TIMPANI: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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:
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Standard TBM treatment as described above
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Adalimumab arm 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
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
|
| No Intervention: Control arm - Standard TBM |
Outcome Measures
Primary Outcome Measures
- 3-month all-cause mortality [3 months]
Secondary Outcome Measures
- 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) [9 months]
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
- 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 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
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥18 years
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HIV-1 infection
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ART-naïve or ART discontinued for at least 6 months
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Definite or probable tuberculosis meningitis
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Standard tuberculosis meningitis treatment ≤3 days: anti TB drugs at standard doses and high-dose dexamethasone as per WHO guidelines
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Signed informed consent form by patient or relative.
Exclusion Criteria:
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Other concomitant neurological infection, i.e. toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, bacterial meningitis, neuro-syphilis
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Asymptomatic positive cryptococcal antigen in serum
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HIV-2 infection (single or dual)
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HBsAg positive or anti hepatitis C virus antibodies positive
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Alanine transaminase (ALT)>5 ULN
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Rifampicin-resistant TB detected by GeneXpert MTB/RIF Ultra
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History of previous TB treatment in patients with GeneXpert MTB/RIF Ultra negative or unavailable
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Current use of drugs contraindicated with study drugs and that cannot be safely stopped
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Allergy to study drugs or any of their components
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Uncontrolled opportunistic infection
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Moderate to severe cardiac insufficiency (NYHA classes III / IV)
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Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to study procedures
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For women of childbearing age: 1) Pregnancy or breastfeeding; 2) Refusal to use effective contraception to be discussed with the investigator
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Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
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Person under guardianship, or deprived of freedom by a judicial or administrative decision
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Positive SARS COV-2 test (according to hospital procedures at the time of inclusion)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ | Rio De Janeiro | Brazil | 21040-900 | |
| 2 | Instituto Nacional de Saude | Maputo | Mozambique | ||
| 3 | Adult Infectious Diseases Centre, University Teaching Hospital | Lusaka | Zambia |
Sponsors and Collaborators
- ANRS, Emerging Infectious Diseases
Investigators
- Principal Investigator: Nathalie DE CASTRO, MD, AP-HP Hôpital Saint-Louis
- Principal Investigator: Celso KHOSA, MD, Instituto Nacional de Saúde
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ANRS 12404 TIMPANI