Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NCT04145258
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04145258
Recruitment Status : Recruiting
First Posted : October 30, 2019
Last Update Posted : February 15, 2021
Sponsor:
Collaborators:
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
Information provided by (Responsible Party):
ANRS, Emerging Infectious Diseases

Tracking Information
First Submitted Date  ICMJE October 22, 2019
First Posted Date  ICMJE October 30, 2019
Last Update Posted Date February 15, 2021
Actual Study Start Date  ICMJE February 9, 2020
Estimated Primary Completion Date March 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2019)
Rate of all-cause death [ Time Frame: Up to 40 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2019)
  • Rate of all-cause death [ Time Frame: Up to 8 weeks ]
  • Rate of all-cause death or loss to follow-up [ Time Frame: Up to 40 weeks ]
  • Rate of new central neurological event or aggravation of a central neurological event existing at baseline [ Time Frame: Up to 40 weeks ]
  • Rate of grade 3-4 adverse events (DAIDS adverse events grading table) [ Time Frame: Up to 40 weeks ]
  • Rate of serious adverse events [ Time Frame: Up to 40 weeks ]
  • Rate of solicited treatment related adverse events [ Time Frame: Up to 40 weeks ]
  • Percentage of patients with disability [ Time Frame: 40 weeks ]
  • M. tuberculosis culture conversion rate [ Time Frame: 1 week and 4 weeks ]
  • Time to culture positivity [ Time Frame: Up to 40 weeks ]
  • Time to first hospital discharge [ Time Frame: Up to 40 weeks ]
  • Cost-effectiveness incremental ratio of trial interventions [ Time Frame: Up to 40 weeks ]
  • Prevalence of resistance to anti-TB drugs among patients with positive culture at inclusion [ Time Frame: Up to 40 weeks ]
  • Subset of patients: In vitro bactericidal activity of anti-TBM treatment [ Time Frame: 1 week and 4 weeks ]
  • 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
  • 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
  • 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
  • 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
  • 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
  • HIV-infected participants: Rate of new AIDS-defining illnesses [ Time Frame: Up to 40 weeks ]
  • HIV-infected participants: Percentage of participants with virological success (plasma HIV-1 RNA <50 copies/ml) [ Time Frame: 28 weeks and 40 weeks ]
  • HIV-infected participants: CD4 count change from baseline [ Time Frame: 28 weeks and 40 weeks ]
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis
Official Title  ICMJE 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)
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Tuberculous Meningitis
Intervention  ICMJE
  • Drug: Aspirin
    Two tablets of aspirin 100 mg per day from inclusion (D-0) to end of Week-8 (W-8)
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Placebo of aspirin
    • Drug: WHO TBM treatment
  • 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.
    Interventions:
    • Drug: Aspirin
    • Drug: WHO TBM treatment
  • 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.
    Interventions:
    • Drug: Placebo of aspirin
    • Drug: Intensified TBM treatment
  • 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.
    Interventions:
    • Drug: Aspirin
    • Drug: Intensified TBM treatment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 28, 2019)
768
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date March 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Côte D'Ivoire,   Madagascar,   South Africa,   Uganda
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04145258
Other Study ID Numbers  ICMJE ANRS 12398 INTENSE-TBM
EDCTP RIA2017T-2019 ( Other Grant/Funding Number: EDCTP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ANRS, Emerging Infectious Diseases
Study Sponsor  ICMJE ANRS, Emerging Infectious Diseases
Collaborators  ICMJE
  • European Union
  • European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators  ICMJE
Principal Investigator: Fabrice Bonnet, M.D., Ph.D. University Hospital, Bordeaux
PRS Account ANRS, Emerging Infectious Diseases
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP