Overview
Randomized phase II clinical trial which aims to assess the impact on 3-month mortality and safety of adding adalimumab to standard treatment (anti-tuberculosis drugs and corticosteroids) in HIV patients with tuberculosis meningitis in 3 countries (Brazil, Mozambique, and Zambia).
Description
Phase II multicenter, open-label, randomized, proof of concept, comparative trial with a large alpha (type 1 error rate) to evaluate the impact on 3-month mortality of adding the tumor necrosis factor inhibitor adalimumab to the standard treatment with antituberculosis drugs and high-dose steroids in HIV-infected adults diagnosed with tuberculosis meningitis (TBM) in 3 countries (Brazil, Mozambique, and Zambia).
All HIV1-infected patients diagnosed with TBM will be started on standard TB therapy for the duration recommended by national guidelines (2 months intensive phase and 7 months maintenance phase) and high-dose dexamethasone up to 4 weeks.
As soon as possible during the first 3 days of the standard TBM treatment that includes antituberculosis treatment and high-dose steroids, consenting patients will be randomized to standard treatment alone or standard treatment + adalimumab. Randomization will be stratified on country and initial severity using the British Medical Research Council (MRC) score.
Adalimumab arm:
- Standard TBM treatment as described above
- Adalimumab 40 mg: one sub-cutaneous injection, every 2 weeks for 10 weeks (total 6 injections), started as soon as possible during the first 3 days of antituberculosis treatment and high-dose steroids As World Health Organization and national guidelines for early antiretroviral therapy (ART) introduction in patients with TBM advise caution, ART will be started after 4 weeks of TB treatment in both arms if patients are clinically improved (but no later than 8 weeks of anti-TB treatment).
An interim analysis will be performed after 20 patients have been followed up for 3 months in adalimumab arm. This interim analysis will monitor the safety of adding TNF-inhibitor adalimumab.
Eligibility
Inclusion Criteria:
- Age ≥18 years
- HIV-1 infection
- ART-naïve or ART discontinued for at least 6 months
- Definite or probable tuberculosis meningitis
- Standard tuberculosis meningitis treatment ≤3 days: anti TB drugs at standard doses and high-dose dexamethasone as per WHO guidelines
- Signed informed consent form by patient or relative.
Exclusion Criteria:
- Other concomitant neurological infection, i.e. toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, bacterial meningitis, neuro-syphilis
- Asymptomatic positive cryptococcal antigen in serum
- HIV-2 infection (single or dual)
- HBsAg positive or anti hepatitis C virus antibodies positive
- Alanine transaminase (ALT)>5 ULN
- Rifampicin-resistant TB detected by GeneXpert MTB/RIF Ultra
- History of previous TB treatment in patients with GeneXpert MTB/RIF Ultra negative or unavailable
- Current use of drugs contraindicated with study drugs and that cannot be safely stopped
- Allergy to study drugs or any of their components
- Uncontrolled opportunistic infection
- Moderate to severe cardiac insufficiency (NYHA classes III / IV)
- Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to study procedures
- For women of childbearing age: 1) Pregnancy or breastfeeding; 2) Refusal to use effective contraception to be discussed with the investigator
- Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
- Person under guardianship, or deprived of freedom by a judicial or administrative decision
- Positive SARS COV-2 test (according to hospital procedures at the time of inclusion)