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

Tuberculous Meningitis Clinical Trial

— INTENSE-TBM  

Official title:

Intensified Tuberculosis Treatment to Reduce the Mortality of HIV-infected and Uninfected Patients With Tuberculosis Meningitis: a Phase III Randomized Controlled Trial (Acronym: INTENSE-TBM)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04145258
• Other study ID #: ANRS 12398 INTENSE-TBM
• Secondary ID: EDCTP RIA2017T-2
• Status: Recruiting
• Phase: Phase 3
• Start date: February 7, 2021
• Est. completion date: April 2026

Study information

• Verified date: January 2024
• Source: ANRS, Emerging Infectious Diseases
• Contact: Fabrice Bonnet, M.D., Ph.D.
• Phone: +33 (0)5 56 79 58 26
• Email: fabrice.bonnet[@]chu-bordeaux.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 768
• Est. completion date: April 2026
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Meningitis
• Tuberculosis
• Tuberculosis, Meningeal
• Tuberculous Meningitis

Intervention

Drug:
• Aspirin
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
• Placebo of aspirin
Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
• WHO TBM treatment
2 months of (R-H-Z-E) + 7 months of (R-H)
• Intensified TBM treatment
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid

Locations

Country	Name	City	State
Côte D'Ivoire	Cocody University Hospital	Abidjan
Côte D'Ivoire	Treichville University Hospital	Abidjan
Côte D'Ivoire	Yopougon University Hospital	Abidjan
Madagascar	University Hospital Joseph Raseta Befelatanana	Antananarivo
Madagascar	University Hospital Tambohobe	Fianarantsoa
Madagascar	Morafeno University Hospital	Toamasina
South Africa	Kayelitsha District Hospital	Cape Town
South Africa	Mitchells Plain Hospital	Cape Town
South Africa	New Somerset Hospital	Cape Town
South Africa	Dora Nginza Hospital	Port Elizabeth
South Africa	Livingstone and PE Central Hospitals	Port Elizabeth
Uganda	Mbarara Regional Reference Hospital	Mbarara
Uganda	Regional Reference Hospital of Kabale	Mbarara

Sponsors (3)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases	European and Developing Countries Clinical Trials Partnership (EDCTP), European Union

Countries where clinical trial is conducted

Côte D'Ivoire,  Madagascar,  South Africa,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of all-cause death		Up to 40 weeks
Secondary	Rate of all-cause death		Up to 8 weeks
Secondary	Rate of all-cause death or loss to follow-up		Up to 40 weeks
Secondary	Rate of new central neurological event or aggravation of a central neurological event existing at baseline		Up to 40 weeks
Secondary	Rate of grade 3-4 adverse events (DAIDS adverse events grading table)		Up to 40 weeks
Secondary	Rate of serious adverse events		Up to 40 weeks
Secondary	Rate of solicited treatment related adverse events		Up to 40 weeks
Secondary	Percentage of patients with disability		40 weeks
Secondary	M. tuberculosis culture conversion rate		1 week and 4 weeks
Secondary	Time to culture positivity		Up to 40 weeks
Secondary	Time to first hospital discharge		Up to 40 weeks
Secondary	Cost-effectiveness incremental ratio of trial interventions		Up to 40 weeks
Secondary	Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion		Up to 40 weeks
Secondary	Subset of patients: In vitro bactericidal activity of anti-TBM treatment		1 week and 4 weeks
Secondary	Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	1 week and 4 weeks
Secondary	Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid	Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio	1 week and 4 weeks
Secondary	Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid	Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma/CSF AUC ratio	1 week and 4 weeks
Secondary	Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio	1 week and 4 weeks
Secondary	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	1 week and 4 weeks
Secondary	HIV-infected participants: Rate of new AIDS-defining illnesses		Up to 40 weeks
Secondary	HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml)		28 weeks and 40 weeks
Secondary	HIV-infected participants: CD4 count change from baseline		28 weeks and 40 weeks
Secondary	HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	1 week and 4 weeks
Secondary	HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir	Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio	1 week and 4 weeks
Secondary	HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir	Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma /CSF AUC ratio	1 week and 4 weeks
Secondary	HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma /CSF Tmax ratio	1 week and 4 weeks
Secondary	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	1 week and 4 weeks

External Links

•   INTENSE-TBM project website