Tuberculosis, Pulmonary
Conditions
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.
Interventions
DRUG4-month rifapentine-based regimen
8 weeks of isoniazid, pyrazinamide, rifapentine, and moxifloxacin, followed by 9 weeks of isoniazid, rifapentine and moxifloxacin
Sponsors
National Taiwan University
Taipei Veterans General Hospital, Taiwan
Chang Gung Memorial Hospital
Centers for Disease Control, Taiwan
Kaohsiung Veterans General Hospital.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Masking will not be done
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
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| TB disease free survival at 12 months | 12 months after study treatment assignment | Number and follow up time of participants without TB disease at 12 months after study treatment assignment in person-months |
| Grade 3 or higher adverse events during study drug treatment | 0-4 months | The number of participants with grade 3 or higher adverse events during study drug treatment divided by total number of participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to stable sputum conversion (Time in days from conversion of a positive sputum culture to negative sputum culture) | 4, 8, 12, 17 weeks, 6 months, 12 months | Number of days from start of treatment to first negative sputum culture that remain negative thereafter |
| Speed of decline of sputum viable bacilli by automated mycobacteria growth indicator tube (MGIT) days to detection | 2-8 weeks | Number of days from loading of sputum culture into MGIT to the day of detection of viable mycobacteria |
| 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 | Number and follow up time of participants without TB disease 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) in person-months |
| 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 | Number and follow up time of participants without TB disease 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) in person-months |
| Rates of treatment discontinuation for reasons other than ineligibility (late exclusions due to drug resistance or HIV status) | 0-4 months | Number of participants who discontinued treatment for reasons other than ineligibility (late exclusions due to drug resistance or HIV status) divided by total number of participants |
| All-cause mortality at 4 months post-treatment assignment | 4 months | Number of participants who died at 4 months divided by number of participants |
| Attributable mortality at 4 months post-treatment assignment | 4 months | Number of patients who died due to reasons attributable to tuberculosis at 4 months post-treatment assignment divided by number of participants |
| Attributable mortality at 12 months post-treatment assignment | 12 months | Number of patients who died due to reasons attributable to tuberculosis at 12 months post-treatment assignment divided by number of participants |
| Changes in interferon-gamma levels during treatment compared to baseline | 2, 4, 8, 12 weeks | interferon-gamma levels during treatment minus baseline levels |
| Changes in tumor necrosis factor-alpha levels during treatment compared to baseline | 2, 4, 8, 12 weeks | Tumor necrosis factor-alpha levels during treatment minus baseline levels |
| Changes in interleukin-12 and interleukin-6 levels during treatment compared to baseline | 2, 4, 8, 12 weeks | Interleukin-12 levels during treatment minus baseline levels |
| Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels during treatment compared to baseline | 2, 4, 8, 12 weeks | Triggering receptor expressed on myeloid cells-1 (TREM-1) levels during treatment minus baseline levels |
| All-cause mortality at 12 months post-treatment assignment | 12 months | Number of participants who died at 12 months divided by number of participants |
| Early sterilizing activity (Negative sputum cultures at end of intensive 8 weeks phase) | 8 weeks | The number of patients with a negative sputum culture at the end of intensive phase therapy at 8 weeks divided by total number of participants |
Other
| Measure | Time frame | Description |
|---|---|---|
| HLA Genotyping to detect predictors for occurrence of severe drug adverse events including skin rash and hepatitis. | 0-4 months | Identify HLA genotypes associated with severe drug adverse events such as greater than grade 2 hepatitis and/or skin rash |
| Maximum plasma concentration (Cmax) of rifapentine | 0, 2, 4, 8, 12 weeks | Serum concentration of rifapentine by determining area under the curve |
Countries
Taiwan
Outcome results
None listed