Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine Given Daily for LTBI

NCT03474029 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: CDC-NCHSTP-7024
• Study Type: interventional
• Target: 3,400
• Locations: 4 countries
• Sites: 16

Brief Summary

This study is conducted to compare the safety and effectiveness of a novel short 6-week regimen of daily rifapentine (6wP, experimental arm) with a comparator arm of 12-16 weeks of rifamycin-based treatment (standard of care, control arm) of latent M. tuberculosis infection (LTBI). This trial is conducted among persons who are at increased risk of progression to tuberculosis (TB) and require treatment of LTBI. The study will be conducted in low, medium and high TB incidence settings that have treatment of LTBI as their standard of care and offer 12-16 week rifamycin-based therapy as standard of care. The hypothesis of this study is that the safety and effectiveness of the experimental treatment (6wP arm) is non-inferior to a comparator arm of 12-16 weeks of rifamycin-based treatment of LTBI (control arm). Participants are enrolled and randomly assigned to one of the two study arms: experimental 6wP or control. The comparator (control) arm's treatment regimens include 12 weeks of once-weekly isoniazid (INH) and rifapentine (3HP), 12 weeks of daily INH and rifampin (3HR), and 16 weeks of daily rifampin (4R). A total of 560 participants per arm (1,120 total) for the evaluation of safety and 1,700 participants per arm (3,400 total) for the evaluation of effectiveness will be enrolled, given treatment as per randomization assignment, and followed for 24 months from the date of enrollment. After completion of data collection, statistical analyses will be conducted to compare proportions of drug discontinuation due to adverse drug reaction (ADR) and proportions of newly diagnosed tuberculosis between 6wP and control arm.

Conditions

Latent Tuberculosis

Keywords

latent tuberculosis; rifapentine

Outcome Measures

Primary Outcomes (2)

• Treatment discontinuation due to adverse drug reaction

  Safety outcome. Drug discontinuation due to adverse drug reaction (ADR) associated with experimental treatment (6wP) or active comparator treatment (the rifamycin-based 3HP, 3HR, or 4R). Attribution of an adverse event (AE) to study drugs will be initially determined by the local site investigator, reviewed by an independent, blinded adjudication panel and with final attribution determined by the sponsor.

  from the date of enrollment to the date of scheduled completion of assigned treatment

• Culture-confirmed tuberculosis (TB) in participants 18 years old and older and culture-confirmed or clinical TB in participants less then 18 years old.

  Effectiveness outcome. Culture-confirmed tuberculosis (TB) in participants 18 years old and older and culture-confirmed or clinical TB in participants less then 18 years old. Diagnosis of culture-confirmed TB will be performed using liquid and/or solid media methods.

  within 24 months from the date of enrollment

Secondary Outcomes (13)

• Proportion who complete assigned treatment

  from date of enrollment until the maximum accepted time for treatment completion as follows: 9 weeks for 6wP treatment, 16 weeks for 3HP, 16 weeks for 3HP, and 21 weeks for 4R

• Proportion with drug discontinuation for any reason

  from date of enrollment until the maximum accepted time for treatment completion as follows: 9 weeks for 6wP treatment, 16 weeks for 3HP, 16 weeks for 3HP, and 21 weeks for 4R

• Proportion with any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug

  within 6 months from the date of enrollment

• Proportion who have died for any reason

  within 24 months from the date of enrollment

• Proportion with hepatitis and non-hepatotoxic systemic drug reactions

  within 6 months from the date of enrollment

Other Outcomes (4)

• Proportions of drug discontinuation due to adverse drug reactions in experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R

  from date of enrollment until the maximum accepted time for treatment completion as follows: 9 weeks for 6wP treatment, 16 weeks for 3HP, 16 weeks for 3HP, and 21 weeks for 4R

• Proportions of treatment discontinuations for any reason in experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R

  from date of enrollment until the maximum accepted time for treatment completion as follows: 9 weeks for 6wP treatment, 16 weeks for 3HP, 16 weeks for 3HP, and 21 weeks for 4R

