Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis

Phase 3RecruitingNCT04145258

ANRS, Emerging Infectious Diseases768 enrolled

Overview

INTENSE-TBM is randomized controlled, phase III, multicenter, 2 x 2 factorial plan superiority trial assessing the efficacity of two interventions to reduce mortality from tuberculous meningitis (TBM) in adolescents and adults with or without HIV-infection in sub-Saharan Africa: * Intensified TBM treatment with high-dose rifampicin and linezolid, compared to WHO standard TBM treatment. * Aspirin, compared to not receiving aspirin. The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment.

Settings: Côte d'Ivoire, Madagascar, Uganda, South Africa. Follow-up: Participants will be followed up for 40 weeks. Sample size: 768 patients (192 in each arm). Primary analysis: We will use a Cox proportional hazard ratio model to compare intensified TB treatment with WHO standard TB treatment, and aspirin with placebo, adjusting for the initial stratification variables (trial country, HIV status, British Medical Research Council \|BMRC\] severity grade). The primary analysis will be conducted in the intention to treat population. Sub-studies: * The PK-PD sub-study will take place in the 4 participating countries, and involve 40 participants in total. * The Multi-Omics sub-study will only take place in South-Africa. It will involve 160 participants in this country. Participants in each sub-study will sign a specific informed consent.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

768

Conditions

Tuberculous Meningitis

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Age ≥ 15 years 2. TBM defined as "definite", "probable" or "possible" 3. Signed Informed Consent * Definite TBM = at least one of the following criteria: acid-fast bacilli seen in CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial nucleic acid amplification test. * Probable TBM = total modified Marais score ≥12 when neuroimaging is available, or ≥10 when neuroimaging is not available (at least 2 points should come from CSF or cerebral imaging criteria). * Possible TBM = total modified Marais 6-11 when neuroimaging is available, or 6-9 when neuroimaging is not available. Exclusion criteria: * \> 5 days of TB treatment * Renal failure (eGFR\<30 ml/min, CKD-EPI formula). * Neutrophil count \< 0.6 x 109/L. * Hemoglobin concentration \< 8 g/dL. * Total bilirubin \> 2.6 times the Upper Limit of Normal * Platelet count \< 50 x 109/L. * ALT \> 5 times the Upper Limit of Normal. * Clinical evidence of liver failure or decompensated cirrhosis. * For women: more than 17 weeks pregnancy or breastfeeding. * For patients without decrease level of consciousness (Glasgow Coma Scale = 15): Peripheral neuropathy scoring Grade 3 or above on the Brief Peripheral Neuropathy Score (BPNS). * Documented M. tuberculosis resistance to rifampicin. * Positive gram-stain, bacterial culture or cryptococcal antigen in the Cerebral Spinal Fluid. * Evidence of active bleeding (hemoptysis, gastrointestinal bleeding, hematuria, intracranial bleeding). * Inability to collect Cerebral Spinal Fluid, except for patients with confirmed tuberculosis (by rapid molecular test or culture) from another biological sample and clinical and/or CT scan evidence of meningitis. * Major surgery within the last two weeks prior to inclusion. * Ongoing chronic aspirin treatment (eg for cardiovascular risk). * Current use of drugs contraindicated with study drugs and that cannot be safely stopped (see Appendix 1: Drugs contra-indicated with study drugs). * In available history from patients: * Evidence of past intracranial bleeding. * Evidence of past of peptic ulceration. * Evidence of recent (\< 3 month) gastrointestinal bleeding. * Known hypersensitivity contraindicating the use of study drugs . * Evidence of porphyria. * Evidence of hyperuricemia or gout. * Any reason which at the discretion of the investigator would compromise safety and cooperation in the trial.

