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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.: PACTR201104000281203 Date registered: 2011/03/22
TRIAL DESCRIPTION
Public title Dose Ranging Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Higher Doses of Rifampicin
Official scientific title A Phase IIA Dose Ranging Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Higher Doses of Rifampicin in Adult Subjects with Newly Diagnosed, Uncomplicated, Smear-Positive, Pulmonary Tuberculosis.
Brief summary describing the background
and objectives of the trial
The objective of this study is to find the maximum tolerable dose of Rifampicin as monotherapy and in combination with the currently available Isoniazid, Pyrazinamide and Ethambutol. The safety, tolerability, extended early bactericidal activity (EBA) and pharmacokinetics of several doses of Rifampicin with or without standard doses of Isoniazid, Pyrazinamide and Ethambutol in adults with newly diagnosed, uncomplicated, smear positive, pulmonary TB will be assessed.
Type of trial CCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Tuberculosis ,
Purpose of the trial Treatment
Anticipated trial start date 2011-05-16
Actual trial start date
Anticipated date of last follow up 2012-05-14
Actual date of last follow up
Anticipated target sample size (number of participants) 68   
Actual target sample size (number of participants)   
Recruitment status Open to recruitment: actively recruiting participants
Secondary Ids Issuing authority/Trial register Links to Secondary ID

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
Single group: all participants receive same intervention throughout study Non-randomised Open-label (masking not used)

INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental group 20 mg/kg Rifampicin/kg daily dose of 20 mg Rifampicin/kg 7 days baseline, 7 days monotherapy, 7 days combination therapy Monotherapy with 20 mg Rifampicin/kg 15
Experimental group 25 mg/kg Rifampicin/kg daily dose of 25 mg Rifampicin/kg 7 days baseline, 7 days monotherapy, 7 days combination therapy Monotherapy with 25 mg Rifampicin/kg 15
Control group 10 mg Rifampicin/kg daily dose of 10 mg Rifampicin/kg 7 days Monotherapy with 10 mg Rifampicin/kg 8 Uncontrolled
Experimental group 30 mg/kg Rifampicin/kg daily dose of 30 mg Rifampicin/kg 7 days baseline, 7 days monotherapy, 7 days combination therapy Monotherapy with 30 mg Rifampicin/kg 15
Experimental group 35 mg/kg Rifampicin/kg daily dose of 35 mg Rifampicin/kg 7 days baseline, 7 days monotherapy, 7 days combination therapy Monotherapy with 35 mg Rifampicin/kg 15

ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Min age Max age Gender
1.The patient is able and willing to provide written, informed consent prior to all trial-related procedures including HIV testing. 2.The patient is aged between 18 and 65 years, inclusive. 3.The patient has a body weight (in light clothing and with no shoes) between 40 and 85 kg, inclusive. 4.The patient is a newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB patient. 5.The patient has a normal chest X-ray or a picture which in the opinion of the Investigator is compatible with TB. 6.The patient is sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale (Appendix 4)). 7.The patient is able to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production). 8.The patient has a negative serum pregnancy test (female subjects of childbearing potential only) 9.The patient agrees to use a highly effective method of birth control (i.e. two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, condom, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate, partner(s) has/have had a vasectomy) throughout the participation in the trial and for 1 week after last dose, unless she and her partner(s) are sterile (that is, women who have had a bilateral oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months; men who have had bilateral orchidectomy). 10.A Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs). 1.The patient is in poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator. 2.Rifampicin-resistant bacteria have been detected in the patient's sputum specimen collected within the Pre-Treatment Period and tested at the study laboratory. 3.The patient has received treatment with any drug active against MTB within the 3 months prior to Visit 1: isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, quinolones, thioamides. 4.The patient has a history of allergy to isoniazid, ethambutol, rifampicin and pyrazinamide, 5.The patient has a history of previous TB. 6.The patient has Hepatitis B. 7.The patient had Hepatitis C. 8.The patient is infected with HIV and has a CD4 count < 350 cells/uL (Visit 1). 9.The patient is receiving antiretroviral therapy (ART). 10.The patient has been taking rifampicin within 30 days prior to Visit 1. 11.The patient is a diabetic using insulin. 12.The patient is pregnant or breast-feeding (female patients only). 13.The patient has a history and/or presence (or evidence) of neuropathy or epilepsy. 14.The patient has a history of or current clinically relevant cardiovascular disorder such as: a.heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction. b.family history of sudden death of unknown or cardiac-related cause, or of prolonged QTc interval. 15.Concomitant use of any drug known to prolong QTc interval (including amiodarone, bepridil chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). 16.The patient has any disease or condition in which the use of the standard T 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 2010/10/12 Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Groote Schuur Hospital Old Main Building Observatory 7925 South Africa
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 2010/07/01 Pharma-Ethics (pty) Ltd
Ethics Committee Address
Street address City Postal code Country
123 Amcor Road Lyttelton Manor 0157 South Africa
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 2011/11/16 Medicines Control Council
Ethics Committee Address
Street address City Postal code Country
Private Bag X828 Pretoria 0001 South Africa

OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The incidence and severity of adverse events associated with increasing doses of Rifampicin when administered as a single drug. Daily in period Days 1-7
Primary Outcome The incidence and severity of adverse events associated with increasing doses of Rifampicin when combined with Isoniazid, Pyrazinamide and Ethambutol. Daily in period Days 8-14
Secondary Outcome The Early Bactericidal Activity (EBA) expressed as the fall of colony forming units per mL of sputum per day Baseline to Day 2, Baseline to Day 7, Baseline to Day 14, and Day 8 to Day 14.
Secondary Outcome The change in Time to Positivity (TTP) as measured in the Mycobacterium Growth Indicator Tube (Bactec MGIT960 system) Baseline to Day 2, Baseline to Day 7, Baseline to Day 14, and Day 8 to Day 14
Secondary Outcome Pharmacokinetic endpoints for single dose Rifampicin Day 7
Secondary Outcome Pharmacokinetic endpoints for Rifampicin, Isoniazid, Pyrazinamide and Ethambutol Day 14
Secondary Outcome Pharmacodynamic endpoints for single dose Rifampicin Day 7
Secondary Outcome Pharmacodynamic endpoints for Rifampicin, Isoniazid, Pyrazinamide and Ethambutol Day 14

RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
TASK Applied Science Mike Pienaar Boulevard Belville 7531 South Africa
University of Cape Town Lung Institute (Pty) Ltd. George Street Mowbray, Cape Town 7700 South Africa

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 Radboud University Nijmegen Medical Centre Geert Grooteplein 10, P.O. Box 9101 Nijmegen 6500 HB Netherlands University
Secondary Sponsor Prof. David Burger, PharmD, PhD Radboud University Nijmegen Medical Centre, Department of Clinical Pharmacy, Geert Grooteplein 10, P.O. Box 9101 Nijmegen 6500 HB Netherlands University

COLLABORATORS
Name Street address City Postal code Country
Dr. Martin Boeree Radboud University Nijmegen Medical Centre, University Centre for Chronic Diseases, Nijmeegsebaan 31, PO Box 66 Groesbeek 6560 AB Netherlands
Dr. Rob Aarnoutse Radboud University Nijmegen Medical Centre, Pharmacy/Clinical Pharmacy, Geert Grooteplein 10, P.O. Box 9101 Nijmegen 6500 HB Netherlands
Prof. Dr. Andreas Diacon Task Applied Science, M2, Karl Bremer Hospital, Mike Pienaar Boulevard Bellville 7531 South Africa
Dr. Rodney Dawson University of Cape Town Lung Institute (Pty) Ltd., George Street Mowbray, Cape Town 7700 South Africa

CONTACT PEOPLE
Role Name Email Phone Fax
Principal Investigator Prof Andreas Diacon ahd@sun.ac.za +27219389392 +27219389476
Street address City Postal code Country Position / Affiliation
Task Applied Science, M2, Karl Bremer Hospital, Mike Pienaar Boulevard Belville 7531 South Africa National Principal Investigator
Role Name Email Phone Fax
Scientific Enquiries Dr Martin Boeree M.Boeree@uccz.umcn.nl +31246859293
Street address City Postal code Country Position / Affiliation
University Centre for Chronic Diseases Dekkerswald, Nijmeegsebaan 31 Groesbeek 6561 KE Netherlands Chief Investigator
Role Name Email Phone Fax
Public Enquiries Dr Georgette Plemper van Balen G.PlemperVanBalen@ uccz.umcn.nl +31246859563
Street address City Postal code Country Position / Affiliation
University Centre for Chronic Diseases Dekkerswald, Nijmeegsebaan 31 Groesbeek 6561 KE Netherlands Project Manager