Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis

ANRS 12404 TIMPANI: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis: a Phase II, Multicenter, Randomized Clinical Trial

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).

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.

Inclusion Criteria:

• Age ≥18 years
• HIV-1 infection
• 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
• 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