NCT04145258

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.

Trial Health

60
Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
768

participants targeted

Target at P75+ for phase_3

Timeline
Completed

Started Feb 2021

Longer than P75 for phase_3

Geographic Reach
4 countries

13 active sites

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

October 22, 2019

Completed
8 days until next milestone

First Posted

Study publicly available on registry

October 30, 2019

Completed
1.3 years until next milestone

Study Start

First participant enrolled

February 7, 2021

Completed
4.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 1, 2025

Completed
7 months until next milestone

Study Completion

Last participant's last visit for all outcomes

April 1, 2026

Completed
Last Updated

January 22, 2024

Status Verified

January 1, 2024

Enrollment Period

4.6 years

First QC Date

October 22, 2019

Last Update Submit

January 19, 2024

Conditions

Tuberculous Meningitis

Keywords

Tuberculous MeningitisIntensified treatmentHigh dose RifampicinLinezolidAspirinSubsaharan Africa

Outcome Measures

Primary Outcomes (1)

  • Rate of all-cause death

    Up to 40 weeks

Secondary Outcomes (26)

  • 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

  • +21 more secondary outcomes

Study Arms (4)

WHO TBM treatment + placebo

OTHER

* 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 aspirinDrug: WHO TBM treatment

WHO TBM treatment + aspirin

OTHER

* 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: AspirinDrug: WHO TBM treatment

Intensified TBM treatment + placebo

OTHER

* 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 aspirinDrug: Intensified TBM treatment

Intensified TBM treatment + aspirin

OTHER

* 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: AspirinDrug: Intensified TBM treatment

Interventions

AspirinDRUG

Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)

Intensified TBM treatment + aspirinWHO TBM treatment + aspirin
Placebo of aspirinDRUG

Two placebo tablets with the same appearance of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)

Intensified TBM treatment + placeboWHO TBM treatment + placebo
WHO TBM treatmentDRUG

2 months of (R-H-Z-E) + 7 months of (R-H)

Also known as: Standard WHO treatment for TB meningitis
WHO TBM treatment + aspirinWHO TBM treatment + placebo
Intensified TBM treatmentDRUG

2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid

Intensified TBM treatment + aspirinIntensified TBM treatment + placebo

Eligibility Criteria

Age15 Years+
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • \> 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.
  • Ongoing chronic aspirin treatment (eg for cardiovascular risk).
  • +9 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (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

Livingstone and PE Central Hospitals

Port Elizabeth, South Africa

RECRUITING

Mbarara Regional Reference Hospital

Mbarara, Uganda

RECRUITING

Regional Reference Hospital of Kabale

Mbarara, Uganda

RECRUITING

Related Publications (1)

  • 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.

    PMID: 36348453DERIVED

Related Links

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Aspirin

Condition Hierarchy (Ancestors)

Meningitis, BacterialCentral Nervous System Bacterial InfectionsBacterial InfectionsBacterial Infections and MycosesInfectionsTuberculosis, Central Nervous SystemTuberculosis, ExtrapulmonaryTuberculosisMycobacterium InfectionsActinomycetales InfectionsGram-Positive Bacterial InfectionsCentral Nervous System InfectionsCentral Nervous System DiseasesNervous System DiseasesMeningitisNeuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

SalicylatesHydroxybenzoatesPhenolsBenzene DerivativesHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsOrganic Chemicals

Study Officials

  • Fabrice Bonnet, M.D., Ph.D.

    University Hospital, Bordeaux

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Fabrice Bonnet, M.D., Ph.D.

CONTACT

+33 (0)5 56 79 58 26fabrice.bonnet@chu-bordeaux.fr

Xavier Anglaret, M.D., Ph.D.

CONTACT

+33 (0)5 57 57 12 58xavier.anglaret@u-bordeaux.fr

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Masking Details
The trial will be open-label for anti-TB treatment and placebo-controlled for aspirin treatment
Purpose
TREATMENT
Intervention Model
FACTORIAL
Sponsor Type
OTHER GOV
Responsible Party
SPONSOR

Study Record Dates

First Submitted

October 22, 2019

First Posted

October 30, 2019

Study Start

February 7, 2021

Primary Completion

September 1, 2025

Study Completion

April 1, 2026

Last Updated

January 22, 2024

Record last verified: 2024-01

Locations

ZA(5)MA(3)UG(2)CÔ(3)