Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine Given Daily for LTBI
Six Weeks of Daily Rifapentine vs. a Comparator Arm of 12-16 Week Rifamycin-based Treatment of Latent M. Tuberculosis Infection: Assessment of Safety, Tolerability and Effectiveness
Centers for Disease Control and Prevention
3,400 participants
Aug 1, 2019
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria6
- Pregnant women in their second or third trimester (≥14 weeks gestation).
- Stage 1: Include only those who agree to participate in the semi-intensive PK component.
- Stage 2: Include regardless of semi-intensive PK component participation.
- Children aged less than 12 years
- Stage 1: Include only those who agree to participate in the semi-intensive PK component, based on enrollment strategy presented in Appendix I.
- Stage 2: Include regardless of semi-intensive PK component participation, based on PK findings and enrollment strategy described in Appendix I.
Exclusion Criteria25
- Household and other close contacts (> 4 hours of exposure in a one-week period) within 2 years prior to enrollment, of persons with bacteriologically confirmed TB.
- o Acceptable testing approaches for bacteriologic confirmation are 1) culture with rifamycin DST; or, 2) nucleic acid amplification tests (NAATs) that detect M. tuberculosis and detect mutations associated with rifamycin resistance. Additional details on bacteriologic confirmation, including accepted NAATs, will be included in the MOOP.
- 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. Additional guidance and definitions of conversion are in the MOOP.
- 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 3 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 (see Appendix D) and either a positive IGRA or a TST ≥15 mm (TST > 15 mm only applicable for those with recent immigration as their only risk factor for progression to TB).
- Recent (within 3 years prior to enrollment) immigration and seeking refugee/asylum status (see MOOP for additional details) to the United States or other country with low to moderate incidence from a country with an estimated incidence rate of TB > 75 per 100,000 (see Appendix E) and either a positive IGRA or a TST ≥15 mm (TST > 15 mm only applicable for those with recent immigration as their only risk factor for progression to TB).
- Individuals with an increased risk of TB due to medical conditions such as end-stage renal disease.
- Individuals currently using immunosuppressive medications such as chronic steroids.
- Individuals with planned use of TNF-α inhibitors.
- Individuals with planned solid organ or hematologic transplantation
- Willing to provide signed informed consent, or parental permission and participant assent.
- Failure to document positive IGRA or TST
- Current breastfeeding.
- Women who are currently pregnant in their first trimester (<14 weeks gestation) or intend to become pregnant within 120 days of enrollment.
- Non-pregnant women of childbearing potential who refuse to practice an adequate method of contraception (barrier method or non-hormonal intrauterine device) or abstain from activities that could lead to pregnancy.
- Current culture-positive TB, clinical TB, or suspected current TB. (Includes cases in which active TB cannot be excluded with reasonable clinical certainty by the site investigator. If sputum samples have been collected AND site investigators have suspicion of active TB, site investigators must wait to review culture results prior to enrollment.)
- TB resistant to any rifamycin in the source case
- A history of treatment for > 7 consecutive days (if daily dosing) with a rifamycin or >1 week (if weekly dosing) with a rifamycin and INH 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 screening ALT or AST is determined.
- Receiving concomitant medications that are known to be contraindicated with any study drug.
- Weight < 25 kg for participants ≥ 12 years, and weight < 3kg for participants < 12 years
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
600 mg of Rifapentine (RPT) given once daily (o.d., omni die) for 6 weeks (6wP).
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).
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).
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.
Locations(21)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT03474029