High Dose Oral Rifampicin to Improve Survival from Adult TB Meningitis - (HARVEST) Trial
Medical Research Council
Infectious Diseases Institute (IDI)
Tuberculous meningitis, the most severe form of TB, results in death or neurological disability in >50% of those affected, and mortality is 2-3 fold greater in HIV-infected patients. Rifampicin, a primary TB medication, only achieves in cerebrospinal fluid (CSF) 10-20% of the levels observed in blood. We propose a phase III randomized, double-blind placebo-controlled clinical trial evaluating whether ~3.5x higher oral dose rifampicin has a 6-month survival benefit as the primary endpoint, additionally pharmacokinetic measurements and safety are included as important secondary endpoints. This trial builds up a series of phase II trials conducted in Indonesia by our team members which demonstrated that higher rifampicin IV doses were associated with lower mortality. In follow up oral rifampicin phase II trials, based on pharmacokinetic analyses, the optimal oral dose is estimated to be approximately 35 mg/kg/day. In the prior phase II trials as well as in pulmonary TB trials, there were not excess adverse events observed with higher dose rifampicin therapy at doses of 35 mg/kg/day. To simplify future implementation, we will use a single (flat) increase in rifampicin for all participants of 900mg in Indonesia and 1200mg in Uganda/South Africa, corresponding a total rifampicin dose of approx. 35mg/kg, during the first 8 weeks of treatment. This can easily be added to fixed dose combination therapy provided by most national TB programs.
6.1 Pharmaceuticals / Research Grant