Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis

HIV I Infection Clinical Trial

— TIMPANI  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05590455
• Other study ID #: ANRS 12404 TIMPANI
• Status: Recruiting
• Phase: Phase 2
• Start date: April 11, 2023
• Est. completion date: December 2025

Study information

• Verified date: September 2023
• Source: ANRS, Emerging Infectious Diseases
• Contact: Vanessa MACHAULT, PhD
• Phone: +335 57 57 57 63
• Email: vanessa.machault[@]u-bordeaux.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: December 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• HIV I Infection
• Meningitis
• Tuberculosis
• Tuberculosis, Meningeal
• Tuberculous Meningitis

Intervention

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

Locations

Country	Name	City	State
Brazil	Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ	Rio De Janeiro
Mozambique	Instituto Nacional de Saude	Maputo
Zambia	Adult Infectious Diseases Centre, University Teaching Hospital	Lusaka

Sponsors (1)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases

Countries where clinical trial is conducted

Brazil,  Mozambique,  Zambia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	3-month all-cause mortality		3 months
Secondary	3-month incidence of severe/life threatening bacterial infections and opportunistic infections		3 months
Secondary	3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption		3 months
Secondary	3-month incidence of all grade 3 and 4 adverse events		3 months
Secondary	9-month all-cause mortality		9 months
Secondary	9-month disability free survival (using Rankin score)	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	9 months
Secondary	3-month and 9-month incidence of all grade infectious diseases and opportunistic infections		3 months and 9 months
Secondary	9-month neurological disability score (Rankin score)	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	9 months
Secondary	Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months		up to 9 months
Secondary	Time to discharge		up to 9 months
Secondary	Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4		week 0, week1 and week4
Secondary	CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4,		week1 and week4
Secondary	Proportion of patients with HIV RNA<50 copies/mL at 9 months		9 months
Secondary	CD4 counts at 9 months (and gain from baseline)		9 months
Secondary	Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, W4		week 0, week1 and week4
Secondary	Inflammatory biomarkers in blood at W0, W4, W10, M6 and M9		week 0, week4, week10, 6 months and 9 months
Secondary	Cytokines profiles in blood at W0, W4, W10, M6 and M9		week 0, week4, week10, 6 months and 9 months