A Trial to Investigate the Safety, Tolerability, and Drug Levels in Blood After Single and Multiple Doses of LEO 32731 in Healthy People

Study Overview
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Brief Summary
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This is a phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of 4 different oral formulations of LEO 32731 in healthy subjects. The trial will be conducted in 3 parts at a single site. Each eligible subject will be enrolled into 1 group only and will participate in 3 treatment periods.

Detailed Description
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Part 1 will evaluate the pharmacokinetics of single doses of 4 test formulations of LEO 32731 compared with a reference formulation. Part 2 will evaluate the effect of food on the pharmacokinetics of selected test formulations of LEO 32731. Part 3 will evaluate the tolerability and safety of selected test formulations of LEO 32731 after multiple dosing. Based on data from Part 1, up to 3 formulations will be taken forward to Part 2. If none of the formulations are considered appropriate to take forward to Part 2, the trial will stop after Part 1. Similarly, based on data from Part 2, up to 2 formulations will be taken forward to Part 3. If none of the formulations are considered appropriate to take forward to Part 3, the trial will stop after Part 2.

Official Title
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A Phase 1, 3-part, Single (Open-label) and Multiple (Double-blind, Placebo-controlled) Oral Dose Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of LEO 32731 Formulations in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: LEO 32731 modified release tablet
* Drug: LEO 32731 blend, hard capsule
* Drug: LEO 32731 API, hard capsule
* Drug: LEO 32731 soft capsule
* Drug: LEO 32731 gastro-resistant capsule
* Drug: LEO 32731
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Age 18 to 65 years, inclusive. Body mass index of 18.5 to 29.9 kg/m2, inclusive. In good health, at the discretion of the investigator, as determined by: medical history, physical examination, vital sign assessment (specifically, blood pressure must be within normal reference range), 12-lead ECG, clinical laboratory evaluations, aspartate aminotransferase and alanine aminotransferase not above the upper limit of normal (Gilbert's syndrome is not acceptable). Female subjects of childbearing potential must be willing to use a highly effective form of birth control in conjunction with a barrier method of contraception throughout the trial and for at least 90 days after final follow-up. Male subjects with a female partner of childbearing potential must be willing to use a highly effective form of birth control in conjunction with male barrier method of contraception (i.e. male condom with spermicide) throughout the trial and for at least 90 days after final follow-up. Key exclusion criteria: Systemic or topical treatment within 14 days prior to first dose administration unless in the opinion of the investigator the medication will not interfere with the trial procedures or compromise safety. Any medications, including St. John's wort, known to chronically alter drug absorption or elimination processes within 30 days prior to first dose administration. Subjects who smoke more than an average of 10 cigarettes per day. History of chronic alcohol or drug abuse within 12 months prior to screening. Subjects with ≥3 bowel movements per day. Any disorder which is not stable and could: Affect the safety of the subject throughout the trial; Influence the findings of the trial; Impede the subject's ability to complete the trial. Examples include but are not limited to cardiovascular, GI, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, immunological, and psychiatric disorders and major physical impairment.

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: Sequential Assignment
Interventional Model Description: Part 1 (single dose, cross-over) Part 2 (single dose, cross-over with food effect evaluation) Part 3 (multiple dose, parallel)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1-1<br>Part 1: Subjects will receive 3 doses of LEO 32731 in different formulations, as follows (1 dose per formulation/treatment period): LEO 32731 modified release tablet; LEO 32731 blend, hard capsule; LEO 32731 API hard capsule (reference formulation). | Drug: LEO 32731 modified release tablet<br>* At each dosing, subjects will swallow the appropriate number of tablets with approximately 240 mL of water at room temperature.<br>Drug: LEO 32731 blend, hard capsule<br>* At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.<br>Drug: LEO 32731 API, hard capsule<br>* At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.<br>|
| Active Comparator: Group 1-2<br>Part 1: Subjects will receive 3 doses of LEO 32731 in different formulations, as follows (1 dose per formulation/treatment period): LEO 32731 soft capsule; LEO 32731 gastro-resistant capsule; LEO 32731 API hard capsule (reference formulation). | Drug: LEO 32731 API, hard capsule<br>* At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.<br>Drug: LEO 32731 soft capsule<br>* At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.<br>Drug: LEO 32731 gastro-resistant capsule<br>* At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.<br>|
| Experimental: Group 2-1<br>Part 2: Subjects will receive 3 doses of the same LEO 32731 formulation under different conditions, as follow (1 dose per condition/treatment period): fasted, after low-fat breakfast, after high-fat breakfast. The formulation depends on the outcome of Part 1. | Drug: LEO 32731<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>|
| Experimental: Group 2-2<br>Part 2: Subjects will receive 3 doses of the same LEO 32731 formulation under different conditions, as follow (1 dose per condition/treatment period): fasted, after low-fat breakfast, after high-fat breakfast. The formulation depends on the outcome of Part 1. | Drug: LEO 32731<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>|
| Experimental: Group 2-3<br>Part 2: Subjects will receive 3 doses of the same LEO 32731 formulation under different conditions, as follow (1 dose per condition/treatment period): fasted, after low-fat breakfast, after high-fat breakfast. The formulation depends on the outcome of Part 1. | Drug: LEO 32731<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>|
| Placebo Comparator: Group 3-1<br>Subjects will be dosed twice daily from Days 1-17 (morning dose only on Day 17) with LEO 32731 or placebo. The formulation depends on the outcome of Part 2. | Drug: LEO 32731<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>Other: Placebo<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>|
| Placebo Comparator: Group 3-2<br>Subjects will be dosed twice daily from Days 1-17 (morning dose only on Day 17) with LEO 32731 or placebo. The formulation depends on the outcome of Part 2. | Drug: LEO 32731<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>Other: Placebo<br>* At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1. AUC0-∞ | AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 1. Relative bioavailability (F-rel) | F-rel: AUC0 ∞ test formulations/AUC0-∞ reference formulation (derived from the statistical analysis of AUC0-∞) | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 1. C-max | C-max: Maximum observed plasma concentration | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 1. t-max | t-max: Time to reach maximum observed plasma concentration | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 2. AUC0-∞ | AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 2. Relative bioavailability (F-rel) | F-rel: AUC0 ∞ test formulations/AUC0-∞ reference formulation (derived from the statistical analysis of AUC0-∞) | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 2. C-max | C-max: Maximum observed plasma concentration | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 2. t-max | t-max: Time to reach maximum observed plasma concentration | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 3. Number of GI-related AEs and number of subjects with GI-related AEs during the treatment period | AEs: adverse events; GI: gastrointestinal | From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period. | AEs: adverse events; GI: gastrointestinal | 24 days (from first dose in first treatment period until end of last treatment period) in Part 1 | 
| Part 1. Number of total AEs and number of subjects with AEs during each combination of treatment and period | AEs: adverse events | 24 days (from first dose in first treatment period until end of last treatment period) in Part 1 | 
| Part 1. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose | 
| Part 1. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose | 
| Part 1. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose | 
| Part 1. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose | 
| Part 1. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 | 
| Part 1. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 | 
| Part 1. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | QTcF: QT interval corrected for heart rate according to Fridericia's method. Normal: ≤450 msec for males and ≤470 msec for females. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 | 
| Part 1. AUC0-t | AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 1. t1/2 | t1/2: apparent terminal half-life | Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 | 
| Part 2. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period. | AEs: adverse events; GI: gastrointestinal | 28 days (from first dose in first treatment period until end of last treatment period) in Part 2 | 
| Part 2. Number of total AEs and number of subjects with AEs during each combination of treatment and period | AEs: adverse events | 28 days (from first dose in first treatment period until end of last treatment period) in Part 2 | 
| Part 2. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose | 
| Part 2. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose | 
| Part 2. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose | 
| Part 2. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator | At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose | 
| Part 2. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 | 
| Part 2. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 | 
| Part 2. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | QTcF: QT interval corrected for heart rate according to Fridericia's method. Normal: ≤450 msec for males and ≤470 msec for females. Clinical significance of abnormal values as judged by the investigator | At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 | 
| Part 2. AUC0-t | AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 2. t1/2 | t1/2: apparent terminal half-life | Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 | 
| Part 3. AUC0-∞ | AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity | Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 | 
| Part 3. C-max | C-max: Maximum observed plasma concentration | Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 | 
| Part 3. t-max | t-max: Time to reach maximum observed plasma concentration | Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 | 
| Part 3. AUC0-t | AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration | Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 | 
| Part 3. t1/2 | t1/2: apparent terminal half-life | Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 | 
| Part 3. Number of total AEs and number of subjects with AEs during the treatment period | AEs: adverse events | From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3 | 
| Part 3. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Days 1, 3, 5, 7, 9, and 11: predose and 4 hours postdose; Day 17: predose, 4 hours, and 12 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Days 1, 3, 5, 7, 9, and 11: predose and 4 hours postdose; Day 17: predose, 4 hours, and 12 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Days 1, 3, 5, 7, 9, and 11: predose and 4 hours postdose; Day 17: predose, 4 hours, and 12 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Days 1, 3, 5, 7, 9, and 11: predose and 4 hours postdose; Day 17: predose, 4 hours, and 12 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Day 1: predose and 4 hours postdose; Days 3, 5, 7, 9, 11, and 17: 4 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Day 1: predose and 4 hours postdose; Days 3, 5, 7, 9, 11, and 17: 4 hours postdose; Day 19 (=48 hours postdose) | 
| Part 3. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' | QTcF: QT interval corrected for heart rate according to Fridericia's method. Normal: ≤450 msec for males and ≤470 msec for females. Clinical significance of abnormal values as judged by the investigator | At screening and during the treatment period in Part 3: Day 1: predose and 4 hours postdose; Days 3, 5, 7, 9, 11, and 17: 4 hours postdose; Day 19 (=48 hours postdose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy