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

NCT ID: NCT01802502

Last Updated: 2014-06-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-30
• Study Completion Date: 2014-04-30

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.

Conditions

Tuberculous Meningitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rifampicin 600 mg

Subjects in this arm receive 600 mg rifampicin intravenously

Group Type: ACTIVE_COMPARATOR

Rifampicin intravenous

Intervention Type: DRUG

rifampicin 750 mg

Subjects in this arm receive 750 mg rifampicin orally

Group Type: EXPERIMENTAL

Oral rifampicin

Intervention Type: DRUG

rifampicin 900 mg

Subjects in this arm receive rifampicin 900 mg orally

Group Type: EXPERIMENTAL

Oral rifampicin

Intervention Type: DRUG

Interventions

Rifampicin intravenous

Intervention Type: DRUG

Oral rifampicin

Intervention Type: DRUG

Other Intervention Names

Rifadin; Rifampisin (Kimia Farma, Bandung, Indonesia)

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

Universitas Padjadjaran

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rovina Ruslami, M.D., PhD

Role: PRINCIPAL_INVESTIGATOR

Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung

Locations

Hasan Sadikin Hospital

Bandung, West Java, Indonesia

Countries

Indonesia

References

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.

Reference Type: BACKGROUND

PMID: 23103177 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20822958 (View on PubMed)

Other Identifiers

TB-201302.01

Identifier Type: -

Identifier Source: org_study_id