XC8 Safety, Tolerability and Pharmacokinetics in Healthy Volunteers

Study Overview
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Brief Summary
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A double-blind, randomized, placebo-controlled, Phase I clinical study of the safety and tolerability of increasing doses of XC8 after single and repeated oral administration in healthy volunteers. The volunteers received the study drug once, and then continued daily intake for 14 days after a 6-day break. The primary objective of the study was to evaluate the safety and tolerability profile for XC8 after single and multiple administration based on the frequency and severity of adverse events and changes in vital signs, laboratory results, electrocardiography and results of the physical examination. The secondary objective of the study was to assess pharmacokinetics of XC8.

Detailed Description
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One Russian center was approved for participation in this study. One center was initiated. Healthy volunteers were enrolled in 1 center. The study consisted of 4 periods: screening, single administration, multiple administration and follow-up. All eligible subjects were randomized into the study in appropriate cohort groups sequentially. Cohort 1 - XC8 or Placebo 2 mg once and then daily 14 days after a 6-day break; Cohort 2 - XC8 or Placebo 10 mg once and then daily during 14 days after a 6-day break; Cohort 3 - XC8 or Placebo 50 mg once and then daily during 14 days after a 6-day break; Cohort 4 - XC8 or Placebo 200 mg once and then daily during 14 days after a 6-day break. The decision regarding increasing of the study drug dose for a subsequent cohort was made by the Data Safety Monitoring Committee on the basis of preliminary safety results assessment. A total of 20 volunteers received XC8 (2 mg, 10 mg, 50 mg or 200 mg) and a total of 8 volunteers received the placebo during the study participation. The follow-up period lasted for 4 weeks.

Official Title
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A Double-blind, Randomized, Placebo-controlled Study of the Safety and Tolerability of Increasing Doses of XC8 After Single and Repeated Oral Administration in Healthy Volunteers

Conditions
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Asthma

Intervention / Treatment
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* Drug: XC8
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-smoking men aged 18 to 50 years (inclusive); Verified diagnosis healthy according to standard clinical, laboratory and instrumental methods of examination; Body mass index of 19 to 30 kg/m2 (inclusive); Consent to use reliable methods of contraception during the study and 3 months after its completion (condoms with spermicide); Signed patient information sheet and informed consent form for participation in the study. Exclusion Criteria: Hepatic disorder or renal disease; any other disease that, in the opinion investigator, may affect the results of the study, or may lead to the health aggravation during the study; Laboratory abnormalities at screening; Course intake of medicinal products (including herbs and biologically active additives) for preventive or curative purposes within 1 month prior to screening; Antibodies to HIV and hepatitis C virus, the presence of the hepatitis B surface antigen, a positive syphilis test; The presence of a sleep disorder (for example, night work, sleep disturbances, insomnia, recent return from another time zone, etc.); Signs of alcohol or drug abuse; taking alcohol or drugs during 4 days before screening; History of allergies (including medicines and food products); Symptomatic rhinitis in anamnesis during 2 years prior to screening (allergic rhinitis, non-allergic rhinitis or pollinosis); Blood donation / plasma, surgical intervention (in a hospital environment) during 12 weeks before screening; Participation in other clinical trials or taking the study drug during 3 months before screening; Impossibility to understand or follow protocol instructions; Smoking 3 months before screening; Lactase deficiency, lactose intolerance, glucose-galactose malabsorption; Acute infectious diseases less than 4 weeks before the start of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The dose cohorts were included into the study subsequently based on preliminary safety results evaluation performed by the Data Safety Monitoring Committee. 4 doses of XC8/placebo (2 mg, 10 mg, 50 mg and 200 mg) were used in the study.The duration of exposure to the study drug was 15 days in each cohort: Day 1, once, at the step of single administration, and then in 6 days, daily, 1 time a day for 14 days at the step of multiple administration.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XC8 2 mg<br>Cohort 1: 6 subjects were randomized in a 2:1 ratio to be treated either with 2 mg XC8 (4 subjects) or placebo (2 subjects, see placebo arm). | Drug: XC8<br> <br> * Other names: Histamine glutarimide;|
| Experimental: XC8 10 mg<br>Cohort 2: 6 subjects were randomized in a 2:1 ratio to be treated either with 10 mg XC8 (4 subjects) or placebo (2 subjects, see placebo arm). | Drug: XC8<br> <br> * Other names: Histamine glutarimide;|
| Experimental: XC8 50 mg<br>Cohort 3: 6 subjects were randomized in a 2:1 ratio to be treated either with 50 mg XC8 (4 subjects) or placebo (2 subjects, see placebo arm). | Drug: XC8<br> <br> * Other names: Histamine glutarimide;|
| Experimental: XC8 200 mg<br>Cohort 4: 10 subjects were randomized in a 4:1 ratio to be treated either with 200 mg XC8 (8 subjects) or placebo (2 subjects, see placebo arm). | Drug: XC8<br> <br> * Other names: Histamine glutarimide;|
| Placebo Comparator: Placebo<br>Placebo comparator arm consists of 8 subjects (2 subjects in each cohort). | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse events per treatment arm | Adverse events will be summarized descriptively by treatment arm. Verbatim terms will be mapped to preferred terms and organ systems using the current Medical Dictionary for Regulatory Activities version. For each preferred term, frequency counts and percentages will be calculated by cohort.The nature, severity, seriousness, and relationship to study medication will be summarized for all study subjects | Change from pre-dose to Day 50 | 
| Physical examination | Physical examination results will be listed for following: general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen (including liver examination), extremities, and nervous system. | Day 1 till Day 36 | 
| 12-lead ECG | 12-lead ECG results will be analyzed descriptively | Change from pre-dose till Day 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of XC8 by assessing AUC0-inf | Area under the curve concentration of the drug-time from the time of administration of the drug till infinity | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing Cmax | Maximum plasma concentration | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing AUC0-t | Area under the curve concentration of the drug-time from the time of administration of the drug till the time (t) the last blood sampling | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing Tmax | Time to maximum drug concentration in the blood plasma administration | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing T1/2 | Terminal elimination half-life | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing kel | Elimination rate constant | Day 1 and 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 2 and Day 22 (24 hours ±10 minutes post dose), Day 3 (48 hours ±10 minutes post dose), Day 4 (72 hours ±10 minutes post dose), Day 8 to 12 and 15 (Pre dose) | 
| Pharmacokinetics of XC8 by assessing Cav | Average concentration over one dosing interval | Day 8 to 12 and 15 (Pre dose); Day 21 (Pre dose, and 20 min, 40 min, 1, 2, 4, 6 and 10 hours post dose), Day 22 (24 hours ±10 minutes post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, Phase I, Histamine glutarimide, PHARMENTERPRISES