Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics After Single and Multiple Doses of LEO 142397 in Healthy People, Including Japanese

Study Overview
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Brief Summary
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This is the first clinical trial with LEO 142397. The purpose of the trial is to assess the safety and tolerability of LEO 142397, along with the pharmacokinetics (what the body does to the drug) and the pharmacodynamics (what the drug does to the body) in healthy people. The trial consists of 2 parts: In Part 1, participants will receive a single dose of LEO 142397. There will be up to 8 different dose groups. In Part 2, participants will receive a daily dose of LEO 142397 for 14 days. There will be up to 6 different dose groups. Each participant will be enrolled into 1 dose group in either Part 1 or Part 2.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LEO 142397 in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: LEO 142397
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key inclusion Criteria: Body mass index of 18.0-32.0 kg/m2, inclusive. In good health at screening and check-in as judged by the investigator based on medical history, physical examination, vital signs assessment, 12-lead electrocardiogram, and clinical laboratory evaluations: Aspartate aminotransferase and alanine aminotransferase values ≤1.5 times the upper limit of normal. Congenital nonhaemolytic hyperbilirubinaemia (including suspicion of Gilbert's syndrome) is not acceptable. Haemoglobin value, neutrophil count, and lymphocyte count ≥ the lower limit of normal. Female subjects of childbearing potential must use a highly effective form of birth control, in conjunction with adequate barrier contraception, from randomisation until 90 days after the follow-up visit. Male subjects with female partner of childbearing potential must use adequate male barrier contraception, in conjunction with a highly effective form of female contraception for the partner, from randomisation until 90 days after the follow-up visit. Key exclusion criteria: Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of any drug. Any medication, including St. John's wort, known to chronically alter drug absorption or elimination processes within 30 days prior to the first dose. History of any significant infectious disease, as assessed by the investigator, within 2 weeks prior to the first dose. Current active tuberculosis based on QuantiFERON-TB Gold test. Positive hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibodies at screening. Electrocardiogram abnormalities at screening or check-in. Smoking of >10 cigarettes per day, on average, within the last 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single ascending dose Cohort A<br>Single dose of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort B<br>Single dose of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort C<br>2 single doses, separated by a washout of ≥7 days. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort D<br>2 single doses, separated by a washout of ≥7 days. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort E<br>Single dose of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort F<br>Single dose of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort G<br>Single dose of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Single ascending dose Cohort H<br>Single dose of LEO 142397 or placebo - tentative, female-only cohort (to be included only if the number of women recruited in the remaining cohorts is insufficient to assess the pharmacokinetics of LEO 142397 in women). Dose level ≥ that in Cohort C and ≤ that in Cohort D. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort K<br>Multiple doses of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort L<br>Multiple doses of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort M<br>Multiple doses of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort N<br>Multiple doses of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort O<br>Multiple doses of LEO 142397 or placebo. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Multiple ascending dose Cohort P<br>Multiple doses of LEO 142397 or placebo in Japanese-only subjects. Same dose level as for Cohort M. | Drug: LEO 142397<br>* A compound in development by LEO Pharma A/S<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1. Number of treatment-emergent adverse events per subject |  | From Day 1 (postdose) up to Day 8 | 
| Part 1. Having clinically significant abnormalities in systolic blood pressure | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 8 | 
| Part 1. Having clinically significant abnormalities in diastolic blood pressure | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 8 | 
| Part 1. Having clinically significant abnormalities in heart rate | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 8 | 
| Part 1. Having clinically significant abnormalities in oral body temperature | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 8 | 
| Part 1. Having an abnormal ECG | ECG: electrocardiogram. Abnormal ECG (yes/no) defined as: QT interval corrected for heart rate using Fridericia's formula (QTcF) of >450 msec for males / >470 msec for females, or change from baseline of >30 msec | From Day 1 (postdose) up to Day 8 | 
| Part 2. Number of treatment-emergent adverse events per subject |  | From Day 1 (postdose) up to Day 21 | 
| Part 2. Having clinically significant abnormalities in systolic blood pressure | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 21 | 
| Part 2. Having clinically significant abnormalities in diastolic blood pressure | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 21 | 
| Part 2. Having clinically significant abnormalities in heart rate | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 21 | 
| Part 2. Having clinically significant abnormalities in oral body temperature | Clinical significance (yes/no) of abnormal values as judged by the investigator | From Day 1 (postdose) up to Day 21 | 
| Part 2. Having an abnormal ECG | ECG: electrocardiogram. Abnormal ECG (yes/no) defined as: QT interval corrected for heart rate using Fridericia's formula (QTcF) of >450 msec for males / >470 msec for females, or maximum change from baseline of >30 msec | From Day 1 (postdose) up to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1. AUC0-∞ | AUC0-∞: area under the plasma concentration-time curve from time zero to infinity | Derived from plasma concentration-time profile from 0-48 hours postdose | 
| Part 1. Cmax | Cmax: maximum plasma concentration | Derived from plasma concentration-time profile from 0-48 hours postdose | 
| Part 2. Accumulation ratio |  | Derived from plasma concentration-time profile from 0-24 hours postdose on Day 1 and Day 14 | 
| Part 2. AUC0-24 | AUC0-24: area under the plasma concentration-time curve from time zero to 24 hours postdose | Derived from plasma concentration-time profile from 0-24 hours postdose on Day 1 and Day 14 | 
| Part 2. Cmax | Cmax: maximum plasma concentration | Derived from plasma concentration-time profile from 0-24 hours postdose on Day 1 and Day 14 |