• Effectiveness of experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R

  within 24 months from the date of enrollment

Study Arms (2)

6 weeks of daily rifapentine (6wP)

EXPERIMENTAL

Rifapentine daily for 6 weeks: 600 mg of Rifapentine (RPT) given once daily for 6 weeks

Drug: Rifapentine daily for 6 weeks

12-16 week rifamycin-based regimen

ACTIVE COMPARATOR

A 12-16 week rifamycin-based regimen available at the participant's site: "Rifapentine and Isoniazid weekly for 12 weeks" (3HP) or "Rifampin and Isoniazid daily for 12 weeks" (3HR) or "Rifampin daily for 16 weeks" (4R)

Drug: Rifapentine and Isoniazid weekly for 12 weeks; Drug: Rifampin and Isoniazid daily for 12 weeks; Drug: Rifampin daily for 16 weeks

Interventions

Rifapentine daily for 6 weeks DRUG

600 mg of Rifapentine (RPT) given once daily (o.d., omni die) for 6 weeks (6wP).

Also known as: priftin

6 weeks of daily rifapentine (6wP)

Rifapentine and Isoniazid weekly for 12 weeks DRUG

Rifapentine (RPT) 900 mg and isoniazid (INH) 900 mg given once-weekly for 12 weeks (3HP).\* \*Dose adjustments based on patient's weight will be made according to ATS/CDC/IDSA guidelines. RPT 900 mg once-weekly for persons weighing \> 50 kg. For persons weighing \< 50 kg, the following doses will be given: weight \> 25-32 kg - RPT 600 mg; weight \> 32-50 kg - RPT 750 mg; + INH 15 mg/kg (round up to nearest 50 or 100 mg; 900 mg max).

12-16 week rifamycin-based regimen

Rifampin and Isoniazid daily for 12 weeks DRUG

Rifampin (RIF) 600 mg and Isoniazid (INH) 300 mg given once-daily for 12 weeks (3HR)\*. \*Dose adjustments based on patient's weight will be made according to ATS/CDC/IDSA guidelines. RIF 600 mg daily for persons weighing \> 50 kg. For persons weighing \< 50 kg, give 10 mg/kg daily; round up to nearest 50 or 100 mg; + INH 5 mg/kg daily (rounded up to nearest 50 or 100 mg; 300 mg max).

12-16 week rifamycin-based regimen

Rifampin daily for 16 weeks DRUG

Rifampin (RIF) 600 mg given once-daily for 16 weeks (4R).\* \*Dose adjustments based on patient's weight will be made according to ATS/CDC/IDSA guidelines. RIF 600 mg daily for persons weighing \> 50 kg. For persons weighing \< 50 kg, 10 mg/kg daily; round up to nearest 50 or 100 mg.

12-16 week rifamycin-based regimen

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or non-pregnant, non-breastfeeding females \> 12 years old. Women of child-bearing potential who are not surgically sterilized must agree to practice an adequate method of contraception (barrier method or non-hormonal intrauterine device) or abstain from heterosexual intercourse during study drug treatment.
• Persons with LTBI who do not have evidence of TB disease and are at increased risk of progression to TB. M. tuberculosis infection may be demonstrated by either a positive tuberculin skin test (TST) or a positive interferon gamma release assay (IGRA; e.g., QuantiFERON or T.SPOT.TB). Persons with LTBI at increased risk of progression to TB are those with one of the following:
• Household and other close contacts (\> 4 hours of exposure in a one week period) within 2 years prior to enrollment, of persons with culture-confirmed TB A positive nucleic acid amplification test (NAAT)/GeneXpert in the source case may be used for enrollment prior to culture confirmation
• Recent M. tuberculosis infection, defined as converting from a documented negative to positive TST or IGRA within 2 years prior to enrollment. Persons without known close contact to someone with active pulmonary TB who have a conversion by IGRA may require additional evaluation to rule out a false conversion.
• HIV co-infection (with CD4+ T-lymphocyte count \> 100 cells/mm3).
• ≥ 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray and no prior history of treatment for TB or LTBI.
• Recent (within 3 years prior to enrollment) immigration to the United States or other country with low to moderate TB incidence, with abnormal chest X-ray, and no evidence of active TB.
• Recent (within 2 years prior to enrollment) immigration to the United States or other country with low to moderate TB incidence, from a country with an estimated incidence rate of TB \> 150 per 100,000
• An increased risk of TB due to medical conditions such as end-stage renal disease, or due to use of immunosuppressive medications such as chronic steroids or TNF-alpha inhibitors.
• Willing to provide signed informed consent, or parental permission and participant assent.

