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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Tuberculous Meningitis, HIV I Infection

Intervention / Treatment
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* Drug: Adalimumab Injection


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase II multicenter, open-label, randomized, proof of concept, comparative trial with a large alpha (type 1 error rate). 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adalimumab arm<br>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 | Drug: Adalimumab Injection<br>* 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<br>|
| No Intervention: Control arm<br>- Standard TBM | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month all-cause mortality |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month incidence of severe/life threatening bacterial infections and opportunistic infections |  | 3 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 | 
| 9-month all-cause mortality |  | 9 months | 
| 9-month disability free survival (using Rankin score) | MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all No significant disability despite symptoms; able to carry out all usual duties and activities Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Moderate disability; requiring some help, but able to walk without assistance Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability; bedridden, incontinent and requiring constant nursing care and attention Dead | 9 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) | MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all No significant disability despite symptoms; able to carry out all usual duties and activities Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Moderate disability; requiring some help, but able to walk without assistance Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability; bedridden, incontinent and requiring constant nursing care and attention Dead | 9 months | 
| Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months |  | up to 9 months | 
| Time to discharge |  | up to 9 months | 
| Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4 |  | week 0, week1 and week4 | 
| CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4, |  | week1 and week4 | 
| Proportion of patients with HIV RNA<50 copies/mL at 9 months |  | 9 months | 
| CD4 counts at 9 months (and gain from baseline) |  | 9 months | 
| Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, 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 |