Phase 1 Study of PBTZ169

Open-label Prospective Noncomparative Study of Safety, Tolerability and Pharmacokinetics of PBTZ169 After Single and Multiple Fasting Oral Administration in Increasing Doses in Healthy Volunteers

Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in fasted healthy volunteers after single and multiple oral administration

Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in adult man healthy volunteers after single and multiple oral fasting administration. Study was conducted in one study center in Russian Federation. The study included two stages:

• Stage 1 - single oral fasting administration with dose escalation in 5 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group);
• Stage 2 - multiple oral fasting administration with dose escalation in 2 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group).

Screening procedures for each cohort performed within 7 days before the drug prescription and after the end of administration period in previous cohort. Screening in cohorts 2 and 6 was started only after safety tolerability and PK data analysis of previous cohorts.

All volunteers met the study inclusion/exclusion criteria was included successively into the following cohorts on Stage 1 (actual data):

• Cohort 1 (C1) - 6 volunteers of the main group each of whom received once single dose of the drug - 1 capsule containing 40 mg of PBTZ169;
• Cohort 2 (C2) - 6 volunteers of the main group each of whom received once 80 mg of PBTZ169 (2 capsules 40 mg);
• Cohort 3 (C3) - 6 volunteers of the main group each of whom received once 160 mg of PBTZ169 (4 capsules 40 mg);
• Cohort 4 (C4) - 6 volunteers of the main group each of whom received once 320 mg of PBTZ169 (8 capsules 40 mg);
• Cohort 5 (C5) - 6 volunteers of the main group each of whom received once 640 mg of PBTZ169 (16 capsules 40 mg).

On Stage 2 (actual data):

• Cohort 6 (C6) - 5 volunteers of the main group each of whom received 320 mg of PBTZ169 (8 capsules 40 mg) once daily for 14 days;
• Cohort 7 (C7) - 5 volunteers of the main group each of whom received 640 mg of PBTZ169 (16 capsules 40 mg) once daily for 14 days.

Safety was assessed throughout the study. For every volunteer series of urine and venous blood samples was collected for the safety, tolerability and PK assessment of PBTZ169.

Inclusion Criteria:

1. Written informed consent received from a volunteer.

2. Man aged 18 to 45 years old, inclusive.

3. Body mass index of 18.5-25 kg/m2.

4. Verified diagnosis: "healthy" according to data of standard clinical, laboratory and instrumental examination methods performed at screening:

   • Absence of deviations of physical examination parameters and vital signs (systolic blood pressure - 100-129 mm Hg, inclusive; diastolic blood pressure - 70-89 mm Hg, inclusive; heart rate - 60-80 bpm, inclusive);
   • Absence of deviations of laboratory parameters (complete blood count, blood biochemistry, urinalysis and tests for HIV, HBV, HCV, syphilis);
   • Normal parameters of 12-lead ECG;
   • Normal results of photofluorographic or X-ray examination (the results received maximum 6 months before screening can be used).

5. Ability, according to investigators opinion, to comply with all requirements of the protocol.

6. Agreement to use double contraception method during the study participation and for 3 months after the test drug administration - combination of male condom with not less than one of the following methods:

   • female partner using hormonal contraception;
   • using aerosols, creams, suppositories and other agents containing spermicides;
   • female partner using intrauterine device

Exclusion Criteria:

1. Aggravated allergic history, including presence of at least one episode of drug allergy.
2. Chronic diseases of cardiovascular, bronchopulmonary, neuroendocrine systems, ENT and gastrointestinal, hepatic, renal, blood and cutaneous diseases.
3. Chronic diseases of eyes except for mild to moderate myopia, hypermetropia and astigmatism.
4. Gastrointestinal surgeries (except for appendectomy performed not less than 1 year before screening).
5. Acute infections within less than 4 weeks before screening.
6. Regular drug administration within less than 4 weeks before screening.
7. Regular administration or application (including topical) of hormonal drugs for more than 1 week within less than 45 days before the screening.
8. Administration of drugs exerting evident effects on hemodynamics, hepatic function, etc. (barbiturates, omeprazole, cimetidine, etc.) within less than 45 days before the screening.
9. Positive tests for narcotic and psychotropic agents.
10. Donation (450 mL of blood or plasma) within less than 3 months before the screening.
11. Intake of more than 10 U of alcohol per week (1 unit of alcohol is equivalent to 500 mL of beer, 200 mL of vine or 50 mL of strong alcoholic drink) or historical data on alcoholism, narcomania, drug abuse.
12. Mental illnesses.
13. Smoking within half a year before the screening.
14. Previous participation in this clinical study and withdrawal from it due to any reason.
15. Participation in other clinical studies of drugs within less than 6 months before the screening.
16. Planned conception or sperm donation during the study after the test drug administration or during 3 months after the date of drug administration.