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NCT Number: NCT03474029

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

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.

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Key information

Conditions

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

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Liverpool Hospital, Sydney, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Persons with LTBI who do not have evidence of TB disease (see exclusion criteria) 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

Treatment and study plan

Rifapentine daily for 6 weeks

Drug

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

Other names: priftin

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).

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).

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.

Primary outcomes

  1. Treatment discontinuation due to adverse drug reaction

    Time frame: from the date of enrollment to the date of scheduled completion of assigned treatment

    • 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.

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

    Time frame: within 24 months from the date of enrollment

    • 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.

Secondary outcomes

  1. Proportion who complete assigned treatment

    Time frame: 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 complete assigned study treatment during the study period. Treatment completion is defined as taking at least 90% of the prescribed doses within the protocol-defined time period.

  2. Proportion of Participants Who Complete Assigned Study Treatment

    Time frame: 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 complete assigned study treatment during the study period. Treatment completion is defined as taking at least 90% of the prescribed doses within the protocol-defined time period.

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

    Time frame: within 6 months from the date of enrollment

    Proportion of participants who experience at least one Grade 3, 4, or 5 adverse event related to study drug during the study period. Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death). Relationship to study drug will be determined by the site investigator and reviewed by an independent blinded adjudication panel.

  4. Proportion of Participants Who Die From Any Cause

    Time frame: within 24 months from the date of enrollment

    Proportion of participants who die from any cause during the study period. Deaths will be ascertained through participant follow-up, medical records, or death registries and reviewed by an independent blinded adjudication panel.

  5. Proportion of Participants With Hepatotoxicity or Non-Hepatotoxic Systemic Drug Reactions

    Time frame: within 6 months from the date of enrollment

    Proportion of participants who experience at least one event of hepatotoxicity or non-hepatotoxic systemic drug reaction during the study period. Hepatotoxicity and systemic drug reactions will be defined per protocol and graded using Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Relationship to study drug will be determined by the investigator.

  6. Proportion of Participants with Culture-Confirmed or Clinical Tuberculosis (TB)

    Time frame: within 24 months from the date of enrollment

    Proportion of participants who develop culture-confirmed or clinical tuberculosis (TB) during the study period, regardless of age. Culture-confirmed TB will be based on microbiological confirmation using liquid and/or solid culture methods. Clinical TB will be defined according to protocol-specified diagnostic criteria and adjudicated by an independent blinded panel.

  7. Proportion of Participants Who Develop Tuberculosis (TB) Among Those Who Complete Assigned Study Treatment

    Time frame: within 24 months from the date of enrollment

    Proportion of participants who develop tuberculosis (TB) among those who complete assigned study treatment during the study period. Completion of treatment is defined per protocol. TB will be defined as culture-confirmed or clinical TB based on microbiological or protocol-specified clinical criteria and reviewed by an independent blinded adjudication panel.

  8. Proportion of Participants With HIV Infection Who Discontinue Study Treatment Due to Adverse Drug Reactions

    Time frame: 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 HIV-infected patients with 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 determined by the local site investigator.

  9. Safety (defined as treatment discontinuation due to adverse drug reaction) among participants < 18 years old.

    Time frame: 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 < 18 years old with 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 determined by the local site investigator.

  10. Tolerability (defined as proportion of with drug discontinuation for any reason) among participants with human immunodeficiency virus (HIV) infection.

    Time frame: 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 HIV-infected patients with drug discontinuation for any reason

  11. Tolerability (defined as proportion of with drug discontinuation for any reason) among participants < 18 years old.

    Time frame: 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 < 18 years old with drug discontinuation for any reason

  12. Effectiveness among participants with human immunodeficiency virus (HIV) infection.

    Time frame: within 24 months from the date of enrollment

    Proportion of HIV-infected patients with 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.

  13. Effectiveness among participants < 18 years old.

    Time frame: within 24 months from the date of enrollment

    Proportion of participants < 18 years old with culture-confirmed tuberculosis or clinical TB. Diagnosis of culture-confirmed TB will be performed using liquid and/or solid media methods.

  14. Proportion with any grade 3, 4, or 5 (i.e., death) adverse event during the time period of 6 months after enrollment

    Time frame: within 6 months from the date of enrollment

    Proportion of participants who experience at least one Grade 3, 4, or 5 adverse event within 6 months after enrollment. Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death).

  15. Effectiveness among pregnant participants

    Time frame: within 24 months from the date of enrollment

    Proportion of pregnant participants with culture-confirmed tuberculosis or clinical TB. Diagnosis of culture-confirmed TB will be performed using liquid and/or solid media methods.

  16. Safety (defined as treatment discontinuation due to adverse drug reaction) among pregnant participants.

    Time frame: 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 pregnant participants with drug discontinuation due to adverse drug reaction (ADR) associated with experimental treatment (6wP) or active comparator treatment (the rifamycin-based 3HP, 3HR, or 4R) .

  17. Tolerability (defined as proportion of with drug discontinuation for any reason) among pregnant participants

    Time frame: 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 pregnant participants with drug discontinuation for any reason

Other outcomes

  1. Proportion of Participants Who Discontinue Study Treatment Due to Adverse Drug Reactions by Treatment Arm

    Time frame: 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 permanently discontinue study treatment due to adverse drug reactions (ADRs), summarized separately for the experimental arm (6wP) and each comparator regimen (3HP, 3HR, and 4R). Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, and attribution to study drug will be determined by the investigator and reviewed by an independent blinded adjudication panel.

  2. Proportion of Participants Who Discontinue Study Treatment for Any Reason by Treatment Regimen

    Time frame: 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 discontinue study treatment for any reason during the study period, summarized separately for the experimental arm (6wP) and each comparator regimen (3HP, 3HR, and 4R).

  3. Proportion of Participants Who Develop Tuberculosis (TB) by Treatment Regimen

    Time frame: within 24 months from the date of enrollment

    Proportion of participants with 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.

  4. Proportion of Participants With Drug-Resistant Tuberculosis (TB) Among Those Who Develop TB by Comparator Regimen

    Time frame: within 24 months from the date of enrollment

    Proportion of participants who develop tuberculosis (TB) and have resistance to rifamycins or isoniazid, summarized separately for each comparator regimen (3HP, 3HR, and 4R). Drug resistance will be determined by phenotypic drug susceptibility testing of Mycobacterium tuberculosis isolates.

  5. Treatment Acceptability Score (Likert-Scale TB Treatment Acceptability Questionnaire)

    Time frame: within 24 months from the date of enrollment

    Participant-reported treatment acceptability score assessed using a Likert-scale tuberculosis (TB) treatment acceptability questionnaire evaluating domains including usability, treatment duration, pill burden, perceived risks versus benefits, and opportunity cost.

    • Scale range: 6 to 30
    • Interpretation: Higher scores indicate greater treatment acceptability

  6. Health-Related Quality of Life Score (PROMIS-29+2 [PROPr] and PROMIS Pediatric Profile)

    Time frame: within 24 months from the date of enrollment

    Health-related quality of life (HrQoL) assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS-29+2 Profile v2.1 [PROPr] for adults and PROMIS Pediatric Profile v3). Scores include physical and mental health component scores derived from PROMIS domains.

    • Scale range: 0 to 100 (standardized T-scores; mean 50, SD 10)
    • Interpretation: Higher scores indicate better health-related quality of life

  7. Area Under the Plasma Concentration-Time Curve (AUC₀-₂₄) of Rifapentine in Participants Receiving 6wP

    Time frame: within 24 months from the date of enrollment

    Population pharmacokinetic parameter AUC₀-₂₄ of rifapentine estimated using nonlinear mixed-effects modeling based on plasma concentration data collected in participants receiving 6 weeks of daily rifapentine (6wP). Unit: µg·h/mL

  8. Correlation Between Rifapentine AUC₀-₂₄ and Treatment Discontinuation Due to Adverse Drug Reactions

    Time frame: within 24 months from the date of enrollment

    Correlation between rifapentine area under the plasma concentration-time curve from 0 to 24 hours (AUC₀-₂₄; µg·h/mL), measured using validated LC-MS/MS assays, and treatment discontinuation due to adverse drug reactions (% of participants) among participants receiving 6 weeks of daily rifapentine (6wP). Adverse drug reactions will be assessed by the investigator and graded using CTCAE v5.0.

  9. Correlation Between Rifapentine AUC₀-₂₄ and Treatment Completion

    Time frame: Within 24 months from the date of enrollment

    Correlation between rifapentine area under the plasma concentration-time curve from 0 to 24 hours (AUC₀-₂₄; µg·h/mL), measured using validated LC-MS/MS assays, and treatment completion (% of participants completing assigned treatment per protocol) among participants receiving 6 weeks of daily rifapentine (6wP).

Study contacts

Contact information is provided by the study sponsor or research team.

Amber B Robinson, PhD

CONTACT

[email protected]

1-800-CDC-INFO

TBTC Research Administrator

CONTACT

[email protected]

+1 (800)-232-4636

Sponsors and collaborators

Lead sponsor

Centers for Disease Control and Prevention

Fed

Registry information

Official study title

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

Acronym: ASTERoiD

Important dates

Study start
2019
Primary completion
2029
Study completion
2029
First posted
Mar 22, 2018
Registry last updated
May 6, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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