Single-Dose Escalation Study Followed by a Multiple-Dose Escalation Study of SKL24741 in Healthy Subjects

NCT04505397 | Completed Phase 1 FDA Drug

• 1 other identifier: SKL24741C001
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Outcome Measures

Primary Outcomes (15)

• Adverse events (Incidence of treatment-emergent adverse events)

  The number \[count\] and percentage \[%\] of subjects experiencing an adverse event

  From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Clinically significant laboratory assessments

  Hematology, coagulation, clinical chemistry, urinalysis, and cholesterol

  From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Electrocardiogram outcomes

  Standard electrocardiograms (ECGs) parameters will be measured, including heart rate (HR) \[beats/min\], RR \[millisecond\], PR \[millisecond\], QT \[millisecond\], QTc intervals \[millisecond\], and QRS duration \[millisecond\]. Extensive triplicate 12-lead ECGs, except for the food effect cohort, will be collected at various time points.

  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)

• Vital sign

  Blood pressure (systolic and diastolic measurements in supine and standing in the same sequence in each subject, in order to allow orthostatic measurements) \[mmHg\]

  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)

• Vital sign

  Temperature \[Celsius\]

  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)

• Vital sign

  Heart rate \[beats/min\]

  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)

• Vital sign

  Respiratory rate \[breaths/min\]

  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)

• Vital signs

  Arterial oxygen saturation (SaO2) (using pulse oximetry) \[%\]

  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)

• Physical examination

  Full physical examination (review of all body systems - head/neck/thyroid, eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and neurological. Breast, anorectal, and genital examinations)

  Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Physical examination

  Height \[centimeter\]

  Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Physical examination

  Weight \[kg\]

  Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Physical examination

  BMI \[kg/m\^2\]

  Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Physical examination

  Abbreviated (symptom-directed) physical examination.

  Full (complete) physical examination at screening only. From Screening until follow-up (14-16 days after dosing day or final dosing day)

• Peak expiratory flow rate

  Peak expiratory flow rate \[L/min\], the maximum rate that a person can exhale during a short maximal expiratory effort after a full inspiration

  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)

• Columbia-Suicide Severity Rating Scale (Part B only)

  Columbia-Suicide Severity Rating Scale (C-SSRS) is a brief questionnaire that provides for the identification, quantification, and standardized assessment of the occurrences and severity of suicidal ideation and behavior. The changes from baseline and clinical abnormalities will be assessed (units on a scale).

  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 (9)

• Maximum concentration (Cmax) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single and/or multiple dose administration of SKL24741

  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

• 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

  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

• 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

  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

• 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

  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

• 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

  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 (2)

• 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

  In Part A, pre-dose and up to 240 hours post-dose urine samples.

• Renal clearance (CLr) of SKL24741, SKL24742 (if appropriate), and possible metabolites (if deemed necessary) following the single dose administration of SKL24741

  In Part A, pre-dose and up to 240 hours post-dose urine samples.

Study Arms (22)

Single Ascending Dose Level 1

EXPERIMENTAL

4 Subjects will receive one dose of 10 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 2

EXPERIMENTAL

4 Subjects will receive one dose of 25 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 3

EXPERIMENTAL

4 Subjects will receive one dose of 50 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 4

EXPERIMENTAL

4 Subjects will receive one dose of 100 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 5

EXPERIMENTAL

4 Subjects will receive one dose of 200 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 6

EXPERIMENTAL

4 Subjects will receive one dose of 300 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 7

EXPERIMENTAL

4 Subjects will receive one dose of 400 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 8

EXPERIMENTAL

4 Subjects will receive one dose of 800 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 9

EXPERIMENTAL

4 Subjects will receive one dose of 1200 mg and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Single Ascending Dose Level 10

EXPERIMENTAL

4 Subjects will receive one dose on the outcome of preceding dose levels and 2 subjects will receive one dose of placebo

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 1

EXPERIMENTAL

6 Subjects will receive one dose of 50 mg each day for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose).

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 2

EXPERIMENTAL

6 Subjects will receive one dose of 200 mg each day for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose).

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 3

EXPERIMENTAL

6 Subjects will receive one dose of 400 mg each day for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose).

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 4

EXPERIMENTAL

6 Subjects will receive one dose of 800 mg each day for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose).

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 5

EXPERIMENTAL

6 Subjects will receive one dose of 1200 mg each day for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose).

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 6

EXPERIMENTAL

6 Subjects will receive one dose of 1200 mg each day (using tablet formulation instead of capsule formulation\*) for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose). \*Tablet formulation is utilized, instead of capsule formulation, in the marked dose levels.

Drug: SKL24741; Drug: Placebo

Food Effect Cohort

EXPERIMENTAL

After completing the fasting Single Ascending Dose escalation, the same 6 subjects who received one dose of 50 mg under fasting conditions will return to the clinic after a washout period for a second confinement to receive a second dose (same as fasting) under fed conditions.

