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

Brief Title

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

Official Title

A Randomized Double Blind Placebo Controlled Trial of Adjunctive Dexamethasone for the Treatment of HIV-infected Adults With Tuberculous Meningitis

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.
    

Detailed Description

      Mycobacterium tuberculosis causes ~9 million new cases of tuberculosis and ~1.5 million
      deaths annually, around 0.4 million of whom are co-infected with HIV. Tuberculous meningitis
      (TBM) is the most severe form of tuberculosis, killing around 30% of all sufferers despite
      appropriate anti-tuberculosis chemotherapy. It is especially common in young children, and in
      those infected with HIV.

      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
      HIV-infected patients, remains uncertain. The primary objective of this trial is to determine
      whether or not adjunctive corticosteroids reduce deaths from TBM in HIV-infected adults.

      Adjunctive dexamethasone might improve outcomes from HIV-associated TBM by diverse
      mechanisms. First, it may control the early intracerebral inflammatory response, reducing
      cerebral oedema and intra-cranial pressure. Second, it may prevent the potentially
      life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Third,
      it may prevent the incidence of anti-retroviral (ARV) treatment-associated neurological
      immune reconstitution inflammatory syndrome (IRIS). Finally, dexamethasone may help reduce
      the risk of drug-induced liver injury and thereby improve outcome by enabling uninterrupted
      anti-tuberculosis treatment.

      The current evidence-base for using adjunctive corticosteroids for the treatment of
      HIV-associated TBM is restricted to 98 adults recruited to a trial in Vietnam published in
      2004. This trial randomized a total of 545 subjects (98 of them HIV-positive) and reported an
      overall reduction in 9-month mortality due to dexamethasone from 41.3% (112/271) to 31.8%
      (87/274) (hazard ratio of time to death 0.69; 95% CI 0.52-0.92, P=0.01). While there was no
      clear evidence of treatment effect heterogeneity according to HIV status, the number of
      included HIV-infected subjects was low and the observed benefit in that subgroup was smaller:
      61.4% (27/44) in the dexamethasone group died, compared to 68.5% (37/54) in the placebo group
      (hazard ratio of time to death 0.86; 95% CI 0.52-1.41; P=0.55).

      There are limited data from HIV-infected patients with TBM treated with dexamethasone, but
      findings from studies using corticosteroids in HIV-infected individuals with other forms of
      tuberculosis and other opportunistic infections suggest corticosteroids may cause harm in
      those with advanced HIV infection. There is evidence that corticosteroids may increase the
      risk of HIV-associated malignancies, especially Kaposi sarcoma. Furthermore, a recent trial
      of adjunctive dexamethasone for HIV-associated cryptococcal meningitis performed in Southeast
      Asia and Africa found dexamethasone was associated with worse outcomes, with increased risk
      of secondary infections, hyperglycaemia and electrolyte abnormalities, and disability.

      On the basis of these limited data most international guidelines cautiously recommend
      dexamethasone should be given for HIV-associated TBM, but all acknowledge the paucity of
      evidence and the need for additional controlled trial data. Our trial will meet the need for
      more data and aims to provide definitive evidence as to the risk/benefit of adjunctive
      dexamethasone in the treatment of this important and very severe disease.

      Our 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

Overall survival until 12 months after randomisation

Secondary Outcome

 Neurological disability at 12 months (modified Rankin score)

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

520

Start Date

May 25, 2017

Completion Date

May 1, 2022

Primary Completion Date

May 1, 2022

Eligibility 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)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Guy Thwaites, MD, , 

Location Countries

Indonesia

Location Countries

Indonesia

Administrative Informations


NCT ID

NCT03092817

Organization ID

26TB


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

May 2021