Clinical trial NCT04856644: Evaluation of the Efficacy and Safety of a 4-month Daily Regimen (2HZPM/2HPM) for Treatment of Pulmonary TB
Official title: Evaluation of the Efficacy and Safety of a Short-course, Daily, 4-month Regimen Including Isoniazid, Pyrazinamide, Rifapentine and Moxifloxacin (2HZPM/2HPM) for the Treatment of Drug-susceptible Pulmonary Tuberculosis in Taiwan (ESCAPE-TB)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Tuberculosis, Pulmonary
Lead sponsor: Kaohsiung Veterans General Hospital.
Sponsor class: OTHER
Collaborators: name: National Taiwan University
name: Taipei Veterans General Hospital, Taiwan
name: Chang Gung Memorial Hospital
name: Centers for Disease Control, Taiwan
First posted: 2021-04-23
Enrollment: 333
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The intervention group: all patients recruited into the study will receive the 4-month regimen The comparator group: historical control in those who received the standard 6-month regimen
Primary purpose: TREATMENT

Brief summary: The development of efficacious, safe, and shorter treatment regimens could significantly improve TB management and treatment success rates. This prospective, 3-year, single arm study is to evaluate the efficacy and safety of a short-course, 4-month regimen including isoniazid(H), pyrazinamide(P), rifapentine (P), and moxifloxacin(M) (2HZPM/2HPM) for the treatment of drug-susceptible, pulmonary tuberculosis, and compared with a historical control group receiving the standard six-month regimen.

Detailed description: Shorter regimens have the potential to impact on TB control by reducing TB incidence and mortality, and improve outcomes by increasing patient adherence to treatments and decreasing duration to cure, in addition to reducing costs to the health system and the patient. The purpose of this prospective, three year, single arm study is to evaluate whether a short course, four-month regimen containing rifapentine and moxifloxacin (2HZPM/2HPM) are as effective and/or as tolerable as the standard six-month regimen for the treatment of drug-susceptible, pulmonary tuberculosis (TB). A historical group receiving the standard six-month regimen is used as control at a ratio of 1:2. The pharmacokinetic and pharmacodynamic profile of rifapentine in Asian patients. Analysis of of histocompatibility leucocyte antigen (HLA) associations with adverse events and changes in biomarkers will be done.

Eligibility criteria: Inclusion Criteria:

1. Suspected newly diagnosed pulmonary TB plus one of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for Mycobacterium tuberculosis by culture or "Gene Xpert MTB/RIF" testing, with rifamycin resistance not detected, OR c) histopathologic findings compatible with mycobacterial infection including a positive acid-fast stain
2. Patient with a history of being untreated for 3 years after cure from a previous episode of TB can be included.
3. Age 20 years or older
4. For women of childbearing potential, a negative pregnancy test at or within seven (7) days prior to screening is required, and must agree to practice a barrier method of contraception during study drug treatment, or be surgically sterilized or have an intrauterine contraceptive device in place.
5. Laboratory parameters performed at or within 14 days prior to enrollment:

   * Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal
   * Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal
   * Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal or Creatinine clearance (CrCl) level greater than 30 mL/min.
   * Serum or plasma potassium level greater than or equal to 3.5 milliequivalent/L
   * Hemoglobin level of 7.0 g/dL or greater
   * Platelet count of 100,000/mm3 or greater
6. Patient signed a written informed consent

Exclusion Criteria:

1. Pregnant or breast-feeding.
2. Unable to take oral medications.
3. Previously enrolled in this study.
4. Received any investigational drug in the past 3 months.
5. More than 14 days of systemic treatment with any antituberculous drugs preceding initiation of study drugs.
6. Known history of prolonged QT syndrome.
7. Suspected or documented TB involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis.
8. Weight less than 40.0 kg.
9. Known allergy or intolerance to any of the study medications.
10. Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.
11. Medical conditions, including HIV infection and others conditions that, in the investigator's judgment, make study participation not in the individual's best interest.
12. Late exclusions: Drug-resistant TB by either rapid sputum based test (Gene Expert) or resistance testing using an indirect susceptibility test in liquid culture to isoniazid, rifampin, ethambutol, pyrazinamide or resistance to moxifloxacin or rifapentine by microdilution agar proportion test.

Primary outcomes:
measure: TB disease free survival at 12 months
timeFrame: 12 months after study treatment assignment
measure: Grade 3 or higher adverse events during study drug treatment
timeFrame: 0-4 months
Secondary outcomes:
measure: Early sterilizing activity (Negative sputum cultures at end of intensive 8 weeks phase)
timeFrame: 8 weeks
measure: Time to stable sputum conversion (Time in days from conversion of a positive sputum culture to negative sputum culture)
timeFrame: 4, 8, 12, 17 weeks, 6 months, 12 months
measure: Speed of decline of sputum viable bacilli by automated mycobacteria growth indicator tube (MGIT) days to detection
timeFrame: 2-8 weeks
measure: TB disease-free survival at 12 months after study treatment assignment assuming all losses to follow-up and non-TB deaths have an unfavorable outcome (Sensitivity analyses assuming all losses to follow-up and non-TB deaths have an unfavorable outcome)
timeFrame: 12 months
measure: TB disease-free survival at 12 months after study treatment assignment assuming all losses to follow-up and non-TB deaths have an favorable outcome (Sensitivity analyses assuming all losses to follow-up and non-TB deaths have an favorable outcome)
timeFrame: 12 months
measure: Rates of treatment discontinuation for reasons other than ineligibility (late exclusions due to drug resistance or HIV status)
timeFrame: 0-4 months
measure: All-cause mortality at 4 months post-treatment assignment
timeFrame: 4 months
measure: All-cause mortality at 12 months post-treatment assignment
timeFrame: 12 months
measure: Attributable mortality at 4 months post-treatment assignment
timeFrame: 4 months
measure: Attributable mortality at 12 months post-treatment assignment
timeFrame: 12 months
measure: Changes in interferon-gamma levels during treatment compared to baseline
timeFrame: 2, 4, 8, 12 weeks
measure: Changes in tumor necrosis factor-alpha levels during treatment compared to baseline
timeFrame: 2, 4, 8, 12 weeks
measure: Changes in interleukin-12 and interleukin-6 levels during treatment compared to baseline
timeFrame: 2, 4, 8, 12 weeks
measure: Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels during treatment compared to baseline
timeFrame: 2, 4, 8, 12 weeks
Other outcomes:
measure: HLA Genotyping to detect predictors for occurrence of severe drug adverse events including skin rash and hepatitis.
timeFrame: 0-4 months
measure: Maximum plasma concentration (Cmax) of rifapentine
timeFrame: 0, 2, 4, 8, 12 weeks
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan City
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital
Study officials:
affiliation: Kaohsiung Veterans General Hospital.
name: Susan Shin-Jung Lee, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: