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
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|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Care Provider)|
|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|
Active Comparator: Dexamethasone
standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks
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
Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose
- 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.
- 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.
- 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')
- 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.
- 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.
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
|Contact: Guy Thwaites, MD||(+84 8) 3923 firstname.lastname@example.org|
|Contact: Clinical Trials Unit Oxford University Clinical Research Unit||(+84 8) 3924 1983||CTU-Admin@oucru.org|
|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 email@example.com|
|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|
|Principal Investigator:||Guy Thwaites, MD||University of Oxford, UK|