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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: Placebo of aspirin; Drug: WHO TBM treatment; Drug: Aspirin; Drug: Intensified TBM treatment

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 Type: Interventional
• Enrollment (Estimated): 768
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fabrice Bonnet, M.D., Ph.D.; Phone Number: +33 (0)5 56 79 58 26; Email: fabrice.bonnet@chu-bordeaux.fr
• Study Contact Backup: Name: Xavier Anglaret, M.D., Ph.D.; Phone Number: +33 (0)5 57 57 12 58; Email: xavier.anglaret@u-bordeaux.fr

Study Locations

• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Not yet recruiting
    • Cocody University Hospital
    • Contact: Horo Kigninlman, Prof
  • Abidjan, Côte D'Ivoire
    • Recruiting
    • Treichville University Hospital
    • Contact: Gisèle Kouakou, Prof.
  • Abidjan, Côte D'Ivoire
    • Not yet recruiting
    • Yopougon University Hospital
    • Contact: Thierry Odehoury-Koudou, Prof
• Madagascar
  • Antananarivo, Madagascar
    • Recruiting
    • University Hospital Joseph Raseta Befelatanana
    • Contact: Mamy Jean de Dieu Randria, Prof.
  • Fianarantsoa, Madagascar
    • Recruiting
    • University Hospital Tambohobe
    • Contact: Rivonirina Andry Rakotoarivelo, Prof.
  • Toamasina, Madagascar
    • Not yet recruiting
    • Morafeno University Hospital
    • Contact: Stéphane Dimby Ralandison, Prof
• South Africa
  • Cape Town, South Africa
    • Recruiting
    • Kayelitsha District Hospital
    • Contact: Graeme Meintjes, Prof.
  • Cape Town, South Africa
    • Recruiting
    • Mitchells Plain Hospital
    • Contact: Graeme Meintjes, Prof.
  • Cape Town, South Africa
    • Recruiting
    • New Somerset Hospital
    • Contact: Sean Wassermann, Dr
  • Port Elizabeth, South Africa
    • Recruiting
    • Dora Nginza Hospital
    • Contact: Nowshad Alam, Dr
  • Port Elizabeth, South Africa
    • Recruiting
    • Livingstone and PE Central Hospitals
    • Contact: John Black, Dr.
• Uganda
  • Mbarara, Uganda
    • Recruiting
    • Mbarara Regional Reference Hospital
    • Contact: Conrad Muzoora, Dr.
  • Mbarara, Uganda
    • Recruiting
    • Regional Reference Hospital of Kabale
    • Contact: Marion Namutebi, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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: WHO TBM treatment; 2 months of (R-H-Z-E) + 7 months of (R-H); Other Names: Standard WHO treatment for TB meningitis; Drug: Aspirin; Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of all-cause death	Up to 40 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	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	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	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	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	1 week and 4 weeks
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	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	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	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	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	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	1 week and 4 weeks

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP); European Union
• Investigators: Principal Investigator: Fabrice Bonnet, M.D., Ph.D., University Hospital, Bordeaux

Publications and helpful links

General Publications

• Maitre T, Bonnet M, Calmy A, Raberahona M, Rakotoarivelo RA, Rakotosamimanana N, Ambrosioni J, Miro JM, Debeaudrap P, Muzoora C, Davis A, Meintjes G, Wasserman S, Wilkinson R, Eholie S, Nogbou FE, Calvo-Cortes MC, Chazallon C, Machault V, Anglaret X, Bonnet F. Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial. Trials. 2022 Nov 8;23(1):928. doi: 10.1186/s13063-022-06772-1.

Helpful Links

• INTENSE-TBM project website

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2021
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: October 22, 2019
• First Submitted That Met QC Criteria: October 28, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Actual): January 22, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Aspirin; Linezolid; Tuberculous Meningitis; Intensified treatment; High dose Rifampicin; Subsaharan Africa
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Neuroinflammatory Diseases; Tuberculosis, Extrapulmonary; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: ANRS 12398 INTENSE-TBM; EDCTP RIA2017T-2019 (Other Grant/Funding Number: EDCTP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No