PT - JOURNAL ARTICLE AU - S Dian AU - V Yunivita AU - AR Ganiem AU - T Pramaesya AU - L Chaidir AU - K Wahyudi AU - TH Achmad AU - A Colbers AU - L te Brake AU - R van Crevel AU - R Ruslami AU - R Aarnoutse TI - A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study AID - 10.1101/326587 DP - 2018 Jan 01 TA - bioRxiv PG - 326587 4099 - http://biorxiv.org/content/early/2018/05/21/326587.short 4100 - http://biorxiv.org/content/early/2018/05/21/326587.full AB - Background High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.Methods In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.Results A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).Conclusions Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.