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

Study Overview
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Brief Summary
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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.

Detailed Description
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There is a longstanding hypothesis that death from TBM results from an excessive intracerebral inflammatory response. The corollary of this hypothesis has been that adjunctive anti-inflammatory treatment with corticosteroids (e.g. dexamethasone) improves survival, which has been demonstrated in predominantly HIV-uninfected individuals in a small number of trials. Yet how corticosteroids improve survival, and whether they do so in all patients, remain uncertain and is the focus of the LAST ACT trial. Adjunctive dexamethasone might improve outcomes from TBM by controlling the early intracerebral inflammatory response, reducing cerebral oedema and intra-cranial pressure, and it may prevent the potentially life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Despite the careful study of all participants enrolled into the last dexamethasone trial conducted in Vietnam, an anti-inflammatory effect linked to outcome was not found. An explanation for these puzzling findings was only forthcoming upon the subsequent discovery that a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), which determines the balance of pro- and anti-inflammatory eicosanoids, appeared to predict pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected participants. In a retrospective study, analysing HIV-uninfected Vietnamese adults with TBM enrolled into the earlier randomized controlled trial of adjunctive dexamethasone, the investigators found that the survival benefit of dexamethasone was restricted to the hyper-inflammatory LTA4H TT-genotype patients, with possible harm suggested in the hypo-inflammatory CC-genotype patients. These preliminary findings suggested LTA4H genotype might be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response. Recently, the investigators have extended these original observations in a new cohort of 786 prospectively characterized Vietnamese adults with TBM, all of whom received corticosteroids. In this new cohort the investigators found that LTA4H genotype influences the survival of HIV-uninfected patients, but not those infected with HIV in patients receiving dexamethasone. TT-genotype patients were significantly more likely to survive than CC-genotype patients by both univariable and multivariable analysis, which confirms the previous findings. The investigators now have two independent studies that suggest LTA4H influences pre-treatment inflammatory phenotype in HIV-uninfected Vietnamese adults and dexamethasone-induced survival. The investigators now want to conduct a practice-defining RCT that addresses the hypothesis that in HIV-uninfected adults with TBM, LTA4H genotype can be used to select those most likely to benefit from dexamethasone. The data strongly suggest 'hyperinflammatory' LTA4H TT genotype patients with TBM benefit from dexamethasone. Therefore, these patients will be enrolled to the trial and followed-up for 12 months but will receive open label dexamethasone for the first 6-8 weeks of anti-tuberculosis treatment. The data supports the hypothesis that adjunctive dexamethasone does not benefit, and may cause harm, when given to LTA4H CT or CC-genotype Vietnamese adults with TBM. Therefore, participants with these two genotypes will be randomised to receive 6-8 weeks of placebo or dexamethasone in addition to anti-tuberculosis drugs. The primary objective is to determine whether LTA4H genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. In making this assessment the investigators not only determine whether dexamethasone increases survival and reduces the incidence of new neurological events (the primary endpoint), but also whether it reduces disability assessed by the modified Rankin score 12 months after the start of treatment. The primary endpoint is death 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. 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. The investigators will perform an open, randomised comparison of three management strategies with the aim of demonstrating which strategy results in the least interruption in R and H treatment. All patients enrolled in the trial will be eligible to take part in this study, with the exception of those known to have TBM caused by isoniazid resistant or MDR M. tuberculosis. Consent will be sought at enrolment, with an option given to patients to enrol in the main study, but not the 'drug-induced liver injury strategy study'. Eligible patients will be randomised to one of three strategies: Observe: measure transaminases, bilirubin, and INR every 3 days; do not change/stop anti-tuberculosis drugs unless transaminases rise to ≥10x normal, or total bilirubin rises >2.0mg/dl (>34 µmol/L), or INR >1.5 or symptoms of hepatitis worsen (nausea, vomiting, abdominal pain), in which case go to Strategy 3. Stop Pyrazinamide (Z) alone. Observe, measuring transaminases, bilirubin, and INR every 3 days. If transaminases do not fall to < 5x ULN by day 5, or total bilirubin rises >2.0mg/dl (>34 µmol/L), or INR >1.5 or symptoms of hepatitis worsen at any time (nausea, vomiting, abdominal pain), go to Strategy 3. Current standard of care (the current USA CDC guidelines): stop rifampicin (R), isoniazid (H) and Z immediately and add levofloxacin and an aminoglycoside to ethambutol. Restart R (at full dose) once transaminases are <2X ULN and no hepatitis symptoms. If no increase in transaminases after 7 days add isoniazid (at full dose) and stop levofloxacin and aminoglycoside. If transaminases remain normal on full dose R and H, Z was the likely cause and it should not be re-started and treatment duration should be extended to ≥12 months. If transaminases rise ≥ 5x ULN, or ≥3x ULN with symptoms, at any time after re-introduction of R and/or H the physician should stop R and/or H (depending on which was associated with the transaminase rise). If neither R or H can be used, treat with levofloxacin, an aminoglycoside and ethambutol. If R can be used, but not H, treat with R, levofloxacin and ethambutol. If H can be used, but not R, treat with H, levofloxacin and ethambutol. The primary endpoint is the proportion of time in the 60 days following randomisation during which neither rifampicin nor isoniazid are given (or the subject is dead). For example, if RH is interrupted for 18 days and the participant dies 48 days after randomization, the endpoint will be 50% [(18+(60-48))/60]. Rifampicin and isoniazid are considered critical drugs in early TBM treatment; inability to use these agents (either through bacterial resistance or patient intolerance) is associated with poor outcome. The vast majority of interruptions are expected to be shorter than one month for strategy 3 (standard of care) but as management strategies 1 and 2 delay the time point of the interruption, a longer cut-off of 60 days was chosen.

Official Title
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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

Conditions
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Tuberculosis, Tuberculous Meningitis, Drug-Induced Liver Injury

Intervention / Treatment
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* Drug: Dexamethasone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexamethasone<br>standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks | Drug: Dexamethasone<br>* 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<br>|
| Placebo Comparator: Identical placebo<br>standard anti-tuberculosis drugs plus placebo for 6-8 weeks | Other: Placebo<br>* Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality or new neurological event | 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. | 12 months from randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival until 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. | 12 months after randomization | 
| Neurological disability at 12 months (modified Rankin score) | 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') | at 12 months | 
| Severe (grade 3 and 4) and serious adverse events 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. | by 12 months | 
| Requirement for 'rescue' corticosteroids | 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. | during the 12 month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, tuberculous meningitis, drug induced liver injury, dexamethasone, LTA4H, host genotype, personalized medicine