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Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834     Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za     Website: www.pactr.org

Trial no.: PACTR2009060001493909 Date registered: 2009/06/19
TRIAL DESCRIPTION
Public title High RIF
Official scientific title Pharmacokinetics and -dynamics of high versus standard dose rifampicin in patients with pulmonary tuberculosis in the Kilimanjaro Region, Tanzania
Brief summary describing the background
and objectives of the trial
The current tuberculosis (TB) treatment is lengthy and complex, resulting in problems of nonadherence, inadequate treatment response and resistance development. Shortening the duration of TB treatment will help solving these problems. Increasing the dose of rifampicin in standard TB treatment is expected to reduce treatment duration. This study will focus on the pharmacokinetics and -dynamics of higher than standard doses of rifampicin in first-line TB treatment.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) High RIF
Disease(s) or condition(s) being studied Tuberculosis ,
Purpose of the trial Treatment
Anticipated trial start date 2009-09-01
Actual trial start date 2010-08-13
Anticipated date of last follow up
Actual date of last follow up 2012-01-31
Anticipated target sample size (number of participants) 150   
Actual target sample size (number of participants) 150   
Recruitment status Open to recruitment: actively recruiting participants
Secondary Ids Issuing authority/Trial register Links to Secondary ID
NCT00760149 ClinicialTrials.gov

STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person
allocating the participants to the intervention arms
Masking If masking / blinding was used
Factorial: participants randomly allocated to either no,one,some or all interventions simultaneously Randomised Blocked randomization (block size: 6), after stratification for gender and HIV-status Sealed opaque envelopes Masking/blinding used

INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental group Higher dose rifampicin(900 mg) Rifampicin 900 mg; isoniazid 300 mg; pyrazinamide 30 mg/kg; ethambutol 15 mg/kg; 1 placebo tablet for rifampicin 300 mg. 2 months Higher than standard dose rifampicin (900 mg) in otherwise standard intensive phase TB treatment 50
Experimental group Higher dose rifampicin (1200 mg) Rifampicin 1200 mg; isoniazid 300 mg; pyrazinamide 30 mg/kg; ethambutol 15 mg/kg. 2 months Higher than standard dose rifampicin (1200 mg) in otherwise standard intensive phase TB treatment 50
Control group Standard, first-line TB treatment during intensive phase of TB treatment Rifampicin 600 mg; isoniazid 300 mg; pyrazinamide 30 mg/kg; ethambutol 15 mg/kg; 2 placebo tablets for rifampicin 300 mg. 2 months No intervention for the control group (except for two placebo tablets in addition to the standard TB treatment regimen). 50 Dose comparison

ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Min age Max age Gender
1. Participant has newly diagnosed pulmonary tuberculosis, confirmed by a positive smear of at least two spontaneously produced sputum samples with ZN staining. 2. Participant is willing to be tested for HIV. 3. Participant is at least 18, but no more than 65 years of age at the day of the first dosing of study medication. 4. Participant is admitted to Kibong'oto National Tuberculosis Hospital (KNTH) or Kilimanjaro Christian Medical Centre (KCMC) during the intensive phase of TB treatment. 5. Participant is able and willing to attend to KNTH or KCMC regularly during the continuation phase of TB treatment. 6. Participant is able to understand and willing to sign the Informed Consent Form prior to screening evaluations. 1. Participant has been treated with anti-tuberculosis drugs during the past three years. 2. Participant's body weight is less than 50 kg. 3. Participant has abnormal liver function test or creatinine (defined as levels higher than the upper limit of normal). 4. Participant has a relevant 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). 5. Participant is on anti-retroviral treatment at inclusion. 6. Participant has a CD4 count less than 350 cells/mm3 7. Participant has a Karnovsky score of less than 40. 8. Participant is pregnant or breastfeeding. 9. Participant is using immunosuppressive drugs, such as steroids or cyclofosfamides. 10. Participant has a rifampin resistant or Multi Drug Resistant (MDR-) TB for which another than the standard regimen is needed. 18 Years 65 Years Both

ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2007/12/07 KCMC Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
KCMC Moshi 2240 United Republic of Tanzania
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2008/08/14 National Institute for Medical Research
Ethics Committee Address
Street address City Postal code Country
NIMR Dar es Salaam 9653 United Republic of Tanzania
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval
Name of the ethics committee
Yes 2009/03/24 Tanzanian Food and Drug Authority
Ethics Committee Address
Street address City Postal code Country
Nelson Mandela Road Dar es Salaam 77150 United Republic of Tanzania

OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Pharmacokinetics of rifampicin 24h Pharmacokinetics curve at steady state; week 3 after start of treatment.
Primary Outcome Occurrence of adverse events Week 0, 1, 2, 4, 6, 8, 10 and 12 after start of treatment
Primary Outcome Short-term bacteriological response (sputum culture conversion and Serial Sputum Colony Forming Units Count, SSCC) Week 0, 1, 2, 3, 4, 5, 6, 7, 8
Secondary Outcome Accuracy of surrogate markers (SSCC, mRNA, cytokines) Week 0, 1, 2, 3, 4, 5, 6, 7, 8
Secondary Outcome Occurrence of mixed Mycobacterium tuberculosis strain infections Week 0

RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kilimanjaro Christian Medical Centre (KCMC) KCMC Moshi 3010 United Republic of Tanzania
Kibong'oto National Tuberculosis Centre (KNTH) Kibong'oto Sanya Juu 12 United Republic of Tanzania

FUNDING SOURCES
Name of source Street address City Postal code Country
European & Developing Countries Clinical Trials Partnership (EDCTP) Laan van Nieuw Oost Indiƫ 334 The Hague Netherlands

SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor African Poverty Related Infection Oriented Research Initiative (APRIORI) Radboud Nijmegen Medical Centre Nijmegen 9101, 6500 HB Netherlands University
Primary Sponsor African Poverty Related Infection Oriented Research Initiative (APRIORI) Radboud Nijmegen Medical Centre Nijmegen 9101, 6500 HB Netherlands University
Primary Sponsor Prof. Dr. D.M. Burger Radboud University Nijmegen Medical Centre, Geert Grooteplein 10 Nijmegen 6525 GA Netherlands University
Secondary Sponsor Dr. M.J. Boeree University Centre for Chronic Diseases Dekkerswald, Nijmeegsebaan 31 Groesbeek 6561 KE Netherlands University
Secondary Sponsor Dr. R.E. Aarnoutse Radboud University Nijmegen Medical Centre, Geert Grooteplein 10 Nijmegen 6525 GA Netherlands University

COLLABORATORS
Name Street address City Postal code Country
Radboud University Nijmegen Medical Centre Geert Grooteplein 8 Nijmegen 6525 GA Netherlands
Kilimanjaro Christian Medical Centre (KCMC) KCMC Moshi 3010 United Republic of Tanzania
Kibong'oto National Tuberculosis Hospital (KNTH) Kibong'oto Sanya Juu 12 United Republic of Tanzania
Radboud University Nijmegen Medical Centre Geert Grooteplein 8 Nijmegen 6525 GA Netherlands
Kilimanjaro Christian Medical Centre (KCMC) KCMC Moshi 3010 United Republic of Tanzania
Kibong'oto National Tuberculosis Hospital (KNTH) Kibong'oto Sanya Juu 12 United Republic of Tanzania
University Centre for Chronic Diseases Dekkerwald Nijmeegsebaan 31 Groesbeek 6561 KE Netherlands
RIVM, National Institute for Public Health and the Environment Bilthoven 3720 BA Netherlands

CONTACT PEOPLE
Role Name Email Phone Fax
Principal Investigator Dr Rob Aarnoutse r.aarnoutse@akf.umcn.nl +31 24 3616405
Street address City Postal code Country Position / Affiliation
Geert Grooteplein 10 Nijmegen 9101, 6500 HB Netherlands Department of Clinical Pharmacy, pharmacist
Role Name Email Phone Fax
Public Enquiries Dr Martin Boeree m.boeree@ulc.umcn.nl +31 24 6859297
Street address City Postal code Country Position / Affiliation
Nijmeegsebaan 31 Groesbeek 66, 6560 AB Netherlands Respiratory medicine physician, medical director University Lung Centre Dekkerswald
Role Name Email Phone Fax
Scientific Enquiries Dr Gibson Kibiki gkibiki@gmail.com +255 754 572767
Street address City Postal code Country Position / Affiliation
KCMC Moshi 3010 United Republic of Tanzania Internal medicine physician