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

Tuberculosis, Pulmonary Clinical Trial

— ESCAPE-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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04856644
• Other study ID #: KSVGH-20561
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: May 1, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2021
• Source: Kaohsiung Veterans General Hospital.
• Contact: Susan Shin-Jung Lee, M.D., Ph.D.
• Phone: +886-7342-2121
• Email: ssjlee28[@]yahoo.com.tw
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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. 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 366
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• 4-month rifapentine-based regimen
8 weeks of isoniazid, pyrazinamide, rifapentine, and moxifloxacin, followed by 9 weeks of isoniazid, rifapentine and moxifloxacin

Locations

Country	Name	City	State
Taiwan	Kaohsiung Veterans General Hospital	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Linkou Chang Gung Memorial Hospital	Taoyuan City

Sponsors (5)

Lead Sponsor	Collaborator
Kaohsiung Veterans General Hospital.	Centers for Disease Control, Taiwan, Chang Gung Memorial Hospital, National Taiwan University, Taipei Veterans General Hospital, Taiwan

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	HLA associations with severe drug adverse events	HLA Genotyping to detect predictors for occurrence of severe drug adverse events including skin rash and hepatitis.	0-4 months
Other	Maximum plasma concentration (Cmax) of rifapentine	Serum concentration of rifapentine by determining area under the curve	0, 2, 4, 8, 12 weeks
Primary	Treatment Efficacy	TB disease-free survival at 12 months after study treatment assignment	12 months after study treatment assignment
Primary	Safety and tolerability	The proportion of participants with grade 3 or higher adverse events during study drug treatment	0-4 months
Secondary	Early sterilizing activity	The proportion of patients with a negative sputum culture at the end of intensive phase therapy at 8 weeks	8 weeks
Secondary	Sputum culture conversion	Time to stable sputum culture conversion	4, 8, 12, 17 weeks, 6 months, 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	All-cause mortality	All-cause mortality at 4 months and 12 months post-treatment assignment	4, 12 months
Secondary	Attributable mortality	Attributable mortality at 4 months and 12 months post-treatment assignment	4, 12 months
Secondary	Changes in interferon-gamma levels	Changes in interferon-gamma levels during treatment compared to baseline	2, 4, 8, 12 weeks
Secondary	Changes in tumor necrosis factor-alpha levels	Changes in tumor necrosis factor-alpha levels during treatment compared to baseline	2, 4, 8, 12 weeks
Secondary	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
Secondary	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