Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients with Tuberculosis MeNIngitis
- Conditions
- HIV I InfectionTuberculous Meningitis
- Interventions
- Registration Number
- NCT05590455
- Lead Sponsor
- ANRS, Emerging Infectious Diseases
- Brief Summary
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).
- Detailed 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 130
- 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.
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Adalimumab arm Adalimumab Injection * Standard TBM treatment * 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
- Primary Outcome Measures
Name Time Method 3-month all-cause mortality 3 months
- Secondary Outcome Measures
Name Time Method 3-month incidence of severe/life threatening bacterial infections and opportunistic infections 3 months Time to discharge up to 9 months CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4, week1 and week4 Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, W4 week 0, week1 and week4 CD4 counts at 9 months (and gain from baseline) 9 months 9-month all-cause mortality 9 months 9-month disability free survival (using Rankin score) 9 months MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all
1. No significant disability despite symptoms; able to carry out all usual duties and activities
2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
3. Moderate disability; requiring some help, but able to walk without assistance
4. Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6. DeadProportion of patients with HIV RNA<50 copies/mL at 9 months 9 months 3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption 3 months 3-month incidence of all grade 3 and 4 adverse events 3 months 3-month and 9-month incidence of all grade infectious diseases and opportunistic infections 3 months and 9 months 9-month neurological disability score (Rankin score) 9 months MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all
1. No significant disability despite symptoms; able to carry out all usual duties and activities
2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
3. Moderate disability; requiring some help, but able to walk without assistance
4. Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6. DeadTime to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months up to 9 months Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4 week 0, week1 and week4 Inflammatory biomarkers in blood at W0, W4, W10, M6 and M9 week 0, week4, week10, 6 months and 9 months Cytokines profiles in blood at W0, W4, W10, M6 and M9 week 0, week4, week10, 6 months and 9 months
Trial Locations
- Locations (3)
Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
🇧🇷Rio De Janeiro, Brazil
Instituto Nacional de Saude
🇲🇿Maputo, Mozambique
Adult Infectious Diseases Centre, University Teaching Hospital
🇿🇲Lusaka, Zambia