Locations (13)

Cocody University Hospital

Abidjan, Côte d’Ivoire

NOT_YET_RECRUITING

Treichville University Hospital

Abidjan, Côte d’Ivoire

RECRUITING

Yopougon University Hospital

Abidjan, Côte d’Ivoire

NOT_YET_RECRUITING

University Hospital Joseph Raseta Befelatanana

Antananarivo, Madagascar

RECRUITING

University Hospital Tambohobe

Fianarantsoa, Madagascar

RECRUITING

Morafeno University Hospital

Toamasina, Madagascar

NOT_YET_RECRUITING

Kayelitsha District Hospital

Cape Town, South Africa

RECRUITING

Mitchells Plain Hospital

Cape Town, South Africa

RECRUITING

New Somerset Hospital

Cape Town, South Africa

RECRUITING

Dora Nginza Hospital

Port Elizabeth, South Africa

RECRUITING

...and 3 more locations

Outcomes

Primary Outcomes

Rate of all-cause death

Time frame: Up to 40 weeks

Secondary Outcomes

Rate of all-cause death

Time frame: Up to 8 weeks

Rate of all-cause death or loss to follow-up

Time frame: Up to 40 weeks

Rate of new central neurological event or aggravation of a central neurological event existing at baseline

Time frame: Up to 40 weeks

Rate of grade 3-4 adverse events (DAIDS adverse events grading table)

Time frame: Up to 40 weeks

Rate of serious adverse events

Time frame: Up to 40 weeks

Rate of solicited treatment related adverse events

Time frame: Up to 40 weeks

Percentage of patients with disability

Time frame: 40 weeks

M. tuberculosis culture conversion rate

Time frame: 1 week and 4 weeks

Time to culture positivity

Time frame: Up to 40 weeks

Time to first hospital discharge

Time frame: Up to 40 weeks

Cost-effectiveness incremental ratio of trial interventions

Time frame: Up to 40 weeks

Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion

Time frame: Up to 40 weeks

Subset of patients: In vitro bactericidal activity of anti-TBM treatment

Time frame: 1 week and 4 weeks

Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid

Plasma Cmax, cerebrospinal fluid \[CSF\] Cmax, and plasma/CSF Cmax ratio

Time frame: 1 week and 4 weeks

Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid

Plasma Cmin, cerebrospinal fluid \[CSF\] Cmin, and plasma/CSF Cmin ratio

Time frame: 1 week and 4 weeks

Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid

Plasma AUC, cerebrospinal fluid \[CSF\] AUC, and plasma/CSF AUC ratio

Time frame: 1 week and 4 weeks

Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid

Plasma Tmax, cerebrospinal fluid \[CSF\] Tmax, and plasma/CSF Tmax ratio

Time frame: 1 week and 4 weeks

Subset of patients: Half-life (t1/2) of rifampicin and linezolid

Plasma t1/2, cerebrospinal fluid \[CSF\] t1/2, and plasma/CSF t1/2 ratio

Time frame: 1 week and 4 weeks

HIV-infected participants: Rate of new AIDS-defining illnesses

Time frame: Up to 40 weeks

HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml)

Time frame: 28 weeks and 40 weeks

HIV-infected participants: CD4 count change from baseline

Time frame: 28 weeks and 40 weeks

HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir

Plasma Cmax, cerebrospinal fluid \[CSF\] Cmax, and plasma/CSF Cmax ratio

Time frame: 1 week and 4 weeks

HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir

Plasma Cmin, cerebrospinal fluid \[CSF\] Cmin, and plasma/CSF Cmin ratio

Time frame: 1 week and 4 weeks

HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir

Plasma AUC, cerebrospinal fluid \[CSF\] AUC, and plasma /CSF AUC ratio

Time frame: 1 week and 4 weeks

HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir

Plasma Tmax, cerebrospinal fluid \[CSF\] Tmax, and plasma /CSF Tmax ratio

Time frame: 1 week and 4 weeks

HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir

Plasma t1/2, cerebrospinal fluid \[CSF\] t1/2, and plasma/CSF t1/2 ratio

Time frame: 1 week and 4 weeks

Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis

Overview

Conditions

Interventions

Eligibility

Locations (13)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts