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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 3,400
- 试验地点
- 30
- 主要终点
- Treatment discontinuation due to adverse drug reaction
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Persons with LTBI who do not have evidence of TB disease (see
排除标准
- •) and are at increased risk of progression to TB. LTBI or 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). Details of testing definitions and requirements for each risk factor are further described in the MOOP. Persons with LTBI at increased risk of progression to TB are those with at least 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 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.
- •For the following special populations, both inclusion criteria above must be met AND the criteria below depending on stage:
- •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 Criteria
- •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
研究组 & 干预措施
6 weeks of daily rifapentine (6wP)
Rifapentine daily for 6 weeks: 600 mg of Rifapentine (RPT) given once daily for 6 weeks
干预措施: Rifapentine daily for 6 weeks (Drug)
12-16 week rifamycin-based regimen
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)
干预措施: Rifapentine and Isoniazid weekly for 12 weeks (Drug)
12-16 week rifamycin-based regimen
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)
干预措施: Rifampin and Isoniazid daily for 12 weeks (Drug)
12-16 week rifamycin-based regimen
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)
干预措施: Rifampin daily for 16 weeks (Drug)
结局指标
主要结局
Treatment discontinuation due to adverse drug reaction
时间窗: from the date of enrollment to the date of scheduled completion of assigned treatment
1\. Safety: Drug discontinuation due to adverse drug reaction (ADR) associated with 6wP and the rifamycin-based comparator arm (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.
Culture-confirmed tuberculosis (TB) in participants 18 years old and older and culture-confirmed or clinical TB in participants less then 18 years old.
时间窗: within 24 months from the date of enrollment
2\. Effectiveness: Culture-confirmed TB in participants \> 18 years old and culture-confirmed or clinical TB in participants \< 18 years old. * Diagnosis of culture-confirmed TB will be performed using liquid and/or solid media. * An independent, blinded adjudication panel will review all TB events.
次要结局
- Proportion with TB among those who complete assigned therapy(within 24 months from the date of enrollment)
- 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 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)
- Proportion with culture-confirmed or clinical TB regardless of age(within 24 months from the date of enrollment)
- Safety (defined as treatment discontinuation due to adverse drug reaction) among participants with human immunodeficiency virus (HIV) infection.(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)
- Safety (defined as treatment discontinuation due to adverse drug reaction) among participants < 18 years old.(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)
- Tolerability (defined as proportion of with drug discontinuation for any reason) among participants with human immunodeficiency virus (HIV) infection.(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)
- Tolerability (defined as proportion of with drug discontinuation for any reason) among participants < 18 years old.(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 among participants with human immunodeficiency virus (HIV) infection.(within 24 months from the date of enrollment)
- Effectiveness among participants < 18 years old.(within 24 months from the date of enrollment)
- 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 any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug(within 6 months from the date of enrollment)
- Proportion of Participants Who Complete Assigned Study 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 of Participants Who Die From Any Cause(within 24 months from the date of enrollment)
- Proportion of Participants With Hepatotoxicity or Non-Hepatotoxic Systemic Drug Reactions(within 6 months from the date of enrollment)
- Proportion of Participants with Culture-Confirmed or Clinical Tuberculosis (TB)(within 24 months from the date of enrollment)
- Proportion of Participants Who Develop Tuberculosis (TB) Among Those Who Complete Assigned Study Treatment(within 24 months from the date of enrollment)
- Proportion of Participants With HIV Infection Who Discontinue Study Treatment Due to Adverse Drug Reactions(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 during the time period of 6 months after enrollment(within 6 months from the date of enrollment)
- Effectiveness among pregnant participants(within 24 months from the date of enrollment)
- Safety (defined as treatment discontinuation due to adverse drug reaction) among pregnant participants.(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)
- Tolerability (defined as proportion of with drug discontinuation for any reason) among pregnant participants(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)