A Trial to Investigate the Safety, Tolerability, and Drug Levels in Blood After Single and Multiple Doses of LEO 32731 in Healthy People
- Conditions
- Healthy
- Interventions
- Drug: LEO 32731 modified release tabletDrug: LEO 32731 blend, hard capsuleDrug: LEO 32731 soft capsuleOther: PlaceboDrug: LEO 32731 API, hard capsuleDrug: LEO 32731 gastro-resistant capsule
- Registration Number
- NCT03812198
- Lead Sponsor
- LEO Pharma
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 66
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Group 1-1 LEO 32731 modified release tablet 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). Group 1-1 LEO 32731 blend, hard capsule 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). Group 1-1 LEO 32731 API, hard capsule 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). Group 1-2 LEO 32731 API, hard capsule 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). Group 1-2 LEO 32731 soft capsule 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). Group 1-2 LEO 32731 gastro-resistant capsule 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). Group 2-1 LEO 32731 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. Group 2-2 LEO 32731 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. Group 2-3 LEO 32731 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. Group 3-1 LEO 32731 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. Group 3-1 Placebo 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. Group 3-2 Placebo 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. Group 3-2 LEO 32731 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.
- Primary Outcome Measures
Name Time Method Part 1. Relative bioavailability (F-rel) Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 F-rel: AUC0 ∞ test formulations/AUC0-∞ reference formulation (derived from the statistical analysis of AUC0-∞)
Part 1. C-max Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 C-max: Maximum observed plasma concentration
Part 1. t-max Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 t-max: Time to reach maximum observed plasma concentration
Part 2. AUC0-∞ Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity
Part 2. Relative bioavailability (F-rel) Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 F-rel: AUC0 ∞ test formulations/AUC0-∞ reference formulation (derived from the statistical analysis of AUC0-∞)
Part 3. Number of GI-related AEs and number of subjects with GI-related AEs during the treatment period From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3 AEs: adverse events; GI: gastrointestinal
Part 1. AUC0-∞ Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity
Part 2. C-max Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 C-max: Maximum observed plasma concentration
Part 2. t-max Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 t-max: Time to reach maximum observed plasma concentration
- Secondary Outcome Measures
Name Time Method Part 1. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period. 24 days (from first dose in first treatment period until end of last treatment period) in Part 1 AEs: adverse events; GI: gastrointestinal
Part 1. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator
Part 1. AUC0-t Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration
Part 1. Number of total AEs and number of subjects with AEs during each combination of treatment and period 24 days (from first dose in first treatment period until end of last treatment period) in Part 1 AEs: adverse events
Part 1. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 1. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator
Part 2. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 72 hours postdose in Treatment period 3 in Part 2 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
Part 2. AUC0-t Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration
Part 1. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 1. t1/2 Calculated using concentration data collected from predose to 48 hours postdose for each treatment period in Part 1 t1/2: apparent terminal half-life
Part 2. Number of total AEs and number of subjects with AEs during each combination of treatment and period 28 days (from first dose in first treatment period until end of last treatment period) in Part 2 AEs: adverse events
Part 2. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 2: predose, 4 hours, 24 hours, and 72 hours postdose Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 2. t1/2 Calculated using concentration data collected from predose to 72 hours postdose for each treatment period in Part 2 t1/2: apparent terminal half-life
Part 3. AUC0-∞ Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity
Part 3. C-max Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 C-max: Maximum observed plasma concentration
Part 3. t-max Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 t-max: Time to reach maximum observed plasma concentration
Part 3. AUC0-t Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 AUC0-t: area under the plasma concentration time curve from time 0 to the time of last observed quantifiable concentration
Part 3. t1/2 Calculated using concentration data collected from predose to 16 hours postdose on Day 17 in Part 3 t1/2: apparent terminal half-life
Part 3. Number of total AEs and number of subjects with AEs during the treatment period From Day 1 (first dose) to Day 19 (end of treatment period) in Part 3 AEs: adverse events
Part 3. Number of subjects with systolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≥90 and ≤140 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 3. Number of subjects with diastolic blood pressure in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≥45 and ≤90 mmHg. Clinical significance of abnormal values as judged by the investigator
Part 3. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator
Part 1. Number of subjects with pulse rate in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening and during each treatment period in Part 1: predose, 4 hours, 24 hours, and 48 hours postdose Normal: ≥40 and ≤100 beats/minute. Clinical significance of abnormal values as judged by the investigator
Part 1. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator
Part 1. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' At screening, predose in Treatment period 1, and 48 hours postdose in Treatment period 3 in Part 1 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
Part 2. Number of GI-related AEs and number of subjects with GI-related AEs during each combination of treatment and period. 28 days (from first dose in first treatment period until end of last treatment period) in Part 2 AEs: adverse events; GI: gastrointestinal
Part 3. Number of subjects with body temperature in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≥35 and ≤37.5°C. Clinical significance of abnormal values as judged by the investigator
Part 3. Number of subjects with PR interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≥120 and ≤220 msec. Clinical significance of abnormal values as judged by the investigator
Part 3. Number of subjects with QRS duration in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) Normal: ≤120 msec. Clinical significance of abnormal values as judged by the investigator
Part 3. Number of subjects with QTcF interval in each of the following categories: 'normal', 'abnormal, not clinically significant', 'abnormal, clinically significant' 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) 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
Trial Locations
- Locations (1)
LEO Pharma Investigational Site
🇬🇧Leeds, United Kingdom