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

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 2

Locations

Tanzania

Study Type

Interventional

Intervention

Rifampicin in higher doses

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring tuberculosis, rifampicin, pharmacokinetics, pharmacodynamics

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

Kibong'oto National Tuberculosis Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Pharmacokinetic parameters of rifampicin, desacetylrifampicin, isoniazid, pyrazinamide, ethambutol

Secondary Outcome Measures

Occurrence of adverse events

Bacteriological response of Mycobacterium tuberculosis

Compare accuracy of surrogate markers (SSCC, mRNA, cytokines) with standard two-month sputum conversion marker

Documenting the occurrence of mixed Mycobacterium tuberculosis strain infections

Full Information

NCT ID

NCT00760149

First Posted

September 25, 2008

Last Updated

September 6, 2013

Sponsor

Radboud University Medical Center

Collaborators

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)

1. Study Identification

Unique Protocol Identification Number

NCT00760149

Brief Title

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

Acronym

High RIF

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2013

Overall Recruitment Status

Completed

Study Start Date

July 2010 (undefined)

Primary Completion Date

September 2013 (Actual)

Study Completion Date

September 2013 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Radboud University Medical Center

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

Keywords

tuberculosis, rifampicin, pharmacokinetics, pharmacodynamics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

150 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Placebo Comparator

Arm Description

Arm Title

Arm Type

Active Comparator

Arm Description

Arm Title

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Rifampicin in higher doses

Intervention Description

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

Primary Outcome Measure Information:

Title

Pharmacokinetic parameters of rifampicin, desacetylrifampicin, isoniazid, pyrazinamide, ethambutol

Time Frame

Steady state, week 6

Secondary Outcome Measure Information:

Title

Occurrence of adverse events

Time Frame

baseline, week 1, 2, 4, 6, 8, 10, 12

Title

Bacteriological response of Mycobacterium tuberculosis

Time Frame

Almost daily during first 8 weeks

Title

Compare accuracy of surrogate markers (SSCC, mRNA, cytokines) with standard two-month sputum conversion marker

Time Frame

Almost daily during first 8 weeks

Title

Documenting the occurrence of mixed Mycobacterium tuberculosis strain infections

Time Frame

Almost daily during first 8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rob Aarnoutse, Pharm-D, PhD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gibson Kibiki, MD, MMed, PhD

Organizational Affiliation

Kilimanjaro Christian Medical Centre,Moshi,Tanzania

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Martin Boeree, MD PhD

Organizational Affiliation

Radboud University Nijmegen Medical Center/UCCZ Dekkerswald

Official's Role

Principal Investigator

Facility Information:

Facility Name

Kibong'oto National Tuberculosis Hospital

City

Sanya Juu

State/Province

Kilimanjaro

ZIP/Postal Code

P.O. box 12

Country

Tanzania

12. IPD Sharing Statement

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

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