Healthy Subjects
Conditions
Brief summary
This was a single centre, open-label, randomised, 5-way crossover study.
Detailed description
This was a single centre, open-label, randomised, 5-way crossover study design to compare the PK of Infacort® versus immediate-release hydrocortisone tablets and to evaluate the dose proportionality of 0.5 mg, 2 mg, 5 mg and 10 mg Infacort®. The study was conducted in 1 cohort of 16 healthy male subjects and comprised a Screening Visit, 5 treatment periods (Treatment Periods 1 to 5) and a Post-study Visit.
Interventions
DRUGInfacort
Multi-particulate granules
DRUGHydrocortisone
Tablet
Sponsors
Simbec Research
Neurocrine UK Limited
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male volunteers between 18 and 60 years of age, inclusive (at Screening Visit). * Subjects with a Body Mass Index (BMI) of 21-28. * Subjects with no clinically significant abnormal serum biochemistry, haematology and urine examination values within 14 days prior to the first dose of investigational medicinal product (IMP). * Subjects with a negative urinary drugs of abuse screen determined within 14 days prior to the first dose of IMP. A positive alcohol test may have been repeated at the discretion of the Investigator. * Subjects with negative human immunodeficiency virus (HIV) and hepatitis B surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results. * Subjects with no clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 14 days prior to the first dose of IMP. * Subjects with no clinically-significant deviation outside the normal ranges for blood pressure and pulse measurements. * Subjects (unless anatomically sterile or where abstaining from sexual intercourse was in-line with the preferred and usual lifestyle of the subject) and sexual partners used effective contraception methods during the trial and for 3 months after the last dose of IMP, for example; oral contraceptive + condom, intra-uterine device (IUD) + condom or diaphragm with spermicide + condom. * Subjects were available to complete the study. * Subjects satisfied a medical examiner about their fitness to participate in the study. * Subjects provided written informed consent to participate in the study.
Exclusion criteria
* A clinically significant history of gastrointestinal disorder likely to influence drug absorption. * Receipt of regular medication within 14 days prior to the first dose of IMP (including high dose vitamins, dietary supplements or herbal remedies). * Receipt of any vaccination within 14 days prior to the first dose of IMP. * Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction. * Presence of clinically significant infections (systemic fungal and viral infections, acute bacterial infections). * Current or previous history of tuberculosis. * A clinically significant history of previous allergy / sensitivity to hydrocortisone and/or dexamethasone. * A clinically significant history or family history of psychiatric disorders/illnesses. * A clinically significant history of drug or alcohol abuse. * Inability to communicate well with the Investigator (i.e., language problem, poor mental development or impaired cerebral function). * Participated in a New Chemical Entity clinical study within the previous 4 months or a marketed drug clinical study within the previous 3 months. (N.B. The washout period between trials was defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study). * Subjects who had consumed more than 2 units of alcohol per day within 7 days prior to the first dose of IMP or had consumed any alcohol within the 48 hr period prior to the first dose of IMP. * Donation of 450 mL or more of blood within the previous 3 months. * Subjects who smoked (or ex-smokers who had smoked within 6 months prior to first dose of IMP). * Subjects who worked shifts (i.e. regularly alternated between days, afternoons and nights).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Infacort vs Hydrocortisone | -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h | To compare the Cmax of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Infacort vs Hydrocortisone | -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h | To compare the Tmax of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg. |
| Area Under the Curve (AUC0-t) of Infacort vs Hydrocortisone | -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h | To compare the AUC0-t of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg. AUC0-t represents the total exposure to drug over time, hence the reporting of a single value below. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h | To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Assessed by Medical Dictionary for Regulatory Activities (MedDRA) Dictionary, Version 16.0. | 1 day | To assess the safety and tolerability of Infacort® throughout the study. For a full list of TEAEs per arm, please refer to the Adverse Events section. |
| Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h | To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg. |
| Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 1 day | To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg. |
Participant flow
Recruitment details
Recruitment Area: United Kingdom Location: Phase 1 Unit
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 5-way crossover study design involving Infacort and hydrocortisone at the following dose strengths:
Infacort 0.5mg Infacort 2mg Infacort 5mg Infacort 10mg Hydrocortisone 10mg
Each IMP was administered to each subject in a randomised, crossover manner over 5 treatment periods (1 treatment/period). During each treatment period, each subject was admitted to the Unit on the afternoon of Day 1 and remained in the Unit until completion of all scheduled assessments on Day 2. Each subject received their scheduled IMP on the morning of Day 2 at \
0700hrs (fasted). Each subject also received 1mg dexamethasone (to suppress endogenous cortisol production) at approximately 2200hrs on Day 1, and at approximately 0600hrs and 1200hrs on Day 2. All doses were administered with 200mL water. There were at least 7 days washout between each dose of IMP. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 40.70 Years STANDARD_DEVIATION 14.37 |
| Body Mass Index (BMI) | 25.34 kg/m^2 STANDARD_DEVIATION 2.085 |
| Drug/Alcohol and HIV/Hepatitis Screening | 0 Participants |
| Height (m) | 1.773 Metres (m) STANDARD_DEVIATION 0.081 |
| Medical History and Concurrent Conditions | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United Kingdom | 16 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
| Weight (kg) | 79.70 Kilograms (kg) STANDARD_DEVIATION 8.543 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 16 | 1 / 16 | 0 / 16 | 4 / 16 | 1 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Curve (AUC0-t) of Infacort vs Hydrocortisone
To compare the AUC0-t of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg. AUC0-t represents the total exposure to drug over time, hence the reporting of a single value below.
