INTENSE-TBM: Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis

Sponsor

ANRS, Emerging Infectious Diseases (Other)

Overall Status

Recruiting

CT.gov ID

NCT04145258

Collaborator

European Union (Other), European and Developing Countries Clinical Trials Partnership (EDCTP) (Other)

768

Enrollment

Locations

Arms

45.8

Anticipated Duration (Months)

59.1

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculous Meningitis	Drug: Aspirin Drug: Placebo of aspirin Drug: WHO TBM treatment Drug: Intensified TBM treatment	Phase 3

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

768 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Feb 7, 2021

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: WHO TBM treatment + placebo Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.	Drug: 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) Drug: WHO TBM treatment 2 months of (R-H-Z-E) + 7 months of (R-H) Other Names: Standard WHO treatment for TB meningitis
Other: WHO TBM treatment + aspirin Inclusion (D-0) to end of Week-8 (W-8): isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.	Drug: Aspirin Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8) Drug: WHO TBM treatment 2 months of (R-H-Z-E) + 7 months of (R-H) Other Names: Standard WHO treatment for TB meningitis
Other: Intensified TBM treatment + placebo Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + placebo of aspirin W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.	Drug: 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) Drug: Intensified TBM treatment 2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
Other: Intensified TBM treatment + aspirin Inclusion (D-0) to end of Week-8 (W-8): high dose rifampicin (35 mg/kg/d) + high dose linezolid (1200 mg/d from D-0 to end of W-4, then 600 mg/d from W-5 to W-8) + isoniazid 5 mg/kg/d + ethambutol 20 mg/kg/d + pyrazinamide 30 mg/kg/d + aspirin 200 mg/d W-9 to W-40: isoniazid 5 mg/kg/d + rifampicin 10 mg/kg/d.	Drug: Aspirin Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8) Drug: Intensified TBM treatment 2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid

Outcome Measures

Primary Outcome Measures

Rate of all-cause death [Up to 40 weeks]

Secondary Outcome Measures

Rate of all-cause death [Up to 8 weeks]
Rate of all-cause death or loss to follow-up [Up to 40 weeks]
Rate of new central neurological event or aggravation of a central neurological event existing at baseline [Up to 40 weeks]
Rate of grade 3-4 adverse events (DAIDS adverse events grading table) [Up to 40 weeks]
Rate of serious adverse events [Up to 40 weeks]
Rate of solicited treatment related adverse events [Up to 40 weeks]
Percentage of patients with disability [40 weeks]
M. tuberculosis culture conversion rate [1 week and 4 weeks]
Time to culture positivity [Up to 40 weeks]
Time to first hospital discharge [Up to 40 weeks]
Cost-effectiveness incremental ratio of trial interventions [Up to 40 weeks]
Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion [Up to 40 weeks]
Subset of patients: In vitro bactericidal activity of anti-TBM treatment [1 week and 4 weeks]
Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid [1 week and 4 weeks]
Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio
Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid [1 week and 4 weeks]
Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio
Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid [1 week and 4 weeks]
Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma/CSF AUC ratio
Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid [1 week and 4 weeks]
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio
Subset of patients: Half-life (t1/2) of rifampicin and linezolid [1 week and 4 weeks]
Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio
HIV-infected participants: Rate of new AIDS-defining illnesses [Up to 40 weeks]
HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml) [28 weeks and 40 weeks]
HIV-infected participants: CD4 count change from baseline [28 weeks and 40 weeks]
HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir [1 week and 4 weeks]
Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio
HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir [1 week and 4 weeks]
Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio
HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir [1 week and 4 weeks]
Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma /CSF AUC ratio
HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir [1 week and 4 weeks]
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma /CSF Tmax ratio
HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir [1 week and 4 weeks]
Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Age ≥ 15 years
TBM defined as "definite", "probable" or "possible"
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.

Contacts and Locations

Locations

	Site	City	Country
1	Cocody University Hospital	Abidjan	Côte D'Ivoire
2	Treichville University Hospital	Abidjan	Côte D'Ivoire
3	Yopougon University Hospital	Abidjan	Côte D'Ivoire
4	University Hospital Joseph Raseta Befelatanana	Antananarivo	Madagascar
5	University Hospital Tambohobe	Fianarantsoa	Madagascar
6	Morafeno University Hospital	Toamasina	Madagascar
7	Kayelitsha District Hospital	Cape Town	South Africa
8	Mitchells Plain Hospital	Cape Town	South Africa
9	New Somerset Hospital	Cape Town	South Africa
10	Dora Nginza Hospital	Port Elizabeth	South Africa
11	Livingstone and PE Central Hospitals	Port Elizabeth	South Africa
12	Mbarara Regional Reference Hospital	Mbarara	Uganda
13	Regional Reference Hospital of Kabale	Mbarara	Uganda