Three Months of Weekly Rifapentine and Isoniazid for M. Tuberculosis Infection
- Conditions
- Tuberculosis
- Interventions
- Drug: RPT + INH once weekly for 3 months given by DOT
- Registration Number
- NCT00023452
- Lead Sponsor
- Centers for Disease Control and Prevention
- Brief Summary
Open-label, multi-center, Phase III clinical trial to compare the effectiveness and tolerability of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose)regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI).
- Detailed Description
The PRIMARY objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered.
SECONDARY Objectives:
* Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.
* Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH.
* Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH.
* Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH.
* Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons.
* Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children \< 18 years old.
* Compare the rates of methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone.
* Describe patterns of antibiotic resistance among M. tuberculosis isolates in patients who develop TB despite treatment of latent infection.
Amendment of the study protocol to allow extension of enrollment to children \< 12 years old and HIV-infected persons:
For assessment of the primary outcome, development of TB, a sample size of approximately 4,000 persons per arm will be required. To assess tolerability (one of the secondary outcomes) in sub-groups, children less than 12 years old and HIV-infected persons, a sample size of 644 per strata will be required. A sample size of 8,053 patients for the primary outcome was reached on February 15, 2008 (with expected follow-up completion time in 2010), leaving approximately 454 additional young children and 200 HIV-infected persons to be enrolled to achieve the targets of 644 for each group. The additional data on tolerability in those sub-groups will available for analysis in 2013.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 8053
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Weekly Isoniazid / Rifapentine RPT + INH once weekly for 3 months given by DOT Isoniazid / Rifapentine (RPT/INH) weekly for 3 months (11 to 12 total doses) given by Directly Observed Therapy (DOT) Daily Isoniazid Isoniazid (INH) daily for 9 months Isoniazid (INH) daily for 9 months (240 to 270 total doses).
- Primary Outcome Measures
Name Time Method Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants Less Than [<]18 Years of Age at 33 Months After Enrollment Baseline up to Month 33 Cumulative TB disease rate defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for Mycobacterium tuberculosis \[MTB\]) and those \<18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, computed tomography \[CT\] scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for acid-fast bacilli \[AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants with (w/)33 months of follow-up calculated using survival analysis methods (Kaplan-Meier approach).
- Secondary Outcome Measures
Name Time Method Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment Baseline up to 33 Months Cumulative TB disease rate was defined as number of participants (regardless of age) with culture-confirmed TB disease (defined as positive culture for MTB\]) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB, or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants <18 Years of Age at 24 Months Following Completion of Study Therapy Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH) Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and those \<18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment Baseline to Month 33 Cumulative TB disease rate was defined as number of HIV-infected participants ≥2 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH]) Discontinuation of study drug due to an adverse drug reaction associated with either 3RPT/INH or 9INH was defined as discontinuing treatment and/or study due to a treatment-related adverse event (AE) (considered either possibly, probably, or definitely related to the study drug by the investigator).
Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH]) Drug toxicities (or AEs) were graded using Common Toxicity Criteria (CTC version 2.0, Publish Date April 30, 1999, Cancer Therapy Evaluation Program). Grade 3 and 4 drug toxicities associated with 3RPT/INH or 9INH were defined as treatment-related Grade 3 or 4 AEs (considered either possibly, probably, or definitely related to the study drug by the investigator).
Percentage of Participants With Death Due to Any Cause Baseline up to Month 35 Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH) Drug discontinuations for any reason associated with 3RPT/INH or 9INH included all reasons for discontinuation from study treatment, regardless of relationship to treatment.
Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone Baseline to Month 33 Among participants concomitantly receiving methadone, the development of methadone withdrawal (defined as having \>3 new symptoms for \>7 days: nausea and vomiting, abdominal cramps, body aches, restlessness, irritability, dilated pupils, tremors, involuntary twitching, lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose flesh, or diarrhea).
Percentage of Participants Who Completed the Treatment Regimen Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH) Completion in the 3RPT/INH arm was defined as: received 12 doses of RPT/INH within 16 weeks (12 weeks optimal). However, participants were considered to have completed therapy if at least 11 doses of RPT/INH had been received (\~90%) during the 16-week time period. Completion in the 9INH arm was defined as: received 270 doses of INH within 52 weeks (39 weeks optimal). However, participants were considered to have completed therapy if at least 240 doses of INH were received (\~90%) during the 52-week period.
Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture Confirmed or Probable (Clinical) TB Disease Among Participants <18 Years of Age Who Completed Study Phase Therapy Within 33 Months of Enrollment Baseline up to Month 33 Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and \<18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and 33 months after enrollment (for those who completed therapy within 33 months) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment Baseline up to Month 33 Drug-susceptibility testing (DST) was performed on isolates of MTB obtained from participants who developed signs and symptoms of active TB disease (including sputum specimens or specimens from appropriate body site for extrapulmonary TB disease). DST was performed at site's local laboratory and sent to Sponsor for confirmatory susceptibility testing. DST included all drugs currently used to treat TB disease, including pyrazinamide (PZA) and fluoroquinolones. Susceptibility was tested for other drugs at the Sponsor laboratory at the following concentrations: INH, 0.02, 1.0, and 5.0 micrograms per milliliter (µg/mL) and rifampin (RIF), 1.0 µg/mL. Isolates resistant to RIF were assumed to be resistant to RPT.
Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH) Cumulative TB disease rate was defined as number of HIV-infected participants with culture-confirmed TB (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment Baseline up to Month 33 Cumulative TB disease rate was defined as number of participants \<18 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment Baseline up to Month 33 Cumulative TB disease rate was defined as number of participants \<12 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease \[cough, fever, night sweats, weight loss, or hemoptysis\] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB\], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Trial Locations
- Locations (26)
Chicago VA Medical Center (Lakeside)
🇺🇸Chicago, Illinois, United States
Michael Debakey Veterans Affairs Medical Center
🇺🇸Houston, Texas, United States
Seattle King County Health Department
🇺🇸Seattle, Washington, United States
UCSD Medical Center
🇺🇸San Diego, California, United States
Audi L. Murphy VA Hospital
🇺🇸San Antonio, Texas, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
University of British Columbia
🇨🇦Vancouver, British Columbia, Canada
Denver Department of Public Health and Hospitals
🇺🇸Denver, Colorado, United States
Montreal Chest Institute McGill University
🇨🇦Montreal, Quebec, Canada
LA County/USC Medical Center
🇺🇸Los Angeles, California, United States
Central Arkansas Veterans Health System
🇺🇸Little Rock, Arkansas, United States
Washington, D.C. VAMC
🇺🇸Washington, District of Columbia, United States
Emory University, Department of Medicine
🇺🇸Atlanta, Georgia, United States
Hines VA Medical Center
🇺🇸Hines, Illinois, United States
New Jersey Medical School
🇺🇸Newark, New Jersey, United States
Columbia University/Presbyterian Medical Center
🇺🇸New York, New York, United States
Harlem Hospital Center
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
University of North Texas Health Science Center
🇺🇸Fort Worth, Texas, United States
University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Universidade Federal do Rio de Janeiro
🇧🇷Rio de Janeiro, Brazil
Agencia de Salut Publica
🇪🇸Barcelona, Spain