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

Brief Title

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

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

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.
    

Detailed Description

      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:

        1. 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.

        2. 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.

        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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

All-cause mortality or new neurological event

Secondary Outcome

 Overall survival until 12 months after randomization

Condition

Tuberculosis

Intervention

Dexamethasone

Study Arms / Comparison Groups

 Dexamethasone
Description:  standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

640

Start Date

February 8, 2018

Completion Date

October 1, 2022

Primary Completion Date

December 1, 2021

Eligibility 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)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Guy Thwaites, MD, (+84 8) 3923 7954, [email protected]

Location Countries

Vietnam

Location Countries

Vietnam

Administrative Informations


NCT ID

NCT03100786

Organization ID

27TB


Responsible Party

Sponsor

Study Sponsor

Oxford University Clinical Research Unit, Vietnam

Collaborators

 Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam

Study Sponsor

Guy Thwaites, MD, Principal Investigator, University of Oxford, UK


Verification Date

September 2020