Clinical trial NCT04505397: Single-Dose Escalation Study Followed by a Multiple-Dose Escalation Study of SKL24741 in Healthy Subjects
Official title: A Phase 1, Randomized, Double-Blinded, Single-Dose Escalation Study Followed by a Multiple-Dose Escalation Study of SKL24741 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: SK Life Science, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Spaulding Clinical Research LLC
name: Covance
First posted: 2020-08-10
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study evaluates SKL24741 safety and tolerability in healthy subjects. Subjects will be randomized to receive oral doses of SKL24741 or placebo. This is a two-part, double-blinded, randomized study of SKL24741.

Detailed description: The study includes a sequential cohort design that is intended to optimize subject safety and assess tolerability, safety, and PK of SKL24741. In the single-dose escalation part of the study (Part A), tolerability, safety, and PK of SKL24741 will be assessed in healthy male subjects under fasting conditions. At an appropriate dose based on PK results, additional cohorts will be repeated with the subjects under fed conditions, in order to evaluate the magnitude on the disposition of SKL24741. To assess the gender effect on the disposition of SKL24741, female subjects will be treated at one dose level under fasting conditions. A preliminary formulation effect may be assessed in a cohort of subjects to compare the capsule versus tablet formulation on the disposition of SKL24741.

Part A Primary Objective: To evaluate the safety and tolerability of single oral ascending doses of SKL24741 administered to healthy male subjects

Part A Secondary Objectives:

* To evaluate the PK of SKL24741 (R-enantiomer), SKL24742 (S-enantiomer) (if appropriate), and its possible metabolites (if deemed necessary) following administration of single oral ascending doses of SKL24741 administered to healthy male subjects
* To assess the food effect on the PK of SKL24741 and SKL24742 (if appropriate) following administration of a single oral dose of SKL24741 administered to healthy male subjects
* To assess the gender effect on the PK of SKL24741 and SKL24742 (if appropriate) following administration of a single oral dose of SKL24741 administered to healthy female subjects

Part A Exploratory Objective: To assess the formulation effect on the PK of SKL24741 and SKL24742 (if appropriate) following administration of a single oral dose of SKL24741 administered to healthy male subjects

Part B Primary Objective: To evaluate safety and tolerability of multiple oral ascending doses of SKL24741 administered for 14 days to healthy male subjects

Part B Secondary Objective: To evaluate the PK of SKL24741, SKL24742 (if appropriate), and its possible metabolites (if deemed necessary) following administration of multiple oral ascending doses of SKL24741 administered to healthy male subjects

Eligibility criteria: Inclusion Criteria:

1. Male subjects of 18 to 50 years of age (inclusive) except for the gender effect cohort
2. Able to read, understand, sign, and date a written informed consent form (ICF) before study participation at screening
3. Agree to use 2 highly effective methods of contraception, including at least one barrier method (Section 10.6.7 for details)
4. Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening
5. Judged to be in good health on the basis of medical history, physical examination, and routine laboratory measurements (i.e., without clinically relevant pathology)
6. Normal electrocardiogram (ECG) (12-lead), arterial blood pressure, and heart rate within the normal range of the study center or considered not clinically significant by the investigator and in agreement with the Sponsor
7. Able to understand and comply with protocol requirements and instructions and likely to complete the study as planned
8. For Part A (gender effect cohort): Female of non-childbearing potential (18 to 50 years of age (inclusive)), who have undergone a sterilization procedure at least 6 months prior to dosing with official documentation (e.g., hysteroscopic sterilization, bilateral tubal ligation or bilateral salpingectomy, hysterectomy, or bilateral oophorectomy), or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per Principal Investigator's judgment

Exclusion Criteria:

