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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: rifampin; Drug: rifapentine; Drug: rifapentine; Drug: rifapentine

• Study Type: Interventional
• Enrollment (Actual): 865
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated or induced sputum.
2. 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.
3. 5 (five) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding initiation of study drugs.
4. 7 (seven) or fewer days of fluoroquinolone therapy in the 30 days preceding initiation of study drugs.
5. Age >= 18 years
6. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix B)
7. Signed informed consent
8. 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.

9. 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:

1. Pregnant or breast-feeding
2. Known intolerance or allergy to any of the study drugs
3. 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.
4. 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.
5. Pulmonary silicosis
6. Central nervous system TB
7. Weight < 40 kg or > 85 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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; Drug: rifapentine; tablet, 15 mg/kg, daily, 8 weeks; Other Names: Priftin; Drug: rifapentine; 20 mg/kg, daily, 8 weeks; Other Names: Priftin
Experimental: 3; rifapentine 15 mg/kg, isoniazid, pyrazinamide, ethambutol	Drug: rifapentine; tablet, 10 mg/kg, daily, 8 weeks; Other Names: Priftin; Drug: rifapentine; tablet, 15 mg/kg, daily, 8 weeks; Other Names: Priftin; Drug: rifapentine; 20 mg/kg, daily, 8 weeks; Other Names: Priftin
Experimental: 4; rifapentine 20 mg/kg, isoniazid, pyrazinamide, ethambutol	Drug: rifapentine; tablet, 10 mg/kg, daily, 8 weeks; Other Names: Priftin; Drug: rifapentine; tablet, 15 mg/kg, daily, 8 weeks; Other Names: Priftin; Drug: rifapentine; 20 mg/kg, daily, 8 weeks; Other Names: Priftin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
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.	• 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.	8 weeks.

Collaborators and Investigators

• Sponsor: Centers for Disease Control and Prevention
• Collaborators: Sanofi
• Investigators: Principal Investigator: Susan Dorman, MD, Johns Hopkins University; Study Chair: Neil Schluger, MD, Columbia University; Study Chair: Jason Stout, MD, Duke University

Publications and helpful links

General Publications

• Dorman SE, Goldberg S, Stout JE, Muzanyi G, Johnson JL, Weiner M, Bozeman L, Heilig CM, Feng PJ, Moro R, Narita M, Nahid P, Ray S, Bates E, Haile B, Nuermberger EL, Vernon A, Schluger NW; Tuberculosis Trials Consortium. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. J Infect Dis. 2012 Oct 1;206(7):1030-40. doi: 10.1093/infdis/jis461. Epub 2012 Jul 30.
• Gewitz AD, Solans BP, Mac Kenzie WR, Heilig C, Whitworth WC, Johnson JL, Nsubuga P, Dorman S, Weiner M, Savic RM; Tuberculosis Trials Consortium of the Centers for Disease Control and Prevention. Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0179420. doi: 10.1128/AAC.01794-20. Epub 2021 Jul 12.
• Jarsberg LG, Kedia K, Wendler J, Wright AT, Piehowski PD, Gritsenko MA, Shi T, Lewinsohn DM, Sigal GB, Weiner MH, Smith RD, Keane J, Jacobs JM, Nahid P. Nutritional markers and proteome in patients undergoing treatment for pulmonary tuberculosis differ by geographic region. PLoS One. 2021 May 5;16(5):e0250586. doi: 10.1371/journal.pone.0250586. eCollection 2021.
• Dorman SE, Savic RM, Goldberg S, Stout JE, Schluger N, Muzanyi G, Johnson JL, Nahid P, Hecker EJ, Heilig CM, Bozeman L, Feng PJ, Moro RN, MacKenzie W, Dooley KE, Nuermberger EL, Vernon A, Weiner M; Tuberculosis Trials Consortium. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med. 2015 Feb 1;191(3):333-43. doi: 10.1164/rccm.201410-1843OC. Erratum In: Am J Respir Crit Care Med. 2015 May 15;191(10):1210.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: June 6, 2008
• First Submitted That Met QC Criteria: June 9, 2008
• First Posted (Estimate): June 10, 2008

Study Record Updates

• Last Update Posted (Estimate): May 8, 2014
• Last Update Submitted That Met QC Criteria: May 7, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: treatment; pulmonary tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifapentine; Rifampin
• Other Study ID Numbers: CDC-NCHSTP-5399