You may not qualify if:

• Current confirmed culture-positive or clinical TB.
• Suspected current TB. Includes cases in which active TB cannot be eliminated as a possibility (by the site investigator)
• TB resistant to any rifamycin in the source case
• A history of treatment for \> 7 consecutive days with a rifamycin or \> 30 consecutive days with INH within 2 years prior to enrollment.
• A documented history of completing an adequate course of treatment for TB disease or LTBI in a person who is HIV-seronegative.
• History of allergy or intolerance to rifamycins.
• Serum alanine aminotransferase (ALT; SGPT) or serum aspartate aminotransferase (AST; SGOT) \> 5x upper limit of normal among persons in whom baseline ALT or AST is determined+.
• HIV-seropositive and on antiretroviral therapy that cannot be given with rifampin or rifapentine due to drug-drug interactions.
• Receiving concomitant medications that are known to be contraindicated with any study drug.
• Females who are currently pregnant, breastfeeding, or intend to become pregnant within 120 days of enrollment.
• Weight \< 25 kg.

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead

Study Sites (16)

Denver Health and Hospital Authority

Denver, Colorado, 80204, United States

RECRUITING

George Washington University

Washington D.C., District of Columbia, 20001, United States

RECRUITING

Washington DC VA Medical Center

Washington D.C., District of Columbia, 20001, United States

RECRUITING

New York Harbor Healthcare System

Manhattan, New York, 10001, United States

RECRUITING

New York City Bureau of TB Control

New York, New York, 11201, United States

RECRUITING

San Antonio VA

San Antonio, Texas, 78201, United States

RECRUITING

Seattle King County Health Department

Seattle, Washington, 98101, United States

RECRUITING

Liverpool Hospital

Sydney, Australia

RECRUITING

Paramatta Chest

Sydney, Australia

RECRUITING

Royal Prince Alfred Hospital

Sydney, Australia

RECRUITING

Calgary TB Clinic

Calgary, Alberta, T1Y 6H6, Canada

RECRUITING

Edmonton TB Clinic

Edmonton, Alberta, Canada

RECRUITING

British Columbia Centre for Disease Control

Vancouver, British Columbia, Canada

RECRUITING

Toronto Western Hospital

Toronto, Ontario, M5P 1N5, Canada

RECRUITING

McGill University Health Centre

Montreal, Quebec, H3A 0G4, Canada

RECRUITING

Desmond Tutu TB Center

Stellenbosch, South Africa

NOT YET RECRUITING

Related Links

• Tuberculosis Trials Consortium (TBTC)

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

rifapentine; Rifampin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Timothy Sterling, MD

  Vanderbilt University Medical Center, USA

  STUDY CHAIR

• Robert Belknap, MD

  Denver Public Health (USA)

  STUDY CHAIR

• Amber Robinson, PhD

  Centers for Disease Control and Prevention

  STUDY DIRECTOR

• Rosanna M Boyd, PhD

  Centers for Disease Control (USA)

  STUDY DIRECTOR

• Dick Menzies, MD

  McGill University

  STUDY CHAIR

Central Study Contacts

Rosanna M Boyd, PhD

CONTACT

+1 (404)-553-7434; icg7@cdc.gov

TBTC Research Administrator

CONTACT

+1 (800)-232-4636; tbtcresearchadmin@cdc.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2018
• First Posted: March 22, 2018
• Study Start: August 1, 2019
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: September 26, 2024

Record last verified: 2024-09

Locations

ZA (1); CA (5); AU (3); US (7)