This was a single centre, open label, randomised, two period, crossover study to evaluate the bioavailability of Chronocort® versus Cortef® immediate release hydrocortisone tablets in dexamethasone-suppressed healthy adult male subjects.
This study was an open-label, randomised, single dose, two-period, crossover study in 25 healthy male subjects. The study comprised of a pre-study screen, followed by 2 treatment periods (1 and 2) and a post-study followup. Screening (Day -28 to Day -1): Screening assessments were carried out within 28 days before first administration of IMP. Eligible subjects were asked to return for the treatment periods. Continued eligibility was confirmed pre-dose during each treatment period. Treatment Periods (Day -1 to Day 1): Eligible subjects received a single-dose of each IMP over 2 treatment periods (1/period as determined by the randomisation schedule), each separated by 7 days washout. Each study period was approximately 2 days in duration, from the afternoon of Day -1 to the morning of Day 1 at 24 hours (h) post-dose. During each treatment period, Subjects arrived at the Clinical Unit on Day -1, IMP was administered on the morning of Day 0 fasted (following an overnight fast of at least 10 h) and subjects were discharged following the 24 h post-dose blood samples and completion of the scheduled measurements. Pharmacokinetic (PK) samples were collected pre-dose at \~ -2min and up to 23 h post-dose (Day 1) (24 samples) for the measurement of cortisol. A further 3 baseline samples were taken for the measurement of cortisol. Safety was also evaluated throughout the study. Post Study: After completion of both study periods, the subjects returned 4-22 days later for the final followup visit.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Single dose of 20mg Chronocort® administered in one treatment period
Single dose of 20mg Cortef® administered in one treatment period
Simbec Research Ltd.
Merthyr Tydfil, United Kingdom
Area under the concentration time curve from time 0 to infinity (AUC0-inf) of Chronocort® to Cortef® based on baseline adjusted and unadjusted serum cortisol concentration calculated for each sampling time point.
Comparing the area under the concentration time curve of Chronocort® compared to Cortef® immediate release hydrocortisone tablets.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol + relative bioavailability - Cmax
The following PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP. ◦ Cmax Maximum plasma cortisol concentration.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol + relative bioavailability - Tmax
The following PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP. ◦ Tmax The time to maximum observed cortisol concentration sampled during a dosing interval.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol + relative bioavailability - Kel
The following PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP. ◦ kel Elimination rate constant.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
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Pharmacokinetic parameters for serum cortisol + relative bioavailability - t1/2
The following PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP. ◦ t1/2 Terminal half-life.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol + relative bioavailability - AUC0-t
The following PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP. ◦ AUC0-t Area under the plasma cortisol concentration-time curve (AUC) from the time of dosing to the time of the last observed concentration.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol - Serum cortisol clearance (CL/F)
Calculated as Dose / AUC0-inf. This PK endpoint was derived from baseline adjusted and unadjusted serum cortisol concentration-time data following administration of each IMP.
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Pharmacokinetic parameters for serum cortisol - Distribution during terminal elimination (Vz/F)
Volume of distribution based on the terminal elimination phase following extravascular administration derived from baseline adjusted and unadjusted serum cortisol
Time frame: Samples taken at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 11,12, 13, 14, 16, 18, 20, 22, and 24 hours (morning of Day 1) in both periods.
Observed changes in Safety Laboratory Data
Observed changes in Safety Laboratory data (biochemistry, haematology \& urinalysis) during the course of the study, with any out of normal range values flagged.
Time frame: Screening, Pre-dose and 10h and 24h post-dose during both treatment periods; Follow up
Observed changes in Vital Signs
Observed changes in vital signs data (blood pressure, pulse rate and oral temperature) during the course of the study, with any out of normal range values flagged.
Time frame: Screening; Pre-dose and at 4 and 10h post-dose during both treatment periods; Follow up
Observed changes in Electrocardiogram (ECG) data during the course of the study
12-Lead ECG parameters (Heart Rate, PR interval, QRS width, QT interval, and QT interval corrected using Bazett's formula (QTcB)) and investigator clinical interpretation was listed with any out of normal range values flagged.
Time frame: Screening, Pre-dose and 10h post-dose during both treatment periods; Follow up
Adverse Events
Adverse events (AEs) observed throughout the study
Time frame: Through study completion - approximately 6 weeks