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

This study has been completed.
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:
NCT00694629
First received: June 6, 2008
Last updated: May 7, 2014
Last verified: May 2014
  Purpose

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.

Condition Intervention Phase
Pulmonary Tuberculosis
Drug: rifampin
Drug: rifapentine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: TBTC Study 29: Evaluation of a Rifapentine-containing Regimen for Intensive Phase Treatment of Pulmonary Tuberculosis

Resource links provided by NLM:


Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • time to culture-conversion [ Time Frame: 2-, 4-, 6-, and 8-week cultures (10, 20, 30, 40 doses) ] [ Designated as safety issue: No ]
  • proportion of patients with any Grade 3 or 4 adverse reactions [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • compare adverse events and 2-month culture conversion rates among HIV-infected patients vs. HIV-uninfected patients [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  • • To determine the tolerability and safety, and estimate the antimicrobial activity, of experimental regimens that include higher doses of rifapentine. [ Time Frame: 8 weeks. ] [ Designated as safety issue: Yes ]
    • 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.


Enrollment: 865
Study Start Date: December 2008
Study Completion Date: December 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
rifampin, isoniazid, pyrazinamide, ethambutol
Drug: rifampin
tablet, 10 mg/kg, daily, 8 weeks
Other Name: Rifadin
Experimental: 2
rifapentine 10 mg/kg, isoniazid, pyrazinamide, ethambutol
Drug: rifapentine
tablet, 10 mg/kg, daily, 8 weeks
Other Name: Priftin
Experimental: 3
rifapentine 15 mg/kg, isoniazid, pyrazinamide, ethambutol
Drug: rifapentine
tablet, 15 mg/kg, daily, 8 weeks
Other Name: Priftin
Experimental: 4
rifapentine 20 mg/kg, isoniazid, pyrazinamide, ethambutol
Drug: rifapentine
20 mg/kg, daily, 8 weeks
Other Name: Priftin

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00694629

  Show 29 Study Locations
Sponsors and 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
  More Information

Publications:
Responsible Party: Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier: NCT00694629     History of Changes
Other Study ID Numbers: CDC-NCHSTP-5399
Study First Received: June 6, 2008
Last Updated: May 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Centers for Disease Control and Prevention:
pulmonary tuberculosis
treatment

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Rifampin
Rifapentine
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 22, 2014