TBTC Study 29: Rifapentine During Intensive Phase Tuberculosis (TB) Treatment

Protocol Synopsis The goal of this Phase 2 clinical trial is to evaluate the antimicrobial
activity and safety of an experimental intensive phase (first 8 weeks of treatment)
tuberculosis treatment regimen in which rifapentine is substituted for rifampin.

Primary Objective

- To compare the antimicrobial activity and safety of standard daily regimen comprised of
rifampin (approximately 10 mg/kg/dose) + isoniazid + pyrazinamide + ethambutol (RHZE)
to that of an experimental regimen comprised of rifapentine (approximately 10
mg/kg/dose) + isoniazid + pyrazinamide + ethambutol (PHZE).

Secondary Objectives

- To determine and compare for each regimen the time to culture-conversion, using data
from 2-, 4-, 6-, and 8-week cultures (10, 20, 30, 40 doses).

- To determine and compare for each regimen the proportion of patients with any Grade 3
or 4 adverse reactions

- To determine the correlation of the MGIT/BACTEC liquid culture growth index and other
mycobacterial and clinical biomarkers with time to culture conversion and treatment
failure

- To store serum for future assessment of biomarkers of TB treatment response and
hypersensitivity to study drugs.

- To compare adverse events and 2-month culture conversion rates among HIV-infected
patients vs. HIV-uninfected patients

- To determine the tolerability and safety, and estimate the antimicrobial activity, of
experimental regimens that include isoniazid + pyrazinamide + ethambutol plus either
rifapentine 15 mg/kg/dose or rifapentine 20 mg/kg/dose, all administered daily.
Assessment of these doses of rifapentine will be performed as an extension to the main
study after enrollment in the main study has been completed.

Design

This will be a prospective, multicenter, open-label clinical study. Adults suspected of
having pulmonary tuberculosis who meet eligibility criteria will be randomized to receive
either the experimental intensive phase tuberculosis treatment regimen or the standard
intensive phase tuberculosis treatment regimen. Randomization will be stratified by
presence/absence of cavitation on baseline chest radiograph, and by geographic continent.
All doses of study drugs will be given under direct observation and administered 5 days per
week. After a subject completes intensive phase therapy, he/she then will be treated with a
non-experimental continuation phase tuberculosis treatment regimen.

The study extension will be a prospective, multicenter clinical trial. Eligibility criteria
will be the same as for the main study. Participants will be randomized to one of four
regimens: the standard intensive phase treatment regimen, an investigational regimen in
which rifapentine 10 mg/kg/dose is substituted for rifampin, an investigational regimen in
which rifapentine 15 mg/kg/dose is substituted for rifampin, or an investigational regimen
in which rifapentine 20 mg/kg is substituted for rifampin. Randomization will be stratified
by the presence/absence of cavitation on baseline chest radiograph, and by study site. Study
drugs will be administered 7 days per week. After a subject completes intensive phase
therapy, he/she then will be treated with a non-experimental continuation phase tuberculosis
treatment regimen. Subjects will have blood drawn for one pharmacokinetic determination of
rifapentine concentration at or after the week 2 visit during intensive phase therapy.

This study is being conducted in 2 phases.

1. The main study compares a 10 mg/kg dose of rifapentine, open label, against 10 mg/kg
rifampin in an otherwise standard intensive phase regimen of treatment for pulmonary
tuberculosis. The projected sample size was 480 enrollments; 530 patients were
actually enrolled.

2. The study extension evaluates higher doses of rifapentine, with the specific
rifapentine doses (10 mg/kg, 15 mg/kg, and 20 mg/kg) blinded to patients and
clinicians, with data collection and endpoints otherwise similar to the main study.
The projected sample size for the study extension is 320 enrollments.