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

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: Rifampicin intravenous; Drug: Oral rifampicin

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • West Java
    • Bandung, West Java, Indonesia, 40122
      • Hasan Sadikin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rifampicin 600 mg; Subjects in this arm receive 600 mg rifampicin intravenously	Drug: Rifampicin intravenous; Other Names: Rifadin
Experimental: rifampicin 750 mg; Subjects in this arm receive 750 mg rifampicin orally	Drug: Oral rifampicin; Other Names: Rifampisin (Kimia Farma, Bandung, Indonesia)
Experimental: rifampicin 900 mg; Subjects in this arm receive rifampicin 900 mg orally	Drug: Oral rifampicin; Other Names: Rifampisin (Kimia Farma, Bandung, Indonesia)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic profile of several rifampicin dose	We will measure plasma drug concentration at hour 0, 1, 2, 4, 8, and 12, while CSF drug concentration will be measured at a single time point i.e. at hour 3-6 post dose. The sampling days will be (1) within the first three days, and (2) at day 14 of the intensified treatment.	Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality	We will measure early and late mortality	early (1 month) and late (6 months)

Collaborators and Investigators

• Sponsor: Universitas Padjadjaran
• Collaborators: Radboud University Medical Center
• Investigators: Principal Investigator: Rovina Ruslami, M.D., PhD, Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung

Publications and helpful links

General Publications

• Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
• Marais S, Thwaites G, Schoeman JF, Torok ME, Misra UK, Prasad K, Donald PR, Wilkinson RJ, Marais BJ. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010 Nov;10(11):803-12. doi: 10.1016/S1473-3099(10)70138-9. Epub 2010 Sep 6.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: February 27, 2013
• First Submitted That Met QC Criteria: February 28, 2013
• First Posted (Estimate): March 1, 2013

Study Record Updates

• Last Update Posted (Estimate): June 17, 2014
• Last Update Submitted That Met QC Criteria: June 15, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: bioequivalence; rifampicin; tuberculous meningitis; oral administration; intravenous administration
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: TB-201302.01