HIV I Infection, Tuberculous Meningitis
Conditions
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.
Interventions
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
Sponsors
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 3-month all-cause mortality | 3 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 and 12-month all-cause mortality | 9 months and 12 months | — |
| 9-month disability free survival (using Rankin score) | 9 months | MODIFIED RANKIN SCORE (MRS) 0: No symptoms at all 1. No significant disability despite symptoms; able to carry out all usual duties and activities 2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. Moderate disability; requiring some help, but able to walk without assistance 4. Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. 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 1. No significant disability despite symptoms; able to carry out all usual duties and activities 2. Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3. Moderate disability; requiring some help, but able to walk without assistance 4. Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5. Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6. 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 | — |
| 3-month incidence of severe/life threatening bacterial infections and opportunistic infections | 3 months | — |
| 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-1 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 | — |
| Proportion of participants with possible, probable or definite TBM diagnosis at pre-inclusion according to Marais score | Pre-inclusion | Evaluation of TBM diagnosis and differential diagnoses in all pre-included participants: Proportion of participants with possible, probable or definite TBM diagnosis at pre-inclusion according to Marais score |
| Proportion of participants with other CNS disease (opportunistic infections or other neurological conditions) | Pre-inclusion | Evaluation of TBM diagnosis and differential diagnoses in all pre-included participants: Proportion of participants with other CNS disease (opportunistic infections or other neurological conditions) |
| Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4 | week 0, week1 and week4 | — |
Countries
Brazil, Mozambique, Zambia
Contacts
Primary ContactVanessa MACHAULT, PhD
Backup ContactOlivier MARCY, MD PhD
Outcome results
None listed