Healthy
Conditions
Keywords
subjects
Brief summary
The purpose of the study is to find out whether food has an effect on the way the body deals with modified release hydrocortisone, and to compare with the pharmacokinetics of immediate release hydrocortisone (fasted). This information will be used to help doctors with dosing in clinical practice.
Detailed description
This is a phase I study in healthy male volunteers, who will be given dexamethasone to suppress their natural cortisol production. 18 will be consented for the study. They will have had a history and a physical examination, blood tests for routine safety, hepatitis C and Human Immunodeficiency Virus (HIV), drug abuse and Electrocardiograms (ECGs). Following the results of these tests and the inclusion/exclusion criteria for the study, they will be admitted to the phase I unit on the first afternoon (Day -1). They will be given dexamethasone at 22.00hrs that evening, and remain in the unit until the end of the period. Further dexamethasone doses will be given at 06:00, 12:00, and 18:00 hours on Day 1 (plus at 22:00 hours in patients given the modified release study drug). Each volunteer will be admitted for 3 periods of approximately 1.5 days, with a washout of 7 days between periods, and they will be randomised to either fast and take a single 20mg dose of immediate release hydrocortisone, to fast and take a single 20mg dose of the study medication, (a modified release hydrocortisone), or to the fed group, where they take a single dose of 20mg study medication, and have a highly calorific standardised breakfast. The volunteers will have cannulae to enable one pre-dose blood sample to be taken followed by 24 hour Pharmacokinetic (PK) sampling (modified release) and 12 hour PK sampling for the immediate release period. After these samples have been taken the volunteers will be able to leave the unit. There will be another assessment 3 to 5 days after study period 3 with further blood tests, assessment of any adverse events etc.
Interventions
DRUGDexamethasone
Dexamethasone used to suppress endogenous cortisol secretion
DRUGChronocort: fasted
single dose of 20mg modified release hydrocortisone in the absence of food
DRUGImmediate release hydrocortisone: fasted
single dose of 20mg immediate release hydrocortisone in the absence of food
DRUGChronocort: fed
single dose of 20mg modified release hydrocortisone in the presence of food
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) * A body mass index of 21-28 (inclusive). * No clinically significant abnormal serum biochemistry, haematology and urine examination values * A negative urinary drugs of abuse screen. A positive alcohol test may be repeated at the discretion of the investigator. * Negative Human Immunodeficiency Virus (HIV) and Hepatitis b & C results * No clinically significant abnormalities in 12-lead Electrocardiogram (ECG) * No clinically significant deviation outside the normal ranges for blood pressure and pulse measurements * Subjects (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) and sexual partners must use effective contraception methods during the trial and for 3 months after the last dose, for example: * Oral contraceptive + condom * Intra-uterine device + condom * Diaphragm with spermicide + condom * Subjects must be available to complete the study * Subjects must provide 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 (including high dose vitamins, dietary supplements or herbal remedies) * Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction Receipt of any vaccination within the previous one month * Presence of clinically significant infections (systemic fungal and viral infections, acute bacterial infections) * Current of previous history of tuberculosis * A clinically significant history of previous allergy/sensitivity to hydrocortisone and/or dexamethasone * A clinically significant history of family history of psychiatric disorders/illnesses * A clinically significant history of drug or alcohol abuse * Inability to communicate well with the investigator (ie language problem, poor mental development or impaired cerebral function) * Participation in a New Chemical entity clinical study within the previous four months or a marketed drug clinical study within the previous three months * Subjects who have consumed more than two units of alcohol pre day within seven days prior to the first dose or have consumed any alcohol within the 48hr period prior to the first dose * Donation of greater than or equal to 450ml blood within the previous three months * Subjects who smoke or ex-smokers who have smoked within six months prior to first dose * Subjects who work shifts (ie regularly alternate between days, afternoons and nights)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chronocort Cmax | 24 hours | Comparison of fed and fasted Chronocort Cmax for serum cortisol. |
| Comparison of Fed and Fasted Chronocort AUC0-t | 24 hours (at 0h, then 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, 13h, 14h, 15h, 16h, 18h, 20h, 22h and 24h post-dose.) | Area under the curve from 0 to 24 hours for serum cortisol. Please note that the AUC0-t will be presented as a single figure (geometric mean) to represent exposure over time. N.B., the sampling points for Hydrocortisone are as follows: 0h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h and 12h post-dose. However, the results for Hydrocortisone will not be incorporated into the analysis for this outcome measure. |
| Comparison of Fed and Fasted Chronocort Tmax | 24 hours | Comparison of Fed and Fasted Chronocort based on the time to achive the maximum concentration of serum cortisol |
| Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax | 24 hours | Evaluation of the