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

NCT00694629 | Completed Phase 2 DMC

• 1 other identifier: CDC-NCHSTP-5399
• Study Type: interventional
• Target: 865
• Locations: 6 countries
• Sites: 29

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.

Conditions

Pulmonary Tuberculosis

Keywords

pulmonary tuberculosis; treatment

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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.

Study Arms (4)

1

ACTIVE COMPARATOR

rifampin, isoniazid, pyrazinamide, ethambutol

Drug: rifampin

2

EXPERIMENTAL

rifapentine 10 mg/kg, isoniazid, pyrazinamide, ethambutol

Drug: rifapentine

3

EXPERIMENTAL

rifapentine 15 mg/kg, isoniazid, pyrazinamide, ethambutol

Drug: rifapentine

4

EXPERIMENTAL

rifapentine 20 mg/kg, isoniazid, pyrazinamide, ethambutol

Drug: rifapentine

Interventions

rifampin DRUG

tablet, 10 mg/kg, daily, 8 weeks

Also known as: Rifadin

1

rifapentine DRUG

tablet, 10 mg/kg, daily, 8 weeks

Also known as: Priftin

2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• (five) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding initiation of study drugs.
• (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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Sanofi: collaborator

Study Sites (29)

Central Arkansas Veterans Health System

Little Rock, Arkansas, 72205, United States

Location

LA County/USC Medical Center

Los Angeles, California, 90033, United States

Location

University of Southern California Medical Center

Los Angeles, California, 90033, United States

Location

University of California at San Diego

San Diego, California, 92103, United States

Location

University of California, San Francincisco

San Francisco, California, 94110, United States

Location

Denver Department of Public Health and Hospitals

Denver, Colorado, 80204, United States

Location

Washington DC Veterans Administration Medical Center

Washington D.C., District of Columbia, 20422, United States

Location

Emory University School of Medicine

Atlanta, Georgia, 30303, United States

Location

Chicago VA Medical Center (Lakeside)

Chicago, Illinois, 60611, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Hines VA Medical Center

Hines, Illinois, 60141, United States

Location

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21231, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

New Jersey Medical School

Newark, New Jersey, 07107-3001, United States

Location

Columbia University/Presbyterian Medical Center

New York, New York, 10032, United States

Location

Harlem Hospital, Columbia University

New York, New York, 10037, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Nashville VA Medical Center

Nashville, Tennessee, 37212-2637, United States

Location

Veterans Administration Tennessee Valley Health Care System

Nashville, Tennessee, 37232, United States

Location

University of North Texas Health Science Center

Fort Worth, Texas, 76104, United States

Location

Houston Veterans Administration Medical Center

Houston, Texas, 77030, United States

Location

Audi L. Murphy VA Hospital

San Antonio, Texas, 78284, United States

Location

Seattle King County Health Department

Seattle, Washington, 98104, United States

Location

Hopital Universitario Clementino Fraga Filho

Rio de Janeiro, Rio de Janeiro, 2194.590, Brazil

Location

University of Manitoba

Winnepeg, Manitoba, R3A 1R8, Canada

Location

Montreal Chest Institute McGill University

Montreal, Quebec, H2X 2P4Pq Canada, Canada

Location

Nelson R Mandela School of Medicine

Durban, KwaZulu-Natal, South Africa

Location

Agencia de Salut Publica

Barcelona, 08023, Spain

Location

Makerere University Medical School

Kampala, Uganda

Location

Related Publications (5)

• 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.

  PMID: 22850121 RESULT

• 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.

  PMID: 34252302 DERIVED

• 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.

  PMID: 33951066 DERIVED

• Weiner M, Gelfond J, Johnson-Pais TL, Engle M, Johnson JL, Whitworth WC, Bliven-Sizemore E, Nsubuga P, Dorman SE, Savic R; Pharmacokinetics/Pharmacodynamics Group of Tuberculosis Trials Consortium. Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis. J Antimicrob Chemother. 2021 Feb 11;76(3):582-586. doi: 10.1093/jac/dkaa490.

  PMID: 33374006 DERIVED

• 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.

  PMID: 25489785 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Rifampin; rifapentine

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Susan Dorman, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Neil Schluger, MD

  Columbia University

  STUDY CHAIR

• Jason Stout, MD

  Duke University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2008
• First Posted: June 10, 2008
• Study Start: December 1, 2008
• Primary Completion: June 1, 2013
• Study Completion: December 1, 2013
• Last Updated: May 8, 2014

Record last verified: 2014-05

Locations

BR (1); UG (1); CA (2); ES (1); US (23); ZA (1)