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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: 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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom
    • LEO Pharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1-1; 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; At each dosing, subjects will swallow the appropriate number of tablets with approximately 240 mL of water at room temperature.; Drug: LEO 32731 blend, hard capsule; At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.; Drug: LEO 32731 API, hard capsule; At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
Active Comparator: Group 1-2; 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; At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.; Drug: LEO 32731 soft capsule; At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.; Drug: LEO 32731 gastro-resistant capsule; At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
Experimental: Group 2-1; 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; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
Experimental: Group 2-2; 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; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
Experimental: Group 2-3; 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; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
Placebo Comparator: Group 3-1; 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; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.; Other: Placebo; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
Placebo Comparator: Group 3-2; 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; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.; Other: Placebo; At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: LEO Pharma

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2019
• Primary Completion (Actual): June 13, 2019
• Study Completion (Actual): June 13, 2019

Study Registration Dates

• First Submitted: January 18, 2019
• First Submitted That Met QC Criteria: January 22, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): July 1, 2019
• Last Update Submitted That Met QC Criteria: June 28, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: healthy
• Other Study ID Numbers: LP0058-1442; 2018-003282-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data feasibility requests and research proposals are sent to disclosure@leo-pharma.com. If feasibility to share the data from a trial is granted, the ultimate decision is made by an external to the company board (Patient and Scientific Review Board). Data sharing is further subject to signed data sharing agreement. Data will be available in a closed environment for a specified period on time.
• IPD Sharing Access Criteria: External researchers with no commercial interest who provide scientifically sound research proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No