Dose Ranging Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Higher Doses of Rifampicin

• Register: PACTR
• Last refreshed on: 29 April 2013
• Main ID: PACTR201104000281203
• Date of registration: 22/03/2011
• Primary sponsor: Radboud University Nijmegen Medical Centre
• Public title: Dose Ranging Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Higher Doses of Rifampicin
• 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.
• Date of first enrolment: 2011-05-16
• Target sample size: 68
• Recruitment status: Open to recruitment: actively recruiting participa
• URL: HTTP://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?da=true&tno=PACTR201104000281203
• Study type: interventional
• Study design: Single group: all participants receive same intervention throughout study,; Non-randomised,

Countries of recruitment

South Africa

Contacts

• Name: Martin Boeree
• Affiliation: Chief Investigator

• Name: Georgette Plemper van Balen
• Affiliation: Project Manager

Key inclusion & exclusion criteria

Inclusion criteria: 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).

Exclusion criteria: 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

Age minimum: 18 Year
Age maximum: 65 Year
Gender: Both

Health Condition(s) or Problem(s) studied

Tuberculosis
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Primary Outcome(s)

The incidence and severity of adverse events associated with increasing doses of Rifampicin when administered as a single drug.

The incidence and severity of adverse events associated with increasing doses of Rifampicin when combined with Isoniazid, Pyrazinamide and Ethambutol.

Secondary Outcome(s)

Pharmacodynamic endpoints for Rifampicin, Isoniazid, Pyrazinamide and Ethambutol

Pharmacodynamic endpoints for single dose Rifampicin

Pharmacokinetic endpoints for Rifampicin, Isoniazid, Pyrazinamide and Ethambutol

Pharmacokinetic endpoints for single dose Rifampicin

The change in Time to Positivity (TTP) as measured in the Mycobacterium Growth Indicator Tube (Bactec MGIT960 system)

The Early Bactericidal Activity (EBA) expressed as the fall of colony forming units per mL of sputum per day

Source(s) of Monetary Support

European & Developing Countries Clinical Trials Partnership (EDCTP)

Secondary Sponsor(s)

Prof. David Burger, PharmD, PhD