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

Sponsor

Centers for Disease Control and Prevention (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00694629

Collaborator

Sanofi (Industry)

865

Enrollment

Locations

Arms

Duration (Months)

29.8

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

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.
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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Tuberculosis	Drug: rifampin Drug: rifapentine Drug: rifapentine Drug: rifapentine	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

865 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

TBTC Study 29: Evaluation of a Rifapentine-containing Regimen for Intensive Phase Treatment of Pulmonary Tuberculosis

Study Start Date :

Dec 1, 2008

Actual Primary Completion Date :

Jun 1, 2013

Actual Study Completion Date :

Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 rifampin, isoniazid, pyrazinamide, ethambutol	Drug: rifampin tablet, 10 mg/kg, daily, 8 weeks Other Names: Rifadin
Experimental: 2 rifapentine 10 mg/kg, isoniazid, pyrazinamide, ethambutol	Drug: rifapentine tablet, 10 mg/kg, daily, 8 weeks Other Names: Priftin
Experimental: 3 rifapentine 15 mg/kg, isoniazid, pyrazinamide, ethambutol	Drug: rifapentine tablet, 15 mg/kg, daily, 8 weeks Other Names: Priftin
Experimental: 4 rifapentine 20 mg/kg, isoniazid, pyrazinamide, ethambutol	Drug: rifapentine 20 mg/kg, daily, 8 weeks Other Names: Priftin

Outcome Measures

Primary Outcome Measures

The proportion of patients, by regimen, having negative sputum cultures at completion of eight weeks (40 doses) of treatment [completion of eight weeks (40 doses) of treatment]
The proportion of patients, by regimen, who permanently discontinue the assigned study treatment for any reason during the first eight weeks [during the first eight weeks of treatment]

Secondary Outcome Measures

time to culture-conversion [2-, 4-, 6-, and 8-week cultures (10, 20, 30, 40 doses)]
proportion of patients with any Grade 3 or 4 adverse reactions [8 weeks]
correlation of the MGIT/BACTEC liquid culture growth index and other mycobacterial and clinical biomarkers with time to culture conversion and treatment failure [duration of TB treatment]
compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [8 weeks]
• To determine the tolerability and safety, and estimate the antimicrobial activity, of experimental regimens that include higher doses of rifapentine. [8 weeks.]
• 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated or induced sputum.
Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 3 months prior to enrollment.
5 (five) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding initiation of study drugs.
7 (seven) or fewer days of fluoroquinolone therapy in the 30 days preceding initiation of study drugs.
Age >= 18 years
Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix B)
Signed informed consent
Women of child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy.
Laboratory parameters done within 14 days prior to, enrollment:

Serum or plasma alanine aminotransferase (ALT) activity ≤ 3 times the upper limit of normal
Serum or plasma total bilirubin level ≤ 2.5 times the upper limit of normal
Serum or plasma creatinine level ≤ 2 times the upper limit of normal
Complete blood count with hemoglobin level of at least 7.0 g/dL
Complete blood count with platelet count of at least 100,000/mm3
Negative pregnancy test (women of childbearing potential)

Exclusion Criteria:

Pregnant or breast-feeding
Known intolerance or allergy to any of the study drugs
Concomitant disorders or conditions for which isoniazid (INH), rifamycins, pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
Current or planned therapy, during the intensive phase of TB therapy, with combination antiretroviral therapy for HIV, or with cyclosporine or tacrolimus. Cyclosporine and tacrolimus have unacceptable interactions with rifamycins.
Pulmonary silicosis
Central nervous system TB
Weight < 40 kg or > 85 kg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Arkansas Veterans Health System	Little Rock	Arkansas	United States	72205
2	LA County/USC Medical Center	Los Angeles	California	United States	90033
3	University of Southern California Medical Center	Los Angeles	California	United States	90033
4	University of California at San Diego	San Diego	California	United States	92103
5	University of California, San Francincisco	San Francisco	California	United States	94110
6	Denver Department of Public Health and Hospitals	Denver	Colorado	United States	80204
7	Washington DC Veterans Administration Medical Center	Washington DC	District of Columbia	United States	20422
8	Emory University School of Medicine	Atlanta	Georgia	United States	30303
9	Chicago VA Medical Center (Lakeside)	Chicago	Illinois	United States	60611
10	Northwestern University	Chicago	Illinois	United States	60611
11	Hines VA Medical Center	Hines	Illinois	United States	60141
12	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21231
13	Boston Medical Center	Boston	Massachusetts	United States	02118
14	New Jersey Medical School	Newark	New Jersey	United States	07107-3001
15	Columbia University/Presbyterian Medical Center	New York	New York	United States	10032
16	Harlem Hospital, Columbia University	New York	New York	United States	10037
17	Duke University Medical Center	Durham	North Carolina	United States	27710
18	Nashville VA Medical Center	Nashville	Tennessee	United States	37212-2637
19	Veterans Administration Tennessee Valley Health Care System	Nashville	Tennessee	United States	37232
20	University of North Texas Health Science Center	Fort Worth	Texas	United States	76104
21	Houston Veterans Administration Medical Center	Houston	Texas	United States	77030
22	Audi L. Murphy VA Hospital	San Antonio	Texas	United States	78284
23	Seattle King County Health Department	Seattle	Washington	United States	98104
24	Hopital Universitario Clementino Fraga Filho	Rio de Janeiro		Brazil	2194.590
25	University of Manitoba	Winnepeg	Manitoba	Canada	R3A 1R8
26	Montreal Chest Institute McGill University	Montreal	Quebec	Canada	H2X 2P4Pq Canada
27	Nelson R Mandela School of Medicine	Durban	KwaZulu Natal	South Africa
28	Agencia de Salut Publica	Barcelona		Spain	08023
29	Makerere University Medical School	Kampala		Uganda