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

Latent Tuberculosis Clinical Trial

— ASTERoiD  

Official 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03474029
• Other study ID #: CDC-NCHSTP-7024
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: August 1, 2019
• Est. completion date: December 2028

Study information

• Verified date: July 2023
• Source: Centers for Disease Control and Prevention
• Contact: Rosanna M Boyd, PhD
• Phone: +1 (404)-553-7434
• Email: icg7[@]cdc.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3400
• Est. completion date: December 2028
• Est. primary completion date: December 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• 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:

1. 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

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.

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 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

7. 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Latent Tuberculosis
• Tuberculosis

Intervention

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

Locations

Country	Name	City	State
Australia	Liverpool Hospital	Sydney
Australia	Paramatta Chest	Sydney
Australia	Royal Prince Alfred Hospital	Sydney
Canada	Calgary TB Clinic	Calgary	Alberta
Canada	Edmonton TB Clinic	Edmonton	Alberta
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Toronto Western Hospital	Toronto	Ontario
Canada	British Columbia Centre for Disease Control	Vancouver	British Columbia
South Africa	Desmond Tutu TB Center	Stellenbosch
United States	Denver Health and Hospital Authority	Denver	Colorado
United States	New York Harbor Healthcare System	Manhattan	New York
United States	New York City Bureau of TB Control	New York	New York
United States	San Antonio VA	San Antonio	Texas
United States	Seattle King County Health Department	Seattle	Washington
United States	George Washington University	Washington	District of Columbia
United States	Washington DC VA Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Centers for Disease Control and Prevention

Countries where clinical trial is conducted

United States,  Australia,  Canada,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Effectiveness of experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R	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.	within 24 months from the date of enrollment
Other	Proportion with resistance to rifamycins or isoniazid among persons who develop TB to each regimen in the comparator arm: 3HP, 3HR, 4R.		within 24 months from the date of enrollment
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Proportion who have died for any reason		within 24 months from the date of enrollment
Secondary	Proportion with hepatitis and non-hepatotoxic systemic drug reactions		within 6 months from the date of enrollment
Secondary	Proportion with culture-confirmed or clinical TB regardless of age		within 24 months from the date of enrollment
Secondary	Proportion with TB among those who complete assigned therapy		within 24 months from the date of enrollment
Secondary	Safety (defined as treatment discontinuation due to adverse drug reaction) among participants with human immunodeficiency virus (HIV) infection.	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.	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
Secondary	Safety (defined as treatment discontinuation due to adverse drug reaction) among participants < 18 years old.	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.	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
Secondary	Tolerability (defined as proportion of with drug discontinuation for any reason) among participants with human immunodeficiency virus (HIV) infection.	Proportion of HIV-infected patients 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
Secondary	Tolerability (defined as proportion of with drug discontinuation for any reason) among participants < 18 years old.	Proportion of participants < 18 years old 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
Secondary	Effectiveness among participants with human immunodeficiency virus (HIV) infection.	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.	within 24 months from the date of enrollment
Secondary	Effectiveness among participants < 18 years old.	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.	within 24 months from the date of enrollment

External Links

•   Tuberculosis Trials Consortium (TBTC)