Safety, Tolerability, Pharmacokinetics and Food Effects Study of PBTZ169

Study Overview
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Brief Summary
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Open-label prospective non-comparative ascending dose randomized cohort study of single and multiple oral administration of PBTZ169 (capsules 80 mg) in healthy volunteers

Detailed Description
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Open-label prospective non-comparativerandomized cohort study of safety, tolerability, pharmacokinetics and the effect of food of PBTZ169 in adult healthy volunteers after single and multiple oral administration. Study was conducted in one study center in the Russian Federation. The study included two stages: Stage 1 - single or double oral administration with dose escalation (fasted/after meal) in 5 cohorts 10 healthy volunteers each plus 5 back-up volunteers; Stage 2 - multiple oral administration once a day after meal for 14 days in 1 cohort of 10 healthy volunteers.

Official Title
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An Open-label, Prospective Study of Safety, Tolerability, Pharmacokinetics and Food Effects of PBTZ169, 80 mg Capsules, When Used in Ascending Doses in Healthy Volunteers

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: PBTZ169 640 mg OD
* Drug: PBTZ169 640 mg BiD
* Drug: PBTZ169 960 mg SD
* Drug: PBTZ169 1280 mg SD
* Drug: PBTZ169 1280 mg MD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from the volunteer. Men and women aged 18-45 years, inclusive. Body mass index of 18.5-30 kg/m2. Verified healthy diagnosis based on physical examination, vital signs, standard laboratory tests (complete blood count and biochemical blood test, urine analysis) and instrumental tests (ECG, fluorography examination or X-ray examination). Negative results of tests for human immunodeficiency virus (HIV), syphilis, hepatitis B (Hbs Ag) and hepatitis C (antibodies to HCV). Ability to comply with all the requirements of the protocol in the opinion of the investigator. Consent of the participant and his/her partner to use reliable contraceptive methods during the study and within 90 days after the end of their participation. A reliable method of contraception is a combination of a male condom with at least one of the following methods: hormonal contraceptives used by the male's partner (only if she does not participate in this clinical study); use of aerosols, creams, suppositories and other agents containing spermicides; use of intrauterine device by female partner. Exclusion Criteria: History of allergies, including at least one episode of allergy to medications. Chronic diseases of the cardiovascular, bronchopulmonary, neuroendocrine systems, ENT, as well as diseases of the gastrointestinal tract, liver, kidneys, blood, skin. Hypolactasia (lactose intolerance, lactase deficiency) or glucose-galatose malabsorption in medical history. Chronic eye diseases except for myopia, hypermetropia and astigmatism of mild and moderate severity. Surgeries on the gastrointestinal tract (except for appendectomy done more than 1 year before screening). Regular administration or use (including externally) of hormonal agent for more than 1 week less than 45 days before screening Regular administration of medicinal products less than 4 weeks before screening. Use of medicinal products that have a pronounced effect on liver function or hemodynamics (barbiturates, omeprazole, cimetidine, etc.) less than 30 days before screening. Positive test for narcotics and psychotropic products. Blood pressure after resting in supine position for at least 5 minutes above 130 mm Hg (systolic blood pressure) and 90 mm Hg (diastolic blood pressure) or below 110 mm Hg (systolic blood pressure) and 60 mm Hg (diastolic blood pressure). Heart rate (according to ECG) after resting in supine position for at least 5 minutes above 90 bpm or below 60 bpm. Blood donation (450 mL of blood or plasma and more) less than 3 months before the screening. Acute infectious diseases less than 4 weeks before screening. Administration of more than 10 units of alcohol per week (1 unit of alcohol is equivalent to 500 mL of beer, 200 mL of wine or 50 mL of a spirit) or history of alcoholism, drug abuse, substance abuse. Mental diseases. Smoking for three months before screening. Participation in any clinical study less than 3 months before screening. Planned conception or sperm donation during the study after the administration of the investigational product or within 3 months after the last administration of the product. Positive pregnancy test for women. Breastfeeding period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (C1A), PBTZ169<br>Two doses of PBTZ169: 640 mg OD fasted and 640 mg OD after meal. Wash-out period ≥6 days. | Drug: PBTZ169 640 mg OD<br>* Two administrations once a day with a wash-out period: food effect<br>* Other names: Macozinone (PBTZ169);|