1. History of any illness or condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subjects.
2. Smokers (subjects who have smoked within 6 months at screening or those with positive results from smoking screening).
3. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with pharmacokinetics of the trial medication (except appendectomy and simple hernia repair).
4. Regular treatment with prescription medications. Subjects should have ended any prescription medications at least 14 days before the first dosing of the study drug. Potential subjects should only stop any prescribed medication at the direction of a physician.
5. Regular treatment with nonprescription medications. Subjects should have ended any nonprescription medications at least 14 days before the first dosing of the study drug. Potential subjects should consult a physician before stopping any regular treatment with nonprescription medication.
6. Consumption of herbal medications, dietary supplements, and specific fruit products. Subjects should have stopped consumption of herbal medications or dietary supplements (e.g., St. John's Wort, ginkgo biloba, and garlic supplements), vitamins, and grapefruit or grapefruit juice, or Seville oranges at least 14 days before the first dosing of study drug.
7. History of drug or alcohol abuse or addiction within 2 years before the start of study drug dosing, or a positive test results for alcohol or drugs of abuse, such as amphetamine, barbiturate, benzodiazepine, cocaine, methadone, opiates, oxycodone, phencyclidine, propoxyphene, cannabinoid (THC), MDMA (Ecstasy), methaqualone, and tricyclic antidepressant (TCA).
8. Regular consumption of more than 2 units of alcoholic beverages per day or more than 14 units per week (1 unit of alcohol equals 1 pint \[473 mL\] of beer or lager, 1 glass \[125 mL\] of wine, 25 mL shot of 40% spirit) before screening. Subjects may not consume any alcohol from 72 hours before the first dosing of study drug through the completion of the last PK sampling.
9. Consumption of an average of more than 5 servings (8 ounces per serving) per day of coffee, cola, or other caffeinated beverage before screening. Subjects may not consume any caffeinated beverages from 48 hours prior to dosing until the collection of the last PK sample.
10. Participation in a clinical study involving administration of either an investigational or a marketed drug within 2 months or 7 half-lives (whichever is longer) before screening.
11. Blood donation or a significant loss of blood within 60 days of the start of study drug dosing or donation of more than 1 unit of plasma within 7 days before screening.
12. Positive result at screening for any of the following infectious disease tests: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), human immunodeficiency virus antigen and antibody (HIV Ag, HIV Ab)
13. Illness within 5 days before the start of study drug dosing ("illness" is defined as an acute \[serious or non-serious\] condition \[e.g., the flu or the common cold\])
14. History of any known relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients)
15. Subject who is judged not eligible for study participation by investigator

Primary outcomes:
measure: Adverse events (Incidence of treatment-emergent adverse events)
timeFrame: From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Clinically significant laboratory assessments
timeFrame: From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Electrocardiogram outcomes
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, pre-dose until 24 hours post-dose. In Part B, Day1: pre-dose until 8 hours post-dose; Day 2-13: pre-dose only; Day 14: pre-dose until 24 hours post-dose)
measure: Vital sign
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, Day1: pre-dose until 12 hours post-dose. In Part B, Day1: pre-dose until 12 hours post-dose; Day 2-14: pre-dose until 8 hours post-dose)
measure: Vital sign
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, Day1: pre-dose until 12 hours post-dose. In Part B, Day1: pre-dose until 12 hours post-dose; Day 2-14: pre-dose until 8 hours post-dose)
measure: Vital sign
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, Day1: pre-dose until 12 hours post-dose. In Part B, Day1: pre-dose until 12 hours post-dose; Day 2-14: pre-dose until 8 hours post-dose)
measure: Vital sign
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, Day1: pre-dose until 12 hours post-dose. In Part B, Day1: pre-dose until 12 hours post-dose; Day 2-14: pre-dose until 8 hours post-dose)
measure: Vital signs
timeFrame: From Screening until follow-up, including time-point assessments (In Part A, Day1: pre-dose until 12 hours post-dose. In Part B, Day1: pre-dose until 12 hours post-dose; Day 2-14: pre-dose until 8 hours post-dose)
measure: Physical examination
timeFrame: Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Physical examination
timeFrame: Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Physical examination
timeFrame: Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Physical examination
timeFrame: Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Physical examination
timeFrame: Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)
measure: Peak expiratory flow rate
timeFrame: Assessed at admission (Day -1), pre-dose (baseline), 2 and 24 hours post-dose after the first dose (Day 1 dosing) and the last dose (Day 14 dosing for Part B), and follow-up (14-16 days after dosing day or final dosing day)
measure: Columbia-Suicide Severity Rating Scale (Part B only)
timeFrame: From Screening until follow-up (14-16 days after dosing day or final dosing day). Baseline ("Lifetime/Recent") at Screening and "Since Last Visit" versions on other visits
Secondary outcomes:
measure: Maximum concentration (Cmax) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Time to maximum concentration (tmax) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Area under the concentration-time curve (AUC) from 0 to infinity (AUC∞) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: AUC from time 0 to a given time t (AUCt) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: AUC over the dosing interval (AUCτ) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Apparent clearance (CL/F) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Apparent volume of distribution (Vd/F) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Half-life (t1/2) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
measure: Accumulation ratio (Racc) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose plasma samples. In Part B, Days 1 and 7: pre-dose and up to 24 hours post-dose, Days 3-6 and 9-13: pre-dose only, and Day 14: Pre-dose and up to 240 hours post-dose plasma samples
Other outcomes:
measure: Fraction excreted unchanged in the urine (fe) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose urine samples.
measure: Renal clearance (CLr) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single dose administration of SKL24741
timeFrame: In Part A, pre-dose and up to 240 hours post-dose urine samples.
Locations:
city: West Bend
country: United States
facility: Spaulding Clinical Research
state: Wisconsin
Study officials:
affiliation: SK Life Science, Inc.
name: Vijaykumar Vashi, PhD
role: STUDY_DIRECTOR
References: