Clinical trial NCT03474029: Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine Given Daily for LTBI
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Latent Tuberculosis
Keywords: latent tuberculosis
rifapentine
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
First posted: 2018-03-22
Enrollment: 3400
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Treatment discontinuation due to adverse drug reaction
timeFrame: from the date of enrollment to the date of scheduled completion of assigned treatment
measure: Culture-confirmed tuberculosis (TB) in participants 18 years old and older and culture-confirmed or clinical TB in participants less then 18 years old.
timeFrame: within 24 months from the date of enrollment
Secondary outcomes:
measure: Proportion who complete assigned treatment
timeFrame: 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
measure: Proportion with drug discontinuation for any reason
timeFrame: 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
measure: Proportion with any grade 3, 4, or 5 (i.e., death) adverse event associated with study drug
timeFrame: within 6 months from the date of enrollment
measure: Proportion who have died for any reason
timeFrame: within 24 months from the date of enrollment
measure: Proportion with hepatitis and non-hepatotoxic systemic drug reactions
timeFrame: within 6 months from the date of enrollment
measure: Proportion with culture-confirmed or clinical TB regardless of age
timeFrame: within 24 months from the date of enrollment
measure: Proportion with TB among those who complete assigned therapy
timeFrame: within 24 months from the date of enrollment
measure: Safety (defined as treatment discontinuation due to adverse drug reaction) among participants with human immunodeficiency virus (HIV) infection.
timeFrame: 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
measure: Safety (defined as treatment discontinuation due to adverse drug reaction) among participants < 18 years old.
timeFrame: 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
measure: Tolerability (defined as proportion of with drug discontinuation for any reason) among participants with human immunodeficiency virus (HIV) infection.
timeFrame: 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
measure: Tolerability (defined as proportion of with drug discontinuation for any reason) among participants < 18 years old.
timeFrame: 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
measure: Effectiveness among participants with human immunodeficiency virus (HIV) infection.
timeFrame: within 24 months from the date of enrollment
measure: Effectiveness among participants < 18 years old.
timeFrame: within 24 months from the date of enrollment
Other outcomes:
measure: Proportions of drug discontinuation due to adverse drug reactions in experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R
timeFrame: 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
measure: Proportions of treatment discontinuations for any reason in experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R
timeFrame: 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
measure: Effectiveness of experimental (6wP) arm and each treatment regimen in the comparator arm: 3HP, 3HR, 4R
timeFrame: within 24 months from the date of enrollment
measure: Proportion with resistance to rifamycins or isoniazid among persons who develop TB to each regimen in the comparator arm: 3HP, 3HR, 4R.
timeFrame: within 24 months from the date of enrollment
Locations:
city: Denver
country: United States
facility: Denver Health and Hospital Authority
state: Colorado
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Washington
country: United States
facility: Washington DC VA Medical Center
state: District of Columbia
city: Manhattan
country: United States
facility: New York Harbor Healthcare System
state: New York
city: New York
country: United States
facility: New York City Bureau of TB Control
state: New York
city: San Antonio
country: United States
facility: San Antonio VA
state: Texas
city: Seattle
country: United States
facility: Seattle King County Health Department
state: Washington
city: Sydney
country: Australia
facility: Liverpool Hospital
city: Sydney
country: Australia
facility: Paramatta Chest
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
city: Calgary
country: Canada
facility: Calgary TB Clinic
state: Alberta
city: Edmonton
country: Canada
facility: Edmonton TB Clinic
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Centre for Disease Control
state: British Columbia
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Stellenbosch
country: South Africa
facility: Desmond Tutu TB Center
Study officials:
affiliation: Vanderbilt University Medical Center, USA
name: Timothy Sterling, MD
role: STUDY_CHAIR
affiliation: Denver Public Health (USA)
name: Robert Belknap, MD
role: STUDY_CHAIR
affiliation: Centers for Disease Control and Prevention
name: Amber Robinson, PhD
role: STUDY_DIRECTOR
affiliation: Centers for Disease Control (USA)
name: Rosanna M Boyd, PhD
role: STUDY_DIRECTOR
affiliation: McGill University
name: Dick Menzies, MD
role: STUDY_CHAIR
References: