Trial record 1 of 1 for:
NCT04145258
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 : July 15, 2022
|
Sponsor:
ANRS, Emerging Infectious Diseases
Collaborators:
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
Information provided by (Responsible Party):
ANRS, Emerging Infectious Diseases
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
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 |
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 (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) |
| Actual Study Start Date : | February 7, 2021 |
| Estimated Primary Completion Date : | March 2024 |
| Estimated Study Completion Date : | December 2024 |
| Arm | Intervention/treatment |
|---|---|
WHO TBM treatment + placebo
|
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
|
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
|
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
|
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 :
- Rate of all-cause death [ Time Frame: Up to 40 weeks ]
Secondary Outcome Measures :
- 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
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.
| Ages Eligible for Study: | 15 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion criteria:
- 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.
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.
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
| 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
| Côte D'Ivoire | |
| Cocody University Hospital | Not yet recruiting |
| Abidjan, Côte D'Ivoire | |
| Contact: Horo Kigninlman, Prof | |
| Treichville University Hospital | Recruiting |
| Abidjan, Côte D'Ivoire | |
| Contact: Gisèle Kouakou, Prof. | |
| Yopougon University Hospital | Not yet recruiting |
| Abidjan, Côte D'Ivoire | |
| Contact: Thierry Odehoury-Koudou, Prof | |
| Madagascar | |
| University Hospital Joseph Raseta Befelatanana | Recruiting |
| Antananarivo, Madagascar | |
| Contact: Mamy Jean de Dieu Randria, Prof. | |
| University Hospital Tambohobe | Recruiting |
| Fianarantsoa, Madagascar | |
| Contact: Rivonirina Andry Rakotoarivelo, Prof. | |
| Morafeno University Hospital | Not yet recruiting |
| Toamasina, Madagascar | |
| Contact: Stéphane Dimby Ralandison, Prof | |
| South Africa | |
| Kayelitsha District Hospital | Recruiting |
| Cape Town, South Africa | |
| Contact: Graeme Meintjes, Prof. | |
| Mitchells Plain Hospital | Recruiting |
| Cape Town, South Africa | |
| Contact: Graeme Meintjes, Prof. | |
| New Somerset Hospital | Recruiting |
| Cape Town, South Africa | |
| Contact: Sean Wassermann, Dr | |
| Dora Nginza Hospital | Recruiting |
| Port Elizabeth, South Africa | |
| Contact: Nowshad Alam, Dr | |
| Livingstone and PE Central Hospitals | Recruiting |
| Port Elizabeth, South Africa | |
| Contact: John Black, Dr. | |
| Uganda | |
| Mbarara Regional Reference Hospital | Recruiting |
| Mbarara, Uganda | |
| Contact: Conrad Muzoora, Dr. | |
| Regional Reference Hospital of Kabale | Recruiting |
| Mbarara, Uganda | |
| Contact: Marion Namutebi, Dr. | |
Sponsors and Collaborators
ANRS, Emerging Infectious Diseases
European Union
European and Developing Countries Clinical Trials Partnership (EDCTP)
Investigators
| Principal Investigator: | Fabrice Bonnet, M.D., Ph.D. | University Hospital, Bordeaux |
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | ANRS, Emerging Infectious Diseases |
| ClinicalTrials.gov Identifier: | NCT04145258 |
| Other Study ID Numbers: |
ANRS 12398 INTENSE-TBM EDCTP RIA2017T-2019 ( Other Grant/Funding Number: EDCTP ) |
| First Posted: | October 30, 2019 Key Record Dates |
| Last Update Posted: | July 15, 2022 |
| Last Verified: | July 2022 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by ANRS, Emerging Infectious Diseases:
|
Tuberculous Meningitis Intensified treatment High dose Rifampicin |
Linezolid Aspirin Subsaharan Africa |
Additional relevant MeSH terms:
|
Tuberculosis Tuberculosis, Meningeal Meningitis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Neuroinflammatory Diseases Nervous System Diseases Meningitis, Bacterial Central Nervous System Bacterial Infections Tuberculosis, Central Nervous System Tuberculosis, Extrapulmonary |
Central Nervous System Infections Central Nervous System Diseases Aspirin 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 |