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

Universitas Padjadjaran

Status and phase: Completed; Phase 3; Phase 2

Conditions: Tuberculosis, Meningeal

Treatments: Drug: Adjuvant dexamethasone; Drug: Placebo; Drug: Rifampicin; Drug: Other TB drugs

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT02169882

PGA-2000003601 (Other Identifier)

TB-201406.01

Details and patient eligibility

About

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.

Enrollment: 60 patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 3 patient groups

Rifampicin 450 mg (standard dose)

Active Comparator group

Description:

Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT). After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Treatment:

Drug: Adjuvant dexamethasone

Drug: Other TB drugs

Drug: Placebo

Rifampicin 900 mg per oral

Experimental group

Description:

Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Treatment:

Drug: Adjuvant dexamethasone

Drug: Rifampicin

Drug: Other TB drugs

Drug: Placebo

Rifampicin 1350 mg per oral

Experimental group

Description:

Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Treatment:

Drug: Adjuvant dexamethasone

Drug: Rifampicin

Drug: Other TB drugs