High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study

• Status: Completed
• Trial end date: 2017-05-05
• Target enrollment: 0
• Participant gender: All

Summary

Tuberculous meningitis (TBM) is the most severe form of tuberculosis infection with high mortality. Current treatment regimens are not based on clinical trials. Rifampicin is a key drug for TBM, but its penetration into the brain is limited, suggesting that a higher dose may be more effective.

There are several highly relevant, outstanding questions related to the appropriate dose of rifampicin for TBM, before a multicenter phase 3 trial can be performed. These are:

1. Previous phase 2a randomized clinical trial (done in the same setting as this proposed study) suggests that high doses of intravenous rifampicin (600mg, circa 13 mg/mg) for TBM is safe and associated with a survival benefit in adults. Given that i.v. rifampicin is not readily available, this needs to be confirmed using an equivalent higher oral dose of rifampicin.

2. Recent pharmacokinetic analysis of a continuation trial comparing 600 mg i.v. rifampicin with 750 mg and 900 mg oral rifampicin suggests that an even higher dose may be needed; but this has not been examined

3. Based on those previous data, there is a need to explore a longer duration of high-dose rifampicin for a subsequent phase 3 randomized clinical trial; treatment response in the investigators previous trial suggest that the optimal duration may be > 14 days.

4. There is a need to explore relevant treatment endpoints besides mortality including neurological, neuroradiological and inflammatory response.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Universitas Padjadjaran
• Collaborators: Radboud University; United States Agency for International Development (USAID)
• Treatments: BB 1101; Dexamethasone; Dexamethasone 21-phosphate; Dexamethasone acetate; Ethambutol; Pyrazinamide; Pyridoxine; Rifampin

Criteria

Inclusion Criteria:

1. Male or Female, aged 15 years or above.

2. Clinical suspicion of TBM and CSF/blood glucose ratio < 0.5.

3. None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection.

4. Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study.

5. Willingness to allow storage of specimens.

Exclusion Criteria:

Patients may not enter the study if any of the following apply:

1. Liver dysfunction (ALT > 5 times upper limit); kidney dysfunction (eGFR < 50 ml/min)

2. Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age).

3. Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy).

4. Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)