Three Months of Weekly Rifapentine and Isoniazid for M. Tuberculosis Infection

NCT00023452 | Completed Phase 3 Results DMC

• 2 other identifiers: CDC-NCHSTP-3041CDC TBTC Study 26
• Study Type: interventional
• Target: 8,053
• Locations: 4 countries
• Sites: 26

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).

Conditions

Tuberculosis

Keywords

Latent TB infection

Outcome Measures

Primary Outcomes (1)

• 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

  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).

  Baseline up to Month 33

Secondary Outcomes (14)

• 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 Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment

  Baseline up to 33 Months

• 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])

• 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])

• Percentage of Participants With Death Due to Any Cause

  Baseline up to Month 35

Study Arms (2)

Daily Isoniazid

ACTIVE COMPARATOR

Isoniazid (INH) daily for 9 months (240 to 270 total doses).

Drug: Isoniazid (INH) daily for 9 months

Weekly Isoniazid / Rifapentine

EXPERIMENTAL

Isoniazid / Rifapentine (RPT/INH) weekly for 3 months (11 to 12 total doses) given by Directly Observed Therapy (DOT)

Drug: RPT + INH once weekly for 3 months given by DOT

Interventions

RPT + INH once weekly for 3 months given by DOT DRUG

Rifapentine (RPT) 900 mg once-weekly x 12 doses (3 months) for persons \> 50.0 kg. For persons \< 50.0 kg, the following doses will be given (Weight/Dose): 10.0-14.0 kg / 300 mg; 14.1-25.0 kg / 450 mg; 25.1-32.0 kg / 600 mg; 32.1-50.0 kg / 750 mg. PLUS Isoniazid (INH) 15 mg/kg (rounded up to nearest 50 or 100 mg; 900 mg max) once weekly x 12 doses if \> 12 years old. INH 25 mg/kg (round up to nearest 50 or 100 mg; 900 mg max) if 2-11 years old. Therapy will be given by Directly Observed Therapy (DOT).

Also known as: INH, isoniazid, I, Rifapentine, RPT, P, Priftin, 3HP, 3INH/RPT

Weekly Isoniazid / Rifapentine

Isoniazid (INH) daily for 9 months DRUG

Isoniazid (INH) 5 mg/kg (rounded up to nearest 50 or 100 mg; 300 mg max) daily x 270 doses (9 months) For children age 2 - 11, INH 10-15 mg/kg (round up to nearest 50 or 100 mg; 300 mg max) will be given.

Also known as: Isoniazid, INH, I, 9INH

Daily Isoniazid

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.
• 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.
• HIV-seropositive, TST positive (\> 5 mm induration) persons.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• US Department of Veterans Affairs: collaborator

Study Sites (26)

Central Arkansas Veterans Health System

Little Rock, Arkansas, 72205, United States

Location

LA County/USC Medical Center

Los Angeles, California, 90033, United States

Location

UCSD Medical Center

San Diego, California, 92103, United States

Location

University of California, San Francisco

San Francisco, California, 94110, United States

Location

Denver Department of Public Health and Hospitals

Denver, Colorado, 80204, United States

Location

Washington, D.C. VAMC

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

Location

Emory University, Department of Medicine

Atlanta, Georgia, 30303, United States

Location

Chicago VA Medical Center (Lakeside)

Chicago, Illinois, 60611, United States

Location

Hines VA Medical Center

Hines, Illinois, 60141, United States

Location

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21287-0003, 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 Center

New York, New York, 10037, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28203, United States

Location

Duke University Medical Center

Durham, North Carolina, 34222, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

University of North Texas Health Science Center

Fort Worth, Texas, 76107-2699, United States

Location

Michael Debakey Veterans Affairs Medical Center

Houston, Texas, 77009, 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

Universidade Federal do Rio de Janeiro

Rio de Janeiro, cep: 21941.590, Brazil

Location

University of British Columbia

Vancouver, British Columbia, Canada V5Z 4R4, Canada

Location

University of Manitoba

Winnipeg, Manitoba, CANADA R3A 1R8, Canada

Location

Montreal Chest Institute McGill University

Montreal, Quebec, H2X 2P4Pq Canada, Canada

Location

Agencia de Salut Publica

Barcelona, 08023, Spain

Location

Related Publications (9)

• 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.

  PMID: 22150035 RESULT

• Moro RN, Mehaffy C, De P, Phillips E, Borisov AS, Sterling TR, Dobos KM. Assessment for Antibodies to Rifapentine and Isoniazid in Persons Developing Flu-Like Reactions During Treatment of Latent Tuberculosis Infection. J Infect Dis. 2024 Nov 15;230(5):1271-1278. doi: 10.1093/infdis/jiae180.

  PMID: 38640958 DERIVED

• 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.

  PMID: 31690107 DERIVED

• 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.

  PMID: 29393655 DERIVED

• 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.

  PMID: 28087928 DERIVED

• 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.

  PMID: 27243774 DERIVED

• 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.

  PMID: 26951571 DERIVED

• 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.

  PMID: 25904367 DERIVED

• 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.

  PMID: 25580725 DERIVED

Related Links

• (Click here for more information about the Tuberculosis Trials Consortium(TBTC)

MeSH Terms

Conditions

Tuberculosis

Interventions

Isoniazid; rifapentine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr Elsa Villarino
• Organization: CDC

mev1@cdc.gov

404-639-5340

Study Officials

• Elsa M Villarino, MD, MPH

  Centers for Disease Control and Prevention

  STUDY DIRECTOR

• Timothy Sterling, MD

  Vanderbilt University Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2001
• First Posted: September 10, 2001
• Study Start: June 1, 2001
• Primary Completion: October 1, 2010
• Study Completion: September 1, 2013
• Last Updated: August 27, 2024
• Results First Posted: September 27, 2012

Record last verified: 2024-07

Locations

US (21); ES (1); CA (3); BR (1)