| Experimental: Cohort 1 (C1B), PBTZ169<br>Two doses of PBTZ169: 640 mg OD after meal and 640 OD mg fasted. Wash-out period ≥6 days. | Drug: PBTZ169 640 mg OD<br>* Two administrations once a day with a wash-out period: food effect<br>* Other names: Macozinone (PBTZ169);|
| Experimental: Cohort 2 (C2), PBTZ169<br>Single dose of PBTZ169: 960 mg fasted | Drug: PBTZ169 960 mg SD<br>* Once a day fasted<br>* Other names: Macozinone (PBTZ169);|
| Experimental: Cohort 3 (C3), PBTZ169<br>Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg | Drug: PBTZ169 640 mg BiD<br>* Twice a day fasted; 1 day of administration<br>* Other names: Macozinone (PBTZ169);|
| Experimental: Cohort 4 (C4), PBTZ169<br>Single dose of PBTZ169: 1280 mg fasted | Drug: PBTZ169 1280 mg SD<br>* Once a day fasted<br>* Other names: Macozinone (PBTZ169);|
| Experimental: Cohort 5 (C5), PBTZ169<br>Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days | Drug: PBTZ169 1280 mg MD<br>* Once a day after meal, 14 doses<br>* Other names: Macozinone (PBTZ169);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | Safety and tolerability: number of (S)AEs | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 
| Number of Subjects With AEs | Safety and tolerability: number of subjects with adverse events | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CS Changes in Vital Signs | Safety and tolerability:Clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 
| ECG Results (Safety and Tolerability) | Clinically significant abnormal deviations in ECG findings | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 
| Laboratory Examinations Results (Safety and Tolerability) | Complete blood count, biochemical blood test, urine analysis | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 
| Results of Physical Examination: CS Deviations | Safety and tolerability: number of physical examinations with CS deviations in results | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 
| Peak Plasma Concentration (Сmax) | Сmax of PBTZ169 at the timepoints: C1A, C1B, C2 and C4: point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00, 24:00, 48:00 and 72:00 (h:min). C3 (two administrations): point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00 (the point before the second administration from -5 min to -1 min), 12:30, 13:00, 13:30, 14:00, 15:00, 16:00, 18:00, 21:00, 24:00, 48:00 , 72:00 (h:min) after the first administration of the medicinal product. C5 (14 days of intake): 5 minutes before the administration (only until the first dose), 0 min and within 24 h after the administration of the 1st, 7th and last (14th) dose: 0:15, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 (h:min after the administration of a dose of the medicinal product); at 48 h and 72 h points after the last (14th) dose of PBTZ169 | In the dosing interval (up to 72 hours after the last drug administration) | 
| Trough Concentration With Repeated Administration (Ctrough) | PBTZ169 concentration before drug intake (Days 2 - 15) | Up to 72 hours after the last drug administration | 
| Time to Reach Maximum Concentration (Tmax) | Cohort 3: Tmax relative to the time of administration in any dosage interval | Up to 72 hours after the last drug administration | 
| Plasma Half-life Time (T1/2) |  | Up to 72 hours after the last drug administration | 
| Area Under the Concentration-time Curve (AUC0 t) | In the time interval from 0 to time (t) when the last blood sample is collected with a concentration above the limit of quantification. C5: for the data of Day 14 based on measurements within 72 hours after the last dose administration | Up to 72 hours after the last drug administration | 
| Area Under the Concentration-time Curve (AUC0-∞) | In the time interval from 0 to infinity | Up to 72 hours after the last drug administration | 
| Area Under the Concentration-time Curve (AUC0-24) | C5 (multiple administration once a day for 14 days): AUC0-24 was calculated based on measurements within 24 hours after PBTZ169 intake | In the dosing interval (up to 24 hours after drug administration) | 
| Total Clearance (Clt/F) |  | Up to 72 hours after the last drug administration | 
| Volume of Distribution (Vd/F) |  | Up to 72 hours after the last drug administration | 
| Elimination Constant Kel |  | Up to 72 hours after the last drug administration | 
| Relative Bioavailability | f=AUC0-∞(T)/AUC0-∞(R); f'=AUC0-t(T)/AUC0-t(R) Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Up to 72 hours after the last drug administration | 
| Relative Degree of Absorption | f=Cmax(T)/Cmax(R). Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Up to 72 hours after the last drug administration | 
| Number of Subjects With CS Changes in Vital Signs | Safety and tolerability: No. of sbjs with clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Macozinone, PBTZ169, Antimycobacterial, Tuberculosis, Drug Resistant Tubercolosis, MDR-TB, XDR-TB