Time frame: -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h
Population: Two subjects were excluded from the Infacort 10mg analysis population due to inadequate endogenous cortisol suppression prior to dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Area Under the Curve (AUC0-t) of Infacort vs Hydrocortisone | 1836.718 hr*nmol/L | Geometric Coefficient of Variation 17.8 |
| Hydrocortisone | Area Under the Curve (AUC0-t) of Infacort vs Hydrocortisone | 1803.278 hr*nmol/L | Geometric Coefficient of Variation 14.6 |
Primary
Maximum Plasma Concentration (Cmax) of Infacort vs Hydrocortisone
To compare the Cmax of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg.
Time frame: -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h
Population: Two subjects were excluded from the Infacort 10mg analysis population due to inadequate endogenous cortisol suppression prior to dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Maximum Plasma Concentration (Cmax) of Infacort vs Hydrocortisone | 601.843 nmol/L | Geometric Coefficient of Variation 21.5 |
| Hydrocortisone | Maximum Plasma Concentration (Cmax) of Infacort vs Hydrocortisone | 622.384 nmol/L | Geometric Coefficient of Variation 15.8 |
Primary
Time to Reach the Maximum Plasma Concentration (Tmax) of Infacort vs Hydrocortisone
To compare the Tmax of Infacort® versus immediate-release hydrocortisone in a single dose of 10 mg.
Time frame: -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h
Population: Two subjects were excluded from the Infacort 10mg analysis population due to inadequate endogenous cortisol suppression prior to dosing.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Time to Reach the Maximum Plasma Concentration (Tmax) of Infacort vs Hydrocortisone | 0.500 Hour | Standard Deviation 0.4031 |
| Hydrocortisone | Time to Reach the Maximum Plasma Concentration (Tmax) of Infacort vs Hydrocortisone | 1 Hour | Standard Deviation 0.4171 |
Secondary
Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg
To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg.
Time frame: 1 day
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 326.129 H*nmol/L | Geometric Coefficient of Variation 21.3 |
| Hydrocortisone | Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 648.407 H*nmol/L | Geometric Coefficient of Variation 16.6 |
| Infacort 5mg | Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 1127.579 H*nmol/L | Geometric Coefficient of Variation 15.2 |
| Infacort 10mg | Area Under the Curve (AUC0-t) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 1836.718 H*nmol/L | Geometric Coefficient of Variation 17.8 |
Secondary
Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg
To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg.
Time frame: -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 92.220 nmol/L | Geometric Coefficient of Variation 22.9 |
| Hydrocortisone | Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 242.798 nmol/L | Geometric Coefficient of Variation 16 |
| Infacort 5mg | Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 424.310 nmol/L | Geometric Coefficient of Variation 14.8 |
| Infacort 10mg | Maximum Plasma Concentration (Cmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 601.843 nmol/L | Geometric Coefficient of Variation 21.5 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Assessed by Medical Dictionary for Regulatory Activities (MedDRA) Dictionary, Version 16.0.
To assess the safety and tolerability of Infacort® throughout the study. For a full list of TEAEs per arm, please refer to the Adverse Events section.
Time frame: 1 day
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infacort 10mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Assessed by Medical Dictionary for Regulatory Activities (MedDRA) Dictionary, Version 16.0. | 7 TEAEs |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg
To determine the dose proportionality for Infacort® at doses of 0.5 mg, 2 mg, 5 mg and 10 mg.
Time frame: -1h, -0.5h, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 11h, 12h
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Infacort 10mg | Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 0.500 Hours | Standard Deviation 0.2236 |
| Hydrocortisone | Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 0.500 Hours | Standard Deviation 0.301 |
| Infacort 5mg | Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 0.500 Hours | Standard Deviation 0.3162 |
| Infacort 10mg | Time to Maximum Plasma Concentration (Tmax) of Infacort at Doses of 0.5, 2, 5 and 10 mg | 0.500 Hours | Standard Deviation 0.4031 |