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

• ClinicalTrials.gov Identifier: NCT00694629
• Recruitment Status: Completed
• First Posted: June 10, 2008
• Last Update Posted: May 8, 2014
• Sponsor: Centers for Disease Control and Prevention
• Collaborator: Sanofi
• Information provided by (Responsible Party): Centers for Disease Control and Prevention

Tracking Information

• First Submitted Date: June 6, 2008
• First Posted Date: June 10, 2008
• Last Update Posted Date: May 8, 2014
• Study Start Date: December 2008
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2008)

• The proportion of patients, by regimen, having negative sputum cultures at completion of eight weeks (40 doses) of treatment [ Time Frame: 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 [ Time Frame: during the first eight weeks of treatment ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 2, 2011)

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

Original Secondary Outcome Measures (submitted: June 9, 2008)

• time to culture-conversion [ Time Frame: 2-, 4-, 6-, and 8-week cultures (10, 20, 30, 40 doses) ]
• proportion of patients with any Grade 3 or 4 adverse reactions [ Time Frame: 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 [ Time Frame: duration of TB treatment ]
• compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [ Time Frame: 8 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TBTC Study 29: Rifapentine During Intensive Phase Tuberculosis (TB) Treatment
• Official Title: TBTC Study 29: Evaluation of a Rifapentine-containing Regimen for Intensive Phase Treatment of Pulmonary Tuberculosis

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.

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Tuberculosis

Intervention

• Drug: rifampin
  tablet, 10 mg/kg, daily, 8 weeks
  Other Name: Rifadin
• Drug: rifapentine
  tablet, 10 mg/kg, daily, 8 weeks
  Other Name: Priftin
• Drug: rifapentine
  tablet, 15 mg/kg, daily, 8 weeks
  Other Name: Priftin
• Drug: rifapentine
  20 mg/kg, daily, 8 weeks
  Other Name: Priftin

Study Arms

• Active Comparator: 1
  rifampin, isoniazid, pyrazinamide, ethambutol
  Intervention: Drug: rifampin
• Experimental: 2
  rifapentine 10 mg/kg, isoniazid, pyrazinamide, ethambutol
  Intervention: Drug: rifapentine
• Experimental: 3
  rifapentine 15 mg/kg, isoniazid, pyrazinamide, ethambutol
  Intervention: Drug: rifapentine
• Experimental: 4
  rifapentine 20 mg/kg, isoniazid, pyrazinamide, ethambutol
  Intervention: Drug: rifapentine

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 7, 2014): 865
• Original Estimated Enrollment (submitted: June 9, 2008): 480
• Actual Study Completion Date: December 2013
• Actual Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Canada, South Africa, Spain, Uganda, United States

Administrative Information

• NCT Number: NCT00694629
• Other Study ID Numbers: CDC-NCHSTP-5399
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Centers for Disease Control and Prevention
• Original Responsible Party: Stefan Goldberg, CDC
• Current Study Sponsor: Centers for Disease Control and Prevention
• Original Study Sponsor: Same as current
• 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

• PRS Account: Centers for Disease Control and Prevention
• Verification Date: May 2014