Healthy
Conditions
Keywords
healthy
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.
Interventions
DRUGLEO 32731 modified release tablet
At each dosing, subjects will swallow the appropriate number of tablets with approximately 240 mL of water at room temperature.
DRUGLEO 32731 blend, hard capsule
At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
DRUGLEO 32731 API, hard capsule
At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
DRUGLEO 32731 soft capsule
At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
DRUGLEO 32731 gastro-resistant capsule
At each dosing, subjects will swallow the appropriate number of capsules with approximately 240 mL of water at room temperature.
DRUGLEO 32731
At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
OTHERPlacebo
At each dosing, subjects will swallow the appropriate number of tablets or capsules with approximately 240 mL of water at room temperature.
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
3-part, single (open-label) and multiple (double-blind, placebo-controlled)
Intervention model description
Part 1 (single dose, cross-over) Part 2 (single dose, cross-over with food effect evaluation) Part 3 (multiple dose, parallel)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. 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 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 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. 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 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 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 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 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 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 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 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 |
| 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 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 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. 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 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 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 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 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. 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 |
Countries
United Kingdom
Outcome results
None listed