Evaluation of the Efficacy and Safety of a 4-month Daily Regimen (2HZPM/2HPM) for Treatment of Pulmonary TB

Study Overview
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Brief Summary
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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
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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. 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.

Official Title
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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)

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: 4-month rifapentine-based regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Patient with a history of being untreated for 3 years after cure from a previous episode of TB can be included. Age 20 years or older 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. 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 Patient signed a written informed consent Exclusion Criteria: Pregnant or breast-feeding. Unable to take oral medications. Previously enrolled in this study. Received any investigational drug in the past 3 months. More than 14 days of systemic treatment with any antituberculous drugs preceding initiation of study drugs. Known history of prolonged QT syndrome. Suspected or documented TB involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis. Weight less than 40.0 kg. Known allergy or intolerance to any of the study medications. 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. Medical conditions, including HIV infection and others conditions that, in the investigator's judgment, make study participation not in the individual's best interest. 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.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4-month regimen (2HZPM/2HPM)<br>Eight weeks of daily treatment with isoniazid (H), pyrazinamide (Z), rifapentine (P), and moxifloxacin (M), followed by Nine weeks of daily treatment with isoniazid, rifapentine and moxifloxacin | Drug: 4-month rifapentine-based regimen<br>* 8 weeks of isoniazid, pyrazinamide, rifapentine, and moxifloxacin, followed by 9 weeks of isoniazid, rifapentine and moxifloxacin<br>* Other names: priftin;|
| No Intervention: Standard 6-month regimen (2HERZ/4HR) historical control<br>a standard, six-month regimen, with Eight weeks of daily treatment with isoniazid (H), rifampin (R), pyrazinamide (Z) and ethambutol (E) followed by Eighteen weeks of daily treatment with isoniazid and rifampin, with or without ethambutol | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Efficacy | TB disease-free survival at 12 months after study treatment assignment | 12 months after study treatment assignment | 
| Safety and tolerability | The proportion of participants with grade 3 or higher adverse events during study drug treatment | 0-4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early sterilizing activity | The proportion of patients with a negative sputum culture at the end of intensive phase therapy at 8 weeks | 8 weeks | 
| Sputum culture conversion | Time to stable sputum culture conversion | 4, 8, 12, 17 weeks, 6 months, 12 months | 
| Speed of decline of sputum viable bacilli | Speed of decline of sputum viable bacilli by automated mycobacteria growth indicator tube (MGIT) days to detection | 2-8 weeks | 
| TB disease-free survival at 12 months sensitivity analysis (unfavorable outcome) | 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) | 12 months | 
| TB disease-free survival at 12 months sensitivity analysis (favorable outcome) | 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) | 12 months | 
| Rate of treatment discontinuation | Rates of treatment discontinuation for reasons other than ineligibility (late exclusions due to drug resistance or HIV status) | 0-4 months | 
| All-cause mortality | All-cause mortality at 4 months and 12 months post-treatment assignment | 4, 12 months | 
| Attributable mortality | Attributable mortality at 4 months and 12 months post-treatment assignment | 4, 12 months | 
| Changes in interferon-gamma levels | Changes in interferon-gamma levels during treatment compared to baseline | 2, 4, 8, 12 weeks | 
| Changes in tumor necrosis factor-alpha levels | Changes in tumor necrosis factor-alpha levels during treatment compared to baseline | 2, 4, 8, 12 weeks | 
| Changes in interleukin-12 and interleukin-6 levels | Changes in interleukin-12 and interleukin-6 levels during treatment compared to baseline | 2, 4, 8, 12 weeks | 
| Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels | Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels during treatment compared to baseline | 2, 4, 8, 12 weeks |