospital for Tropical Diseases Not yet 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
Contact: Evelyne Kestelyn, PhD    (+84 8) 3924 1983    ekestelyn@oucru.org   
Sub-Investigator: Evelyne Kestelyn, PhD         
Sub-Investigator: Ronald Geskus, MD         
Sub-Investigator: Thao Le Thi Phuong, MSc         
Sub-Investigator: Thuong Nguyen Thuy Thuong, MD         
Pham Ngoc Thach Hospital Not yet recruiting
Ho Chi Minh City, Vietnam
Principal Investigator: Trang Nguyen Thi Mai, Pharm         
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
Investigators
Principal Investigator: Guy Thwaites, MD University of Oxford, UK

Publications:

Responsible Party: Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT03100786     History of Changes
Other Study ID Numbers: 27TB
First Posted: April 4, 2017    Key Record Dates
Last Update Posted: April 10, 2018
Last Verified: April 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 the research and the value of sharing individual level data. The investigators aim to ensure that data generated from all the 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.

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
dexamethasone
LTA4H
host genotype
personalized medicine

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