- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05590455
Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis (TIMPANI)
ANRS 12404 TIMPANI: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis: a Phase II, Multicenter, Randomized Clinical Trial
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Vanessa MACHAULT, PhD
- Phone Number: +335 57 57 57 63
- Email: vanessa.machault@u-bordeaux.fr
Study Contact Backup
- Name: Olivier MARCY, MD PhD
Study Locations
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Rio De Janeiro, Brazil, 21040-900
- Recruiting
- Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
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Contact:
- Sandra WAGNER
- Phone Number: + 55 21 38 65 96 23
- Email: dra.wagner@gmail.com
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Principal Investigator:
- Beatriz Grinsztejn
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Maputo, Mozambique
- Not yet recruiting
- Instituto Nacional de Saúde
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Principal Investigator:
- Celso KHOSA
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Contact:
- Marcia CHILUVANE
- Email: marcia.chiluvane@ins.gov.mz
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-
-
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Lusaka, Zambia
- Not yet recruiting
- Adult Infectious Diseases Centre, University Teaching Hospital
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Principal Investigator:
- Ducan CHANDA
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Contact:
- Christabel Phiri
- Email: chigweyassin@gmail.com
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Contact:
- Seke Muzazu
- Email: sekemuzazu@gmail.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Adalimumab arm
|
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
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No Intervention: Control arm
- Standard TBM
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
3-month all-cause mortality
Time Frame: 3 months
|
3 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
3-month incidence of severe/life threatening bacterial infections and opportunistic infections
Time Frame: 3 months
|
3 months
|
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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 months
|
|
3-month incidence of all grade 3 and 4 adverse events
Time Frame: 3 months
|
3 months
|
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9-month all-cause mortality
Time Frame: 9 months
|
9 months
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9-month disability free survival (using Rankin score)
Time Frame: 9 months
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MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all
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9 months
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3-month and 9-month incidence of all grade infectious diseases and opportunistic infections
Time Frame: 3 months and 9 months
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3 months and 9 months
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9-month neurological disability score (Rankin score)
Time Frame: 9 months
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MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all
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9 months
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Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months
Time Frame: up to 9 months
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up to 9 months
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Time to discharge
Time Frame: up to 9 months
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up to 9 months
|
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Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4
Time Frame: week 0, week1 and week4
|
week 0, week1 and week4
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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
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week1 and week4
|
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Proportion of patients with HIV RNA<50 copies/mL at 9 months
Time Frame: 9 months
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9 months
|
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CD4 counts at 9 months (and gain from baseline)
Time Frame: 9 months
|
9 months
|
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Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, W4
Time Frame: week 0, week1 and week4
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week 0, week1 and week4
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Inflammatory biomarkers in blood at W0, W4, W10, M6 and M9
Time Frame: week 0, week4, week10, 6 months and 9 months
|
week 0, week4, week10, 6 months and 9 months
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Cytokines profiles in blood at W0, W4, W10, M6 and M9
Time Frame: week 0, week4, week10, 6 months and 9 months
|
week 0, week4, week10, 6 months and 9 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Nathalie DE CASTRO, MD, AP-HP Hopital Saint-Louis
- Principal Investigator: Celso KHOSA, MD, Instituto Nacional de Saúde
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Central Nervous System Diseases
- Nervous System Diseases
- Infections
- Central Nervous System Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Meningitis, Bacterial
- Central Nervous System Bacterial Infections
- Tuberculosis, Central Nervous System
- Neuroinflammatory Diseases
- Tuberculosis, Extrapulmonary
- Tuberculosis
- Meningitis
- Tuberculosis, Meningeal
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Tumor Necrosis Factor Inhibitors
- Adalimumab
Other Study ID Numbers
- ANRS 12404 TIMPANI
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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