Tuberculous MeningitisPhase 3INTENSE-TBMNCT04145258
Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis
A Phase 3 study testing Aspirin, WHO TBM treatment and Intensified TBM treatment in people with Tuberculous Meningitis, run by ANRS, Emerging Infectious Diseases at 13 sites in 4 countries.
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… Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Tuberculous Meningitis
- What is being tested?
- Aspirin, WHO TBM treatment and Intensified TBM treatment
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 768 participants
- Where
- 13 sitesin 4 countries
- Study dates
- 7 Feb 2021to 26 Sep 2026
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- > 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.
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- 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.
Trial locations and contacts
13 sites in 4 countries. Contact the study team or a site near you to ask about taking part.
13 sites in 4 countries
South Africa5 sites, 5 recruiting
- Recruiting
Kayelitsha District Hospital
Cape Town
Graeme Meintjes, Prof.
- Recruiting
Mitchells Plain Hospital
Cape Town
Graeme Meintjes, Prof.
- Recruiting
New Somerset Hospital
Cape Town
Sean Wassermann, Dr
- Recruiting
Dora Nginza Hospital
Port Elizabeth
Nowshad Alam, Dr
- Recruiting
Livingstone and PE Central Hospitals
Port Elizabeth
John Black, Dr.
Côte d’Ivoire3 sites, 3 recruiting
- Not yet recruiting
Cocody University Hospital
Abidjan
Horo Kigninlman, Prof
- Recruiting
Treichville University Hospital
Abidjan
Gisèle Kouakou, Prof.
- Not yet recruiting
Yopougon University Hospital
Abidjan
Thierry Odehoury-Koudou, Prof
Madagascar3 sites, 3 recruiting
- Recruiting
University Hospital Joseph Raseta Befelatanana
Antananarivo
Mamy Jean de Dieu Randria, Prof.
- Recruiting
University Hospital Tambohobe
Fianarantsoa
Rivonirina Andry Rakotoarivelo, Prof.
- Not yet recruiting
Morafeno University Hospital
Toamasina
Stéphane Dimby Ralandison, Prof
Uganda2 sites, 2 recruiting
- Recruiting
Mbarara Regional Reference Hospital
Mbarara
Conrad Muzoora, Dr.
- Recruiting
Regional Reference Hospital of Kabale
Mbarara
Marion Namutebi, Dr.
About this study
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)
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.
Read the 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.
- Conditions
- Tuberculous Meningitis
- Being tested
- Aspirin, Placebo of aspirin, WHO TBM treatment, Intensified TBM treatment
- Keywords
- Tuberculous Meningitis, Intensified treatment, High dose Rifampicin, Linezolid, Aspirin, Subsaharan Africa
- Medical subject headings
- Tuberculosis, Meningeal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AspirinDrug
Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
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)
WHO TBM treatmentDrug
Also called Standard WHO treatment for TB meningitis
2 months of (R-H-Z-E) + 7 months of (R-H)
Intensified TBM treatmentDrug
2 months of (HDR-L-H-Z-E) + 7 months of (R-H), with HDR=high-dose rifampicin and L=linezolid
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Placebo of aspirin; Drug: 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. Receives: Drug: Aspirin; Drug: 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. Receives: Drug: Placebo of aspirin; Drug: 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. Receives: Drug: Aspirin; Drug: Intensified TBM treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of all-cause death
Measured: Up to 40 weeks
Secondary outcomes (26)
Rate of all-cause death
Measured: Up to 8 weeks
Rate of all-cause death or loss to follow-up
Measured: Up to 40 weeks
Rate of new central neurological event or aggravation of a central neurological event existing at baseline
Measured: Up to 40 weeks
Rate of grade 3-4 adverse events (DAIDS adverse events grading table)
Measured: Up to 40 weeks
Rate of serious adverse events
Measured: Up to 40 weeks
Rate of solicited treatment related adverse events
Measured: Up to 40 weeks
Percentage of patients with disability
Measured: 40 weeks
M. tuberculosis culture conversion rate
Measured: 1 week and 4 weeks
Time to culture positivity
Measured: Up to 40 weeks
Time to first hospital discharge
Measured: Up to 40 weeks
Cost-effectiveness incremental ratio of trial interventions
Measured: Up to 40 weeks
Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion
Measured: Up to 40 weeks
Subset of patients: In vitro bactericidal activity of anti-TBM treatment
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 1 week and 4 weeks
HIV-infected participants: Rate of new AIDS-defining illnesses
Measured: Up to 40 weeks
HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml)
Measured: 28 weeks and 40 weeks
HIV-infected participants: CD4 count change from baseline
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 1 week and 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2019
- Study start7 Feb 2021
- Primary completion23 Sep 2026 (estimated)
- Study completion26 Sep 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Tuberculous MeningitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 768 participants (estimated)
Sponsor and investigators
- Lead sponsor
- ANRS, Emerging Infectious Diseases
- Sponsor type
- Other government
- Collaborators
- European Union, European and Developing Countries Clinical Trials Partnership (EDCTP)
- Responsible party
- Sponsor
- Investigators
- Fabrice Bonnet, M.D., Ph.D., Principal investigator, University Hospital, Bordeaux
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04145258
- Sponsor's protocol ID
- ANRS 12398 INTENSE-TBM
- Other IDs
- EDCTP RIA2017T-2019
- Acronym
- INTENSE-TBM
- Status last verified
- Jun 2026
- First submitted
- 22 Oct 2019
- Last updated
- 24 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
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.
PubMed 36348453Ariza-Vioque E, Ello F, Andriamamonjisoa H, Machault V, Gonzalez-Martin J, Calvo-Cortes MC, Eholie S, Tchabert GA, Ouassa T, Raberahona M, Rakotoarivelo R, Razafindrakoto H, Rahajamanana L, Wilkinson RJ, Davis A, Maxebengula M, Abrahams F, Muzoora C, Nakigozi N, Nyehangane D, Nanjebe D, Mbega H, Kaitano R, Bonnet M, Debeaudrap P, Miro JM, Anglaret X, Rakotosamimanana N, Calmy A, Bonnet F, Ambrosioni J; INTENSE-TBM Group. Capacity Building in Sub-Saharan Africa as Part of the INTENSE-TBM Project During the COVID-19 Pandemic. Infect Dis Ther. 2022 Aug;11(4):1327-1341. doi: 10.1007/s40121-022-00667-z. Epub 2022 Jun 29.
PubMed 35767219