Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation

Brief Title

Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation

Official Title

Explorative PK Study Comparing 600 mg Rifampicin i.v. With 750 mg and 900 mg Rifampicin Oral in Tuberculous Meningitis Patients

Brief 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.
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Pharmacokinetic profile of several rifampicin dose

Secondary Outcome

 mortality

Condition

Tuberculous Meningitis

Intervention

Rifampicin intravenous

Study Arms / Comparison Groups

 Rifampicin 600 mg

Description:  Subjects in this arm receive 600 mg rifampicin intravenously

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

30

Start Date

June 2013

Completion Date

April 2014

Primary Completion Date

October 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Age 18 years or older

          -  Probable/possible tuberculosis meningitis using uniform case definition

          -  Agree to participate in the study

        Exclusion Criteria:

          -  Patient with antituberculosis treatment within last 2 weeks.

          -  Increase liver function >5x upper limit of normal

          -  Pregnancy
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Rovina Ruslami, M.D., PhD, , 

Location Countries

Indonesia

Location Countries

Indonesia

NCT ID

NCT01802502

Organization ID

TB-201302.01

Responsible Party

Sponsor

Study Sponsor

Universitas Padjadjaran

Collaborators

 Radboud University

Study Sponsor

Rovina Ruslami, M.D., PhD, Principal Investigator, Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung

Verification Date

June 2014