High Dose Oral Rifampicin to Improve Survival from Adult TB Meningitis - (HARVEST) Trial

Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB). TB meningitis results in death or neurological disability in >50%. The risk of death is more than 2-fold greater in HIV-infected persons. The currently recommended initial treatment regimens for TB meningitis and pulmonary TB are identical, despite that fact that rifampicin penetrates very poorly into cerebrospinal fluid (CSF). At the typical rifampicin dose (given at 10mg/kg/day) the concentrations of rifampicin in cerebrospinal fluid (CSF) seldom achieve the levels necessary for activity against TB.

In a small randomised clinical trial in Indonesia of 60 people, our team found that a higher intravenous dose of rifampicin (13mg/kg) led to a 58% reduction in the hazard of death. A follow-up detailed exposure-response analysis revealed that as the level of rifampicin increased, survival improved. In a second phase II trial of rifampicin given orally at a dose of 30mg/kg/day, the favourable blood and CSF drug exposure and survival benefit were confirmed. Based on the exposure-response analysis we believe a >3-fold increase in rifampicin dose is needed to achieve the CSF levels that correlate with better outcomes. This may explain why an oral rifampicin dose of 15 mg/kg evaluated in a large phase III trial in Vietnam did not show any survival benefit overall, although improved survival was seen in individuals with TB resistant to isoniazid.

Data from all these international studies have recently been combined and analysed in a detailed model by our team that has led to our conviction that a flat dose of 1500mg for Asian or 1800mg for Africans will produce rifampicin exposures that correlate with improved outcomes. A phase III study is the rational next step. Based on these studies and pharmacokinetic modelling, we propose to evaluate a 3.5-fold higher oral dose of rifampicin in a double-blinded randomised phase III clinical trial in 600 adult TB meningitis patients in Indonesia, Uganda, and South Africa. In order to simplify future implementation, we have chosen a single (flat) high rifampicin dose for all patients (1500mg in Indonesia and 1800mg in Uganda/South Africa, corresponding to ~35mg/kg), to be administered during the first 8 weeks of treatment. All patients will receive three other first-line TB drugs, standard adjuvant steroids, and anti-retroviral treatment as indicated. The primary outcome will be 6-month mortality. Additionally, we will also evaluate the diagnostic accuracy of the new Xpert MTB/Rif Ultra for diagnosis of TB meningitis while screening patients for this trial.

We expect that a high dose of rifampicin could be implemented broadly and quickly to the benefit of many TB meningitis patients, considering that the drug is widely available at low cost and its properties are known to clinicians all over the world. To confirm this we will carefully examine the cost-effectiveness of the intervention as well as factors relating to the optimal implementation of high dose rifampicin for TB meningitis patients. We expect this trial (if successful) to change the worldwide standard of care for the treatment of TB meningitis.

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.

This project seeks to improve the international standard of care for the treatment of meningitis due to tuberculosis (TB) by testing a higher dose of oral rifampicin (rifampin). This TB infection around the brain is often fatal. One major reason is that rifampicin, a key medicine for the treatment of TB, typically achieves levels in the cerebrospinal fluid (CSF) of only 10-20% of the levels in blood. Thus, the currently recommended rifampicin dosing does not achieve sufficiently high enough levels in the brain and spinal fluid to be active against the tuberculosis bacteria. Not surprisingly, outcomes after TB meningitis are poor with substantial mortality of up to 50% as well as residual neurological damage. This is the outcome with treatment. Without treatment, TB meningitis is universally fatal.

This trial will test a 3.5-times higher dose of rifampicin to determine whether survival and neurological outcomes are improved as well as whether the higher dose is safe.