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

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.

Conditions

• Tuberculosis, Meningeal

Interventions

DRUG

Placebo

Patients receiving 450 mg rifampicin will receive additional 2 placebo tablets, while those who receive 900 mg rifampicin will receive 1 placebo tablet. Patients receiving 1350 mg rifampicin will not receive any placebo tablet. With this arrangement, every subject will receive 3 tablets of study drugs.

DRUG

Rifampicin

Patients in experimental arms will receive either 1 or 2 additional tablets of rifampicin. Placebo tablets will be added accordingly, so that every study subject will receive 3 tablets of rifampicin plus placebo as described in the Arms section.

DRUG

Other TB drugs

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. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

DRUG

Adjuvant dexamethasone

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Sponsors & Collaborators

• United States Agency for International Development (USAID)

  collaborator FED

• Radboud University Medical Center

  collaborator OTHER

• Universitas Padjadjaran

  lead OTHER

Principal Investigators

• Rovina Ruslami, M.D., PhD · Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

15 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-12-01

Primary Completion

2016-11-05

Completion

2017-05-05

Countries

• Indonesia

Study Locations