Study of the Effect of Food Intake on the Bioavailability of XC8 10 mg Film-coated Tablets

Study Overview
=================
Brief Summary
-----------------
Primary objective of the study: evaluation of the effect of food intake on the bioavailability of XC8, film-coated tablets, 10 mg after a single oral administration in fed or fasted condition at a dose of 20 mg (two tablets). Additional objective of the study: evaluation of pharmacokinetic parameters, safety and tolerability of XC8, film-coated tablets, 10 mg in healthy volunteers after single oral administration in fed or fasted condition in a dose of 20 mg (two tablets).

Official Title
-----------------
An Open-label, Randomized, Cross-over Study With 2 Treatments (Fasting and After Meals), 3 Periods, 2 Sequences, and an Adaptive, Two-stage Design to Evaluate the Effect of Food Intake on the Bioavailability of XC8, Film-coated Tablets, 10 mg at a Single Dose of 20 mg in Healthy Volunteers

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: XC8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female volunteers aged 18 to 45 years (inclusive). Presence of written consent of the volunteer to participate in the study in accordance with applicable law. Body mass index (BMI) within the range of 18.5 ≤ BMI ≤ 30 kg/m2 with a body weight not less than 45 kg and not more than 100 kg. Verified diagnosis healthy: no deviations from the reference values of the data of standard clinical, laboratory and instrumental methods of examination. The consent of the volunteer (including the partner) to use adequate methods of contraception during the study and 3 weeks after its completion. Hemodynamic and other vital signs within normal limits (reference intervals are 60-90 bpm at rest for heart rate (HR), 16-20 breaths/min for respiratory rate (RR), 35.5 to 36.9°C for body temperature, normal blood pressure (BP) is considered to be systolic blood pressure (SBP) in the range of 110-130 mmHg; diastolic blood pressure (DBP) is 60-85 mmHg). Exclusion Criteria: Hypersensitivity to the active substance XC8 (N-[2-(1H-imidazol-4-yl)-ethyl]-6-oxo-δ-lactam) and/or any other component of the drug product. A history of allergy. A history of bronchial asthma, recurrent nasal or paranasal sinus polyposis, allergic rhinitis. Hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome. Chronic diseases of the cardiovascular, bronchopulmonary, neuroendocrine, digestive, urinary, hematopoietic, immune and musculoskeletal systems, mental illness in the history. Acute infectious diseases (including influenza, acute respiratory infections) within 30 days prior to the study. Surgical interventions on the gastrointestinal tract in the anamnesis (except appendectomy). Taking any medications, including vitamins, herbal preparations, and dietary supplements within 14 days prior to screening. Taking medications that have significant effects on hemodynamics or liver function (barbiturates, omeprazole, cimetidine, etc.) for less than 30 days before screening. Vital signs outside the reference intervals: SBP less than 110 mmHg or greater than 130 mmHg; DBP less than 60 mmHg or greater than 85 mmHg; HR less than 60 bpm or greater than 90 bpm; body temperature less than 35.5 or greater than 36.9° C, RR less than 16 or greater than 20 bpm. Laboratory values outside the reference intervals. Intake of more than 10 units of alcohol per week (where each unit equals 30 ml of spirits or 120 ml of wine or 330 ml of beer) or anamnestic evidence of alcoholism, drug addiction, substance abuse, drug abuse. Smoking more than 10 cigarettes per day and failure to abstain from smoking 48 hours before the study and during the hospital stay. Special diet (e.g., vegetarian, vegan, restricted salt intake) or lifestyle (night work, extreme physical activity). Consumption of alcohol, caffeine, and xanthine-containing products 72 hours before taking the drug product. Consumption of citrus fruits, cranberries and products containing them, preparations or products containing St. John's wort - 7 days before taking the IP. 17. Dehydration due to diarrhea, vomiting, or other reason within the last 24 hours prior to IP administration. Positive result of examination for antibodies to HIV type 1 and 2, syphilis, markers of hepatitis B and C. Positive result of rapid test for COVID-19. Positive breath alcohol test. Positive urine drug test (cocaine, marijuana, amphetamine, methamphetamine, morphine, barbiturates). Pregnancy, breastfeeding, positive urine pregnancy test (for women of preserved reproductive potential). Use of hormonal contraceptives (oral, transdermal, injectable, implantable) by a female volunteer for 2 months prior to the drug administration. Donation of blood (450 ml or more) within 30 days prior to the study. Participation in a clinical drug study of any phase within 90 days prior to the start of the study. Unavailability for observation during the study, inability to keep the visit schedule, inability to be hospitalized for the required duration, high likelihood of problems with successful insertion of a venous catheter or performing a forearm vein puncture. Belonging to a vulnerable group of volunteers (minors; incapacitated; people with limited free will or possibly participating under compulsion (serving a sentence in prison, being in custody in detention centers, military personnel)), as well as law enforcement officers. Other reasons that, in the opinion of the researcher, prevent the participation of the volunteer in the research or create an unreasonable risk. Withdrawal criteria: Withdrawal of consent to participate in the study. SAE, irrespective of causal relationship to drug intake. Any other AE if the researcher believes it is in the best interest of the volunteer to discontinue participation in the study. Missing two consecutive or four or more blood sampling points to determine pharmacokinetic parameters during the same period of the pharmacokinetics study. Violation of study protocol requirements (including because the volunteer refuses to cooperate with the investigator, is late to the clinic, etc.). Volunteer is undergoing or requires treatment that may affect the pharmacokinetic parameters of the drug. Volunteer requires inpatient treatment while participating in the study. Vomiting and/or diarrhea in volunteer within 24 hours prior to the drug administration or within 2 hours (2 maximum Tmax for XC8) after the drug administration. Positive urine drug test result. Positive breath alcohol test. Positive urine pregnancy test. Positive test for COVID-19. Discontinuation of the study at the discretion of the Sponsor or regulatory agency.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XC8, fasted<br>Administration of XC8 20 mg in fasted state in Dosing Periods 1 and 2 followed by administration of XC8 20 mg in fasted state in Dosing Period 3 | Drug: XC8<br>* XC8 10 mg film-coated tablets, 3 discrete doses of 20 mg each separated by 7-day wash-out periods<br>|
