Clinical trial NCT00023452: Three Months of Weekly Rifapentine and Isoniazid for M. Tuberculosis Infection
Official title: TBTC Study 26: Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for 3 Months Versus Daily Isoniazid for 9 Months for the Treatment of Latent Tuberculosis Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
Keywords: Latent TB infection
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: US Department of Veterans Affairs
First posted: 2001-09-10
Enrollment: 8053
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: 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.

Eligibility criteria: INCLUSION criteria:

* Males or nonpregnant, non-nursing females \> 2 years old.
* Tuberculin (PPD) skin test reactors at high risk for developing TB but without evidence of active TB. High-risk reactors are defined as:

  1. Household and other close contacts of persons with culture-confirmed TB who are TST-positive as part of a contact investigation conducted within two years of the date of enrollment. Close contact is defined as \> 4 hours in a shared airspace during a one-week period. Among close contacts, a positive TST is defined as \> 5 mm induration after 5 TU of PPD placed intradermally using the Mantoux technique.
  2. TST converters--converting from a documented negative to positive TST within a two-year period. This is defined as persons with a tuberculin skin test of \> 10 mm within two years of a nonreactive test or persons with an increase of \> 10 mm within a two-year period.
  3. HIV-seropositive, TST positive (\> 5 mm induration) persons.
  4. Persons with \> 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray, no prior history of TB treatment, \> 5 mm induration on TST, and 3 sputum cultures negative for M. tuberculosis on final report.
* HIV-seropositive close contacts of persons with culture-confirmed TB, regardless of TST status. In addition, HIV-seropositive close contacts of persons with culture-confirmed TB who have a documented history of completing an adequate course of treatment for active TB or latent TB infection, are also eligible.
* Willing to provide signed informed consent, or parental consent and participant assent.

EXCLUSION criteria:

* Current confirmed culture-positive or clinical TB
* Suspected TB (as defined by the site investigator)
* Tuberculosis resistant to isoniazid or rifampin in the source case
* A history of treatment for \> 14 consecutive days with a rifamycin or \> 30 consecutive days with INH during the previous 2 years.
* A documented history of a completing an adequate course of treatment for active TB or latent TB infection in a person who is HIV-seronegative.
* History of sensitivity/intolerance to isoniazid or rifamycins
* Serum aminotransferase aspartate (AST, SGOT) \> 5x upper limit of normal among persons in whom AST is determined
* Pregnant or nursing females
* Persons currently receiving or planning to receive HIV-1 protease inhibitors or nonnucleoside reverse transcriptase inhibitors in the first 90 days after enrollment.
* Weight \< 10.0 kg

Primary outcomes:
measure: 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
timeFrame: Baseline up to Month 33
Secondary outcomes:
measure: 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
timeFrame: Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)
measure: Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment
timeFrame: Baseline up to 33 Months
measure: Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH
timeFrame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])
measure: Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH
timeFrame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])
measure: Percentage of Participants With Death Due to Any Cause
timeFrame: Baseline up to Month 35
measure: Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone
timeFrame: Baseline to Month 33
measure: Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH
timeFrame: Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)
measure: Percentage of Participants Who Completed the Treatment Regimen
timeFrame: Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)
measure: 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
timeFrame: Baseline up to Month 33
measure: Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment
timeFrame: Baseline up to Month 33
measure: Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment
timeFrame: Baseline to Month 33
measure: Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy
timeFrame: Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)
measure: Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
timeFrame: Baseline up to Month 33
measure: Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
timeFrame: Baseline up to Month 33
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: San Diego
country: United States
facility: UCSD Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: Denver Department of Public Health and Hospitals
state: Colorado
city: Washington
country: United States
facility: Washington, D.C. VAMC
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University, Department of Medicine
state: Georgia
city: Chicago
country: United States
facility: Chicago VA Medical Center (Lakeside)
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 Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Houston
country: United States
facility: Michael Debakey Veterans Affairs 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: Universidade Federal do Rio de Janeiro
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Montreal Chest Institute McGill University
state: Quebec
city: Barcelona
country: Spain
facility: Agencia de Salut Publica
Study officials:
affiliation: Centers for Disease Control and Prevention
name: Elsa M Villarino, MD, MPH
role: STUDY_DIRECTOR
affiliation: Vanderbilt University Medical Center
name: Timothy Sterling, MD
role: STUDY_CHAIR
References:
citation: Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, Hackman J, Hamilton CD, Menzies D, Kerrigan A, Weis SE, Weiner M, Wing D, Conde MB, Bozeman L, Horsburgh CR Jr, Chaisson RE; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155-66. doi: 10.1056/NEJMoa1104875.
citation: Hedges KNC, Borisov AS, Saukkonen JJ, Scott NA, Hecker EJ, Bozeman L, Dukes Hamilton C, Kerrigan A, Bessler P, Moreno-Martinez A, Arevalo B, Goldberg SV. Nonparticipation reasons in a randomized international trial of a new latent tuberculosis infection regimen. Clin Trials. 2020 Feb;17(1):39-51. doi: 10.1177/1740774519885380. Epub 2019 Nov 6.
citation: Moro RN, Scott NA, Vernon A, Tepper NK, Goldberg SV, Schwartzman K, Leung CC, Schluger NW, Belknap RW, Chaisson RE, Narita M, Machado ES, Lopez M, Sanchez J, Villarino ME, Sterling TR. Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials. Ann Am Thorac Soc. 2018 May;15(5):570-580. doi: 10.1513/AnnalsATS.201704-326OC.
citation: Moro RN, Sterling TR, Saukkonen J, Vernon A, Horsburgh CR, Chaisson RE, Hamilton CD, Villarino ME, Goldberg S. Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial. Int J Tuberc Lung Dis. 2017 Mar 1;21(3):286-296. doi: 10.5588/ijtld.16.0469. Epub 2017 Jan 13.
citation: Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, Chen MP, Benator DA, Gordin F, Benson CA, Chaisson RE, Villarino ME; Tuberculosis Trials Consortium, the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26ACTG 5259) The investigators of the TB Trials Consortium and the AIDS Clinical Trials Group for the PREVENT TB Trial are listed in the Supplement, item 17. Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS. 2016 Jun 19;30(10):1607-15. doi: 10.1097/QAD.0000000000001098.
citation: Moro RN, Borisov AS, Saukkonen J, Khan A, Sterling TR, Villarino ME, Scott NA, Shang N, Kerrigan A, Goldberg SV. Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada. Clin Infect Dis. 2016 Jun 1;62(11):1390-1400. doi: 10.1093/cid/ciw126. Epub 2016 Mar 6.
citation: Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consortium. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Infect Dis. 2015 Aug 15;61(4):527-35. doi: 10.1093/cid/civ323. Epub 2015 Apr 22.
citation: Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro RN, Shang N, Goldberg SV, Sterling TR; International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015 Mar;169(3):247-55. doi: 10.1001/jamapediatrics.2014.3158.