Clinical trial NCT05590455: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis
Official title: ANRS 12404 TIMPANI: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis: a Phase II, Multicenter, Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Tuberculous Meningitis
HIV I Infection
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
First posted: 2022-10-21
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 3-month all-cause mortality
timeFrame: 3 months
Secondary outcomes:
measure: 3-month incidence of severe/life threatening bacterial infections and opportunistic infections
timeFrame: 3 months
measure: 3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption
timeFrame: 3 months
measure: 3-month incidence of all grade 3 and 4 adverse events
timeFrame: 3 months
measure: 9-month all-cause mortality
timeFrame: 9 months
measure: 9-month disability free survival (using Rankin score)
timeFrame: 9 months
measure: 3-month and 9-month incidence of all grade infectious diseases and opportunistic infections
timeFrame: 3 months and 9 months
measure: 9-month neurological disability score (Rankin score)
timeFrame: 9 months
measure: Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months
timeFrame: up to 9 months
measure: Time to discharge
timeFrame: up to 9 months
measure: Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4
timeFrame: week 0, week1 and week4
measure: CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4,
timeFrame: week1 and week4
measure: Proportion of patients with HIV RNA<50 copies/mL at 9 months
timeFrame: 9 months
measure: CD4 counts at 9 months (and gain from baseline)
timeFrame: 9 months
measure: Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, W4
timeFrame: week 0, week1 and week4
measure: Inflammatory biomarkers in blood at W0, W4, W10, M6 and M9
timeFrame: week 0, week4, week10, 6 months and 9 months
measure: Cytokines profiles in blood at W0, W4, W10, M6 and M9
timeFrame: week 0, week4, week10, 6 months and 9 months
Other outcomes:
Locations:
city: Rio De Janeiro
country: Brazil
facility: Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saude
city: Lusaka
country: Zambia
facility: Adult Infectious Diseases Centre, University Teaching Hospital
Study officials:
affiliation: AP-HP, Hôpital Saint-Louis
name: Nathalie DE CASTRO, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Saúde, Mozambique
name: Celso KHOSA, MD
role: PRINCIPAL_INVESTIGATOR
References: