Latent Tuberculosis
Conditions
Keywords
latent tuberculosis, rifapentine
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.
Interventions
DRUGRifapentine daily for 6 weeks
600 mg of Rifapentine (RPT) given once daily (o.d., omni die) for 6 weeks (6wP).
DRUGRifapentine and Isoniazid weekly for 12 weeks
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).
DRUGRifampin and Isoniazid daily for 12 weeks
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).
DRUGRifampin daily for 16 weeks
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.
Sponsors
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. 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: 1. 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. 2. 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. 3. HIV co-infection (with CD4+ T-lymphocyte count \> 100 cells/mm3) 4. ≥ 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray and no prior history of treatment for TB or LTBI. 5. 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. 6. 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). 7. 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). 8. Individuals with an increased risk of TB due to medical conditions such as end-stage renal disease. 9. Individuals currently using immunosuppressive medications such as chronic steroids. 10. Individuals with planned use of TNF-α inhibitors. 11. Individuals with planned solid organ or hematologic transplantation 2. Willing to provide signed informed consent, or parental permission and participant assent. 3. For the following special populations, both inclusion criteria above must be met AND the criteria below depending on stage: 1. 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. 2. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment discontinuation due to adverse drug reaction | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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. |
| 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 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. |
| Proportion of Participants Who Die From Any Cause | 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. |
| Proportion of Participants With Hepatotoxicity or Non-Hepatotoxic Systemic Drug Reactions | 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. |
| Proportion of Participants with Culture-Confirmed or Clinical Tuberculosis (TB) | 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. |
| 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 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. |
| 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 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. |
| 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 | 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. |
| 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 | Proportion of HIV-infected patients with drug discontinuation for any reason |
| 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 | Proportion of participants \< 18 years old with drug discontinuation for any reason |
| Effectiveness among participants with human immunodeficiency virus (HIV) infection. | 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. |
| Effectiveness among participants < 18 years old. | 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. |
| 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 | 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). |
| Effectiveness among pregnant participants | 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. |
| 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 | 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) . |
| 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 | Proportion of pregnant participants with drug discontinuation for any reason |
Countries
Australia, Benin, Canada, Haiti, South Africa, Uganda, United States, Vietnam
Contacts
CONTACTAmber B Robinson, PhD
CONTACTTBTC Research Administrator
STUDY_CHAIRTimothy Sterling, MD
Vanderbilt University Medical Center
STUDY_CHAIRRobert Belknap, MD
Denver Public Health (USA)
STUDY_DIRECTORAmber Robinson, PhD
Centers for Disease Control and Prevention
STUDY_DIRECTORRosanna M Boyd, PhD
Centers for Disease Control (USA)
STUDY_CHAIRDick Menzies, MD
McGill University
Outcome results
None listed