| Experimental: XC8, fed<br>Administration of XC8 20 mg in fed state in Dosing Periods 1 and 2 followed by administration of XC8 20 mg in fasted state in Dosing Period 3 | Drug: XC8<br>* XC8 10 mg film-coated tablets, 3 discrete doses of 20 mg each separated by 7-day wash-out periods<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax | Maximum plasma concentration (Cmax) of XC8 and its metabolite | From 0 to 24 hours after dosing on Day 1-2, Day 8-9, and Day 15-16 | 
| Pharmacokinetics - AUC0-t | Area under the plasma concentration-time curve from time 0 to t (AUC0-t) of XC8 and its metabolite | From 0 to 24 hours after dosing on Day 1-2, Day 8-9, and Day 15-16 | 
| Pharmacokinetics - AUC0-inf | Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) of XC8 and its metabolite | From 0 to 24 hours after dosing on Day 1-2, Day 8-9, and Day 15-16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability: adverse event (AE) number and frequency | Number and frequency of adverse events (AEs) or serious AEs (SAEs) | From the screening (and signing informed consent form) to Day 16 of the study or to an early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: adverse event (AE) characteristics | Description and severity of AEs or serious AEs (SAEs), concomitant therapy for AEs/SAEs, causal relationship with XC221, outcomes | From the screening (and signing informed consent form) to Day 16 of the study or to an early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: vital signs - systolic blood pressure (SBP) | SBP, mmHg | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: vital signs - diastolic blood pressure (DBP) | DBP, mmHg | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: vital signs - respiratory rate (RR) | RR, breaths per minute | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: vital signs - heart rate (HR) | HR, beats per minute | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: vital signs - body temperature | Body temperature, centigrade scale | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: physical examination results | Physical examination results | Screening, from Day -1 to Day 2, from Day 7 to Day 9, from Day 14 to Day 16 and/or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - color | Color of the urine | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - transparency | Transparency of the urine | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - pH | pH of the urine | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - specific gravity | Specific gravity of the urine | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - nitrites | Nitrites in the urine (+/-) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - protein | Protein in the urine (g/L) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - glucose | Glucose in the urine (mmol/L) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - ketones | Ketones in the urine (mmol/L) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - urobilinogen | Urobilinogen in the urine (mmol/L) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis - bilirubin | Bilirubin in the urine (+/-) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis (microscopy) - red blood cells | Red blood cells in the urine (number in sight) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis (microscopy) - white blood cells | White blood cells in the urine (number in sight) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis (microscopy) - cylinders (except hyaline) | Cylinders (except hyaline) in the urine (number in sight) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: urinalysis (microscopy) - bacteria | Bacteria in the urine (number in sight) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - hemoglobin | Hemoglobin, g/dL | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - red blood cells | Red blood cells, 10^6/uL | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - hematocrit | Hematocrit, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - platelets | Platelets, 10^3/uL | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - white blood cells | White blood cells, 10^3/uL | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - erythrocyte sedimentation rate | Erythrocyte sedimentation rate, mm per hour | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - neutrophils | Neutrophils, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - lymphocytes | Lymphocytes, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - eosinophils | Eosinophils, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - Monocytes | Monocytes, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: complete bood count - basophils | Basophils, % | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - total protein | Total protein in blood serum, g/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - creatinine | Creatinine in blood serum, umol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - urea | Urea in blood serum, mmol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - glucose | Glucose in blood serum, mmol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - total bilirubin | Total bilirubin in blood serum, umol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - direct bilirubin | Direct bilirubin in blood serum, umol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - total cholesterol | Total cholesterol in blood serum, mmol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - triglycerides | Triglycerides in blood serum, mmol/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - alanine transaminase (ALT) | ALT in blood serum, U/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - aspartate transaminase (AST) | AST in blood serum, U/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: blood test results - alkaline phosphatase (ALP) | ALP in blood serum, U/L | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: heart rate (beats per minute) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: PQ interval (ms) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QRS complex (ms) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval (QTc) | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QTc (ms) | Screening and Day 16 or on early termination visit within the time frame of the study (from Day -1 to Day 16) |