Drug: SKL24741

Gender Effect Cohort

EXPERIMENTAL

6 female subjects of non-childbearing potential will receive one dose of 50 mg under fasting conditions.

Drug: SKL24741

Optional Food Effect Cohort

EXPERIMENTAL

Up to 12 male subjects will undergo an open-label, two period, two-sequence crossover design at the maximum daily dose tested in Part A.

Drug: SKL24741

Optional Formulation Effect Cohort

EXPERIMENTAL

Up to 12 male subjects will be treated with the maximum daily dose tested in Part A using open-label, two period, two-sequence crossover design.

Drug: SKL24741

Multiple Ascending Dose Level 7

EXPERIMENTAL

6 Subjects will receive one dose of 2000 mg each day (using tablet formulation instead of capsule formulation\*) for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose). \*Tablet formulation is utilized, instead of capsule formulation, in the marked dose levels.

Drug: SKL24741; Drug: Placebo

Multiple Ascending Dose Level 8

EXPERIMENTAL

6 Subjects will receive one dose each day (using tablet formulation instead of capsule formulation\*) for 14 days and 2 subjects will receive one dose placebo every day for 14 days. The dose will be determined based on the outcome of Part A (Single Ascending Dose) and/or preceding dose levels of Part B (Multiple Ascending Dose). \*Tablet formulation is utilized, instead of capsule formulation, in the marked dose levels.

Drug: SKL24741; Drug: Placebo

Interventions

SKL24741 DRUG

An inhibitor of voltage-gated sodium channels and a possible activator of Big Potassium channels. Administered as an oral dose in the form of a capsule or tablet.

Food Effect Cohort; Gender Effect Cohort; Multiple Ascending Dose Level 1; Multiple Ascending Dose Level 2; Multiple Ascending Dose Level 3; Multiple Ascending Dose Level 4; Multiple Ascending Dose Level 5; Multiple Ascending Dose Level 6; Multiple Ascending Dose Level 7; Multiple Ascending Dose Level 8; Optional Food Effect Cohort; Optional Formulation Effect Cohort; Single Ascending Dose Level 1; Single Ascending Dose Level 10; Single Ascending Dose Level 2; Single Ascending Dose Level 3; Single Ascending Dose Level 4; Single Ascending Dose Level 5; Single Ascending Dose Level 6; Single Ascending Dose Level 7; Single Ascending Dose Level 8; Single Ascending Dose Level 9

Placebo DRUG

Sugar pill manufactured to mimic SKL24741

Multiple Ascending Dose Level 1; Multiple Ascending Dose Level 2; Multiple Ascending Dose Level 3; Multiple Ascending Dose Level 4; Multiple Ascending Dose Level 5; Multiple Ascending Dose Level 6; Multiple Ascending Dose Level 7; Multiple Ascending Dose Level 8; Single Ascending Dose Level 1; Single Ascending Dose Level 10; Single Ascending Dose Level 2; Single Ascending Dose Level 3; Single Ascending Dose Level 4; Single Ascending Dose Level 5; Single Ascending Dose Level 6; Single Ascending Dose Level 7; Single Ascending Dose Level 8; Single Ascending Dose Level 9

Eligibility Criteria

• Age: 18 Years - 50 Years
• Gender Eligibility Details: This study will enroll up to 138 Healthy Male Subjects and 6 Non-childbearing potential Female Subjects.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male subjects of 18 to 50 years of age (inclusive) except for the gender effect cohort
• Able to read, understand, sign, and date a written informed consent form (ICF) before study participation at screening
• Agree to use 2 highly effective methods of contraception, including at least one barrier method (Section 10.6.7 for details)
• Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening
• Judged to be in good health on the basis of medical history, physical examination, and routine laboratory measurements (i.e., without clinically relevant pathology)
• 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
• Able to understand and comply with protocol requirements and instructions and likely to complete the study as planned
• 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

You may not qualify if:

• 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.
• Smokers (subjects who have smoked within 6 months at screening or those with positive results from smoking screening).
• Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with pharmacokinetics of the trial medication (except appendectomy and simple hernia repair).
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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)
• Illness within 5 days before the start of study drug dosing ("illness" is defined as an acute \[serious or non-serious\] condition \[e.g., the flu or the common cold\])
• History of any known relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients)
• Subject who is judged not eligible for study participation by investigator

Sponsors & Collaborators

• SK Life Science, Inc.: lead
• Spaulding Clinical Research LLC: collaborator
• Covance: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Study Officials

• Vijaykumar Vashi, PhD

  SK Life Science, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2020
• First Posted: August 10, 2020
• Study Start: February 13, 2020
• Primary Completion: October 27, 2022
• Study Completion: October 27, 2022
• Last Updated: December 21, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)