PARTNERSHIPS FOR ENHANCED ENGAGEMENT IN RESEARCH (PEER) HEALTH
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 Dates: October 2013 - October 2017
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.
| || |Overall Project Outcomes and Activities:
Initially, this PEER project had aimed to do an explorative pharmacokinetic (PK) study, examining three different oral doses of rifampicin (450 mg, 900 mg, and 1350 mg) in TB meningitis patients. The result of this study was aimed to be a validation of an improved treatment regimen for TB meningitis to overcome bad outcomes of the disease. Along with that, the team aimed to strengthen microbiological diagnosis of TB meningitis cases by performing various confirmation techniques i.e. enhanced staining (cytospin), culture and PCR-based (GeneXpert and in-house PCR) techniques. There was a change in the project objectives in the second year of the project and the team dropped the PK study and focused on three objectives in the third year.
The summary of the project results are as follow:
- Tripling the dose of rifampicin increases exposure both in blood and CSF, increases PK target attainment, and does not increase grade 3 and 4 toxicity. There is a trend that Rifampicin 30 mg/kg dose improves survival.
- An important measure to achieve high confirmatory bacteriological result is to obtain large volume of CSF (more than 7 mL).
- PCR yields more positive confirmation than other modalities. The cytospin method does not significantly improve bacteriological confirmation in TB meningitis patients in Indonesia.
- PK of INH in plasma of TB meningitis equals to that in pulmonary TB, with good penetration of INH to CSF. With 50% of Indonesian population being fast acetylators, there might be association between acetylator status and mortality.
Overall impacts of the research:
Health Cycle 1 Recipients
- The result of bacteriological confirmation has led the team to promote the use of GeneXpert and/or in-house PCR. The benefit of using cytospin is analyzed using data from three different countries.
- The result of PK study of higher dose of Rifampicin has encouraged physicians to use a higher than recommended dose of Rifampicin to treat TB meningitis patients. The Indonesian health policy maker also has approved the administration of higher dose of Rifampicin for extrapulmonary TB, especially TB meningitis.
- A multicenter phase 3 trial for higher dose Rifampicin has been discussed and the plan has been initiated by submitting a proposal to the MRC, UK, and possibly will be funded by NIH/NIAID.
- Data on PK of INH in plasma and CSF is also being used to design clinical trial using higher dose of INH.