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Trial record 1 of 1 for:    NCT04145258
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Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis (INTENSE-TBM)

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ClinicalTrials.gov Identifier: NCT04145258
Recruitment Status : Not yet recruiting
First Posted : October 30, 2019
Last Update Posted : October 30, 2019
Sponsor:
Collaborators:
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
Information provided by (Responsible Party):
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Estimated Study Start Date : April 1, 2020
Estimated Primary Completion Date : July 30, 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
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 Name: Standard WHO treatment for TB meningitis

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 Name: Standard WHO treatment for TB meningitis

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

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




Primary Outcome Measures :
  1. Rate of all-cause death [ Time Frame: Up to 40 weeks ]

Secondary Outcome Measures :
  1. Rate of all-cause death [ Time Frame: Up to 8 weeks ]
  2. Rate of all-cause death or loss to follow-up [ Time Frame: Up to 40 weeks ]
  3. Rate of new central neurological event or aggravation of a central neurological event existing at baseline [ Time Frame: Up to 40 weeks ]
  4. Rate of grade 3-4 adverse events (DAIDS adverse events grading table) [ Time Frame: Up to 40 weeks ]
  5. Rate of serious adverse events [ Time Frame: Up to 40 weeks ]
  6. Rate of solicited treatment related adverse events [ Time Frame: Up to 40 weeks ]
  7. Percentage of patients with disability [ Time Frame: 40 weeks ]
  8. M. tuberculosis culture conversion rate [ Time Frame: 1 week and 4 weeks ]
  9. Time to culture positivity [ Time Frame: Up to 40 weeks ]
  10. Time to first hospital discharge [ Time Frame: Up to 40 weeks ]
  11. Cost-effectiveness incremental ratio of trial interventions [ Time Frame: Up to 40 weeks ]
  12. Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion [ Time Frame: Up to 40 weeks ]
  13. Subset of patients: In vitro bactericidal activity of anti-TBM treatment [ Time Frame: 1 week and 4 weeks ]
  14. Subset of patients: Maximum Plasma Concentration [Cmax] of rifampicin and linezolid [ Time Frame: 1 week and 4 weeks ]
    Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio

  15. Subset of patients: Minimum Plasma Concentration [Cmin] of rifampicin and linezolid [ Time Frame: 1 week and 4 weeks ]
    Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio

  16. Subset of patients: Area Under the Curve [AUC] of rifampicin and linezolid [ Time Frame: 1 week and 4 weeks ]
    Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma/CSF AUC ratio

  17. Subset of patients: Time for maximal concentration [Tmax] of rifampicin and linezolid [ Time Frame: 1 week and 4 weeks ]
    Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio

  18. Subset of patients: Half-life (t1/2) of rifampicin and linezolid [ Time Frame: 1 week and 4 weeks ]
    Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio

  19. HIV-infected participants: Rate of new AIDS-defining illnesses [ Time Frame: Up to 40 weeks ]
  20. HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml) [ Time Frame: 28 weeks and 40 weeks ]
  21. HIV-infected participants: CD4 count change from baseline [ Time Frame: 28 weeks and 40 weeks ]
  22. HIV-infected participants, subset of patients: Maximum Plasma Concentration [Cmax] of of dolutegravir [ Time Frame: 1 week and 4 weeks ]
    Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio

  23. HIV-infected participants, subset of patients: Minimum Plasma Concentration [Cmin] of dolutegravir [ Time Frame: 1 week and 4 weeks ]
    Plasma Cmin, cerebrospinal fluid [CSF] Cmin, and plasma/CSF Cmin ratio

  24. HIV-infected participants, subset of patients: Area Under the Curve [AUC] of dolutegravir [ Time Frame: 1 week and 4 weeks ]
    Plasma AUC, cerebrospinal fluid [CSF] AUC, and plasma /CSF AUC ratio

  25. HIV-infected participants, subset of patients: Time for maximal concentration [Tmax] of dolutegravir [ Time Frame: 1 week and 4 weeks ]
    Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma /CSF Tmax ratio

  26. HIV-infected participants, subset of patients: Half-life (t1/2) of dolutegravir [ Time Frame: 1 week and 4 weeks ]
    Plasma t1/2, cerebrospinal fluid [CSF] t1/2, and plasma/CSF t1/2 ratio



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • Platelet count < 50 x 109/L.
  • Total bilirubin > 2.6 times the Upper Limit of Normal.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04145258


Contacts
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Contact: Fabrice Bonnet, M.D., Ph.D. +33 (0)5 56 79 58 26 fabrice.bonnet@chu-bordeaux.fr
Contact: Xavier Anglaret, M.D., Ph.D. +33 (0)5 57 57 12 58 xavier.anglaret@u-bordeaux.fr

Locations
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Côte D'Ivoire
Cocody University Hospital
Abidjan, Côte D'Ivoire
Contact: Horo Kigninlman, Prof.         
Treichville University Hospital
Abidjan, Côte D'Ivoire
Contact: Gisèle Kouakou, Prof.         
Yopougon University Hospital
Abidjan, Côte D'Ivoire
Contact: Thierry Odehoury-Koudou, Dr.         
Madagascar
University Hospital Joseph Raseta Befelatanana
Antananarivo, Madagascar
Contact: Mamy Jean de Dieu Randria, Prof.         
University Hospital Tambohobe
Fianarantsoa, Madagascar
Contact: Rivonirina Andry Rakotoarivelo, Prof.         
University Hospital Morafeno
Toamasina, Madagascar
South Africa
Groote Schuur Hospital
Cape Town, South Africa
Contact: Robert J Wilkinson, Prof.         
Mitchells Plain Hospital
Cape Town, South Africa
Contact: Graeme Meintjes, Prof.         
New Somerset Hospital
Cape Town, South Africa
Contact: Sean Wassermann, Dr         
Dora Nginza Hospital
Port Elizabeth, South Africa
Livingstone and PE Central Hospitals
Port Elizabeth, South Africa
Contact: John Black, Dr.         
Uganda
Mbarara Regional Reference Hospital
Mbarara, Uganda
Regional Reference Hospital of Kabale
Mbarara, Uganda
Contact: Marion Namutebi, Dr.         
Sponsors and Collaborators
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators
Layout table for investigator information
Principal Investigator: Fabrice Bonnet, M.D., Ph.D. University Hospital, Bordeaux

Additional Information:
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Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier: NCT04145258    
Other Study ID Numbers: ANRS 12398
EDCTP RIA2017T-2019 ( Other Grant/Funding Number: EDCTP )
First Posted: October 30, 2019    Key Record Dates
Last Update Posted: October 30, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Tuberculous Meningitis
Intensified treatment
High dose Rifampicin
Linezolid
Aspirin
Subsaharan Africa
Additional relevant MeSH terms:
Layout table for MeSH terms
Tuberculosis
Tuberculosis, Meningeal
Meningitis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Aspirin
Rifampin
Linezolid
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors