Clinical trial NCT03812198: A Trial to Investigate the Safety, Tolerability, and Drug Levels in Blood After Single and Multiple Doses of LEO 32731 in Healthy People
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: healthy
Lead sponsor: LEO Pharma
Sponsor class: INDUSTRY
First posted: 2019-01-23
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 (single dose, cross-over) Part 2 (single dose, cross-over with food effect evaluation) Part 3 (multiple dose, parallel)
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1. AUC0-∞
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 1. Relative bioavailability (F-rel)
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 1. C-max
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 1. t-max
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 2. AUC0-∞
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 2. Relative bioavailability (F-rel)
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 2. C-max
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 2. t-max
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 3. Number of GI-related AEs and number of subjects with GI-related AEs during the treatment period
timeFrame: From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3
Secondary outcomes:
measure: Part 1. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period.
timeFrame: 24 days (from first dose in first treatment period until end of last treatment period) in Part 1
measure: Part 1. Number of total AEs and number of subjects with AEs during each combination of treatment and period
timeFrame: 24 days (from first dose in first treatment period until end of last treatment period) in Part 1
measure: Part 1. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose
measure: Part 1. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose
measure: Part 1. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose
measure: Part 1. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose
measure: Part 1. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1
measure: Part 1. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1
measure: Part 1. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1
measure: Part 1. AUC0-t
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 1. t1/2
timeFrame: Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1
measure: Part 2. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period.
timeFrame: 28 days (from first dose in first treatment period until end of last treatment period) in Part 2
measure: Part 2. Number of total AEs and number of subjects with AEs during each combination of treatment and period
timeFrame: 28 days (from first dose in first treatment period until end of last treatment period) in Part 2
measure: Part 2. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose
measure: Part 2. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose
measure: Part 2. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose
measure: Part 2. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose
measure: Part 2. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2
measure: Part 2. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2
measure: Part 2. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2
measure: Part 2. AUC0-t
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 2. t1/2
timeFrame: Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2
measure: Part 3. AUC0-∞
timeFrame: Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3
measure: Part 3. C-max
timeFrame: Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3
measure: Part 3. t-max
timeFrame: Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3
measure: Part 3. AUC0-t
timeFrame: Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3
measure: Part 3. t1/2
timeFrame: Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3
measure: Part 3. Number of total AEs and number of subjects with AEs during the treatment period
timeFrame: From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3
measure: Part 3. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
measure: Part 3. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant'
timeFrame: 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)
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
facility: LEO Pharma Investigational Site
Study officials:
affiliation: LEO Pharma
name: Medical Expert
role: STUDY_DIRECTOR
References: