Clinical trial NCT00694629: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Keywords: pulmonary tuberculosis
treatment
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: Sanofi
First posted: 2008-06-10
Enrollment: 865
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: The proportion of patients, by regimen, having negative sputum cultures at completion of eight weeks (40 doses) of treatment
timeFrame: completion of eight weeks (40 doses) of treatment
measure: The proportion of patients, by regimen, who permanently discontinue the assigned study treatment for any reason during the first eight weeks
timeFrame: during the first eight weeks of treatment
Secondary outcomes:
measure: time to culture-conversion
timeFrame: 2-, 4-, 6-, and 8-week cultures (10, 20, 30, 40 doses)
measure: proportion of patients with any Grade 3 or 4 adverse reactions
timeFrame: 8 weeks
measure: correlation of the MGIT/BACTEC liquid culture growth index and other mycobacterial and clinical biomarkers with time to culture conversion and treatment failure
timeFrame: duration of TB treatment
measure: compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients
timeFrame: 8 weeks
measure: • To determine the tolerability and safety, and estimate the antimicrobial activity, of experimental regimens that include higher doses of rifapentine.
timeFrame: 8 weeks.
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Central Arkansas Veterans Health System
state: Arkansas
city: Los Angeles
country: United States
facility: LA County/USC Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California Medical Center
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francincisco
state: California
city: Denver
country: United States
facility: Denver Department of Public Health and Hospitals
state: Colorado
city: Washington DC
country: United States
facility: Washington DC Veterans Administration Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Chicago VA Medical Center (Lakeside)
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Hines
country: United States
facility: Hines VA Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Newark
country: United States
facility: New Jersey Medical School
state: New Jersey
city: New York
country: United States
facility: Columbia University/Presbyterian Medical Center
state: New York
city: New York
country: United States
facility: Harlem Hospital, Columbia University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Nashville VA Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Veterans Administration Tennessee Valley Health Care System
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Houston
country: United States
facility: Houston Veterans Administration Medical Center
state: Texas
city: San Antonio
country: United States
facility: Audi L. Murphy VA Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle King County Health Department
state: Washington
city: Rio de Janeiro
country: Brazil
facility: Hopital Universitario Clementino Fraga Filho
city: Winnepeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Montreal Chest Institute McGill University
state: Quebec
city: Durban
country: South Africa
facility: Nelson R Mandela School of Medicine
state: KwaZulu Natal
city: Barcelona
country: Spain
facility: Agencia de Salut Publica
city: Kampala
country: Uganda
facility: Makerere University Medical School
Study officials:
affiliation: Johns Hopkins University
name: Susan Dorman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Neil Schluger, MD
role: STUDY_CHAIR
affiliation: Duke University
name: Jason Stout, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.