Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Adalimumab Injection.
- Who it may be relevant to
- Registry conditions: Tuberculous Meningitis, HIV I Infection. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Brazil, Mozambique, Zambia
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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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
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).
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.
Interventions
- Drug Adalimumab Injection
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
- 3-month all-cause mortality [Time frame: 3 months]
Secondary outcome measures (12)
- 3-month incidence of severe/life threatening bacterial infections and opportunistic infections [Time frame: 3 months]
- 3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption [Time frame: 3 months]
- 3-month incidence of all grade 3 and 4 adverse events [Time frame: 3 months]
- 9-month and 12-month all-cause mortality [Time frame: 9 months and 12 months]
- 9-month disability free survival (using Rankin score) [Time frame: 9 months]
- 3-month and 9-month incidence of all grade infectious diseases and opportunistic infections [Time frame: 3 months and 9 months]
- 9-month neurological disability score (Rankin score) [Time frame: 9 months]
- Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months [Time frame: up to 9 months]
- Time to discharge [Time frame: up to 9 months]
- Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4 [Time frame: 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, [Time frame: week1 and week4]
- Proportion of patients with HIV-1 RNA<50 copies/mL at 9 months [Time frame: 9 months]
Eligibility criteria
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
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Open label
- Primary purpose
- Treatment
Study locations
Brazil · 1 center
- Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ — Rio de Janeiro
Mozambique · 1 center
- Instituto Nacional de Saude — Maputo
Zambia · 1 center
- Adult Infectious Diseases Centre, University Teaching Hospital — Lusaka
Identifiers
NCT: NCT05590455 · ANRS 12404 TIMPANI