High RIF: Pharmacokinetics and Pharmacodynamics of High Versus Standard Dose Rifampicin in Patients With Pulmonary Tuberculosis

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT00760149

Collaborator

European and Developing Countries Clinical Trials Partnership (EDCTP) (Other), Sanofi (Industry), Kilimanjaro Christian Medical Centre, Tanzania (Other), Kibong'oto National Tuberculosis Hospital, Sanya Juu, Tanzania (Other), University Centre for Chronic Diseases Dekkerswald, Groesbeek, The Netherlands (Other), National Institute for Public Health and the Environment (RIVM) (Other)

150

Enrollment

Location

Arms

Duration (Months)

3.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this phase II clinical trial, the pharmacokinetics, safety and (short-term) efficacy of higher than standard doses rifampicin will be studied during the intensive phase of tuberculosis (TB) treatment. Patients enrolled in this study will either get the standard TB regimen (including 600 mg rifampicin; first study arm), or 900 mg rifampicin plus isoniazid, ethambutol and pyrazinamide in standard dosages (second study arm), or 1200 mg rifampicin plus the other drugs in standard dosages (third study arm). All patients will get the standard TB regimen during the continuation phase of treatment.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifampicin in higher doses	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Pharmacokinetics and Pharmacodynamics of High Versus Standard Dose Rifampicin in Patients With Pulmonary Tuberculosis in the Kilimanjaro Region, Tanzania.

Study Start Date :

Jul 1, 2010

Actual Primary Completion Date :

Sep 1, 2013

Actual Study Completion Date :

Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 50 patients, treated with the standard anti-TB regimen, including rifampicin (600 mg), isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg), administered daily, orally, during the intensive phase of TB treatment. In addition they will receive 2 placebo tablets resembling rifampicin 300 mg.	Drug: Rifampicin in higher doses Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)
Active Comparator: 2 50 patients, treated with rifampicin (900 mg), and the other drugs in standard dosages (isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg)), administered daily, orally, during the intensive phase of TB treatment. In addition they will receive 1 placebo tablet resembling rifampicin 300 mg.	Drug: Rifampicin in higher doses Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)
Active Comparator: 3 50 patients, treated with rifampicin (1200 mg), and the other drugs in standard dosages (isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg)), administered daily, orally, during the intensive phase of TB treatment.	Drug: Rifampicin in higher doses Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)

Arm

Intervention/Treatment

Placebo Comparator: 1

50 patients, treated with the standard anti-TB regimen, including rifampicin (600 mg), isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg), administered daily, orally, during the intensive phase of TB treatment. In addition they will receive 2 placebo tablets resembling rifampicin 300 mg.

Drug: Rifampicin in higher doses

Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)

Active Comparator: 2

50 patients, treated with rifampicin (900 mg), and the other drugs in standard dosages (isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg)), administered daily, orally, during the intensive phase of TB treatment. In addition they will receive 1 placebo tablet resembling rifampicin 300 mg.

Drug: Rifampicin in higher doses

Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)

Active Comparator: 3

50 patients, treated with rifampicin (1200 mg), and the other drugs in standard dosages (isoniazid (300 mg), pyrazinamide (30 mg/kg), ethambutol (15 mg/kg)), administered daily, orally, during the intensive phase of TB treatment.

Drug: Rifampicin in higher doses

Rifampicin 900 mg (study arm 2), and rifampicin 1200 mg (study arm 3)

Outcome Measures

Primary Outcome Measures

Pharmacokinetic parameters of rifampicin, desacetylrifampicin, isoniazid, pyrazinamide, ethambutol [Steady state, week 6]

Secondary Outcome Measures

Occurrence of adverse events [baseline, week 1, 2, 4, 6, 8, 10, 12]
Bacteriological response of Mycobacterium tuberculosis [Almost daily during first 8 weeks]
Compare accuracy of surrogate markers (SSCC, mRNA, cytokines) with standard two-month sputum conversion marker [Almost daily during first 8 weeks]
Documenting the occurrence of mixed Mycobacterium tuberculosis strain infections [Almost daily during first 8 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant has a newly diagnosed pulmonary tuberculosis, confirmed by a positive smear of at least two sputum specimens with ZN staining.
Participant is willing to be tested for HIV.
Participant is at least 18, but not more than 65 years of age at the day of the first dosing of study medication.
Participant is admitted to KNTH or KCMC during the intensive phase of TB treatment.
Participant is able and willing to attend to KNTH or KCMC regularly during the continuation phase of TB treatment.
Participant is able to understand and willing to sign the Informed Consent Form prior to screening evaluations.
Female participants should understand that it is important not to get pregnant during the study. They should agree on taking measures to prevent them from getting pregnant during the study. They should agree on taking measures to prevent them from getting pregnant, such as using a contraceptive device or barrier method.

Exclusion Criteria:

Participant has been treated with anti-tuberculosis drugs during the past three years.
Participant's body weight is less than 50 kg.
Participant has abnormal liver function test or serum creatinine (defined as levels higher than the upper limit of normal).
Participant has a relevant medical history or current condition that might interfere with drug absorption, distribution, metabolism or excretion (i.e. chronic gastro-intestinal disease, Diabetes Mellitus, renal or hepatic disease, use of concomitant drugs that interfere with the pharmacokinetics of anti-TB drugs).
Participant is on anti-retroviral treatment at inclusion.
Participant has a CD4 count less than 350 cells/mm3.
Participant has a Karnofsky score of less than 40.
Participant is pregnant or breastfeeding.
Participant has a Multi Drug Resistant (MDR)-TB for which another than the standard treatment regimen is needed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kibong'oto National Tuberculosis Hospital	Sanya Juu	Kilimanjaro	Tanzania	P.O. box 12

Sponsors and Collaborators

Radboud University Medical Center
European and Developing Countries Clinical Trials Partnership (EDCTP)
Sanofi
Kilimanjaro Christian Medical Centre, Tanzania
Kibong'oto National Tuberculosis Hospital, Sanya Juu, Tanzania
University Centre for Chronic Diseases Dekkerswald, Groesbeek, The Netherlands
National Institute for Public Health and the Environment (RIVM)

Investigators

Principal Investigator: Rob Aarnoutse, Pharm-D, PhD, Radboud University Medical Center
Principal Investigator: Gibson Kibiki, MD, MMed, PhD, Kilimanjaro Christian Medical Centre,Moshi,Tanzania
Principal Investigator: Martin Boeree, MD PhD, Radboud University Nijmegen Medical Center/UCCZ Dekkerswald