Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation
Condition: Tuberculous Meningitis
MeSH terms: Tuberculosis; Tuberculosis, Meningeal; Meningitis
Study type: Interventional
Phase: Phase 2

Summary: 
      Tuberculous (TB) meningitis is the most severe manifestation of TB infection, 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. In a recent phase II
      clinical trial from the investigators group, the first of its kind globally, intensified
      antibiotic treatment, with moxifloxacin and high dose rifampicin, strongly reduced mortality
      of TB meningitis.

      The investigators aim to examine the effect of intensified antibiotic treatment on mortality
      and morbidity of TB meningitis in a phase 3 clinical trial, preceded with an explorative
      pharmacokinetic (PK) study to examine if higher oral doses rifampicin result in exposures
      similar to the i.v. dose used in our phase 2 trial, since oral rifampicin could be
      implemented much easier in low-resource settings.
    

Detailed description: 
      Introduction:

      In a recent clinical trial the investigators have shown that a higher dose of rifampicin
      administered intravenously (600 mg iv) during the first 2 weeks of treatment is safe and
      associated with a survival benefit in adults with TB meningitis. An oral (rather than iv)
      dose would help implementation of intensified treatment for TB meningitis. However, it is
      hard to predict what oral dose of rifampicin will result in rifampicin exposures similar to
      600 mg iv, due to differences in bio-availability (oral vs. iv) and the unpredictable
      dose-concentration relationship (nonlinear pharmacokinetics of rifampicin). Therefore the
      investigators aim to examine the pharmacokinetic of 2 higher doses of rifampicin (750 mg and
      900 mg) given orally, and compare the pharmacokinetic profiles with the result of our
      previous study using 600 mg rifampicin iv.

      General Objective:

      To help establish the optimized treatment regimen for TB meningitis

      Specific Objectives:

        1. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar
           to exposures after intravenous rifampicin 600 mg during the first two days of treatment

        2. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar
           to exposures after 14 days of treatment (stabilized rifampicin concentrations, i..e
           steady-state)

        3. To evaluate the safety and tolerability of high dose of oral rifampicin

        4. To evaluate neurological response and mortality after 2 weeks of treatment with high
           dose rifampicin

      Study Design:

      Explorative pharmacokinetic study; randomized, three-arm, two-period evaluation.

      Study procedure:

      After diagnosis of TB meningitis, eligible patients will be randomized to get either oral 750
      mg, oral 900 mg, or iv 600 mg rifampicin for 14 days in combination with standard oral TB
      drugs (isoniazid 300 mg/day, ethambutol 750 mg/day, and pyrazinamide 1500mg/day) and adjuvant
      dexamethasone i.v. and pyridoxine.

      Serial blood samples will be taken 6 times from 0, 1, 2, 4, 8, and 12 hour after drug
      administration at the first or second day of treatment and at day 14 (steady-state). Single
      cerebrospinal fluid (CSF) sample will be taken 3-6 hours after administration at the same day
      of blood sampling days.
    

Intervention name(s): Rifampicin intravenous; Oral rifampicin
Intervention type(s): Drug; Drug
Other intervention name(s): Rifadin; Rifampisin (Kimia Farma, Bandung, Indonesia)
Intervention MeSH terms: Rifampin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: tuberculous meningitis; rifampicin; bioequivalence; oral administration; intravenous administration