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Cycle 1

High-­dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-­‐Finding Study (ReDEFINe: Rifampicin DosE FINding Study)
Principal Investigator: Rovina Ruslami, Universitas Padjadjaran
NIH-Supported Collaborator: H. Clifford Lane, NIH intramural researcher 
Title of NIH Award: INA-RESPOND (Indonesian Research Partnership in Infectious Disease)

Project Overview

TB meningitis (TBM) is the most severe manifestation of TB, leaving up to 50% of patients dead or neurologically disabled. Current treatment is similar to treatment of lung TB, although penetration of some antibiotics into the brain is poor and the immune-pathology of TB meningitis is very different from pulmonary TB. 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 III trial can be performed. The overall aim is to establish the optimal dose of rifampicin for TBM, which can be evaluated in a follow-­‐up multicenter phase III RCT. The primary objective is to generate pharmacokinetic (PK) data for higher doses of rifampcin patients with TBM. This will be a double-blinded, 1:1:1 randomized, placebo controlled, phase IIb trial. Roughly 60 adult TBM patients will be randomized to one of three arms consisting of varying doses of rifampicin administered orally, as part of a standard 4 drug regimen for TBM. Pharmacokinetics data, safety/tolerability and efficacy data will be collected. Subjects will be followed for 180 days. Finding the right dose of rifampcin could alter the standard of care and reduce mortality and morbidity of this important, and difficult to treat, disease.

PH 1-158 Indonesia photo 1PH 1-158 Indonesia photo 2

Summary of Recent Activities:

In general, year-3 PEER project had 3 main activities:
1. Screening of patients for TBM and evaluation for TBM diagnostic (n=100)
2. Strengthening of TBM diagnosis by adding in-house IS6110 TB PCR (n=200)
3. Pharmacogenetics(n=308) and pharmacokinetic study (n=30) of INH
During the reporting period (April - June 2017), the team completed all the activities. For activity #1 we recruited the last patient on May 30. While for activities #2 and #3, the field works have been completed, genetic analysis is ongoing, meanwhile pharmacokinetic analysis was completed. The research team is at the data cleaning stage and finalizing data analysis, and will soon draft a manuscript. On May 22-24, an international TB meningitis meeting (Tuberculosis Meningitis: Advancing Immunopathogenesis, Diagnosis, and Treatment workshop organized by NIH/NAIAD) was held in Rockville, Maryland. The project PI chaired a session in the workshop while the project co-PI attended as an invited participant. The visit was combined together with meeting the PEER project manager as well as the NIH partners.


Health Cycle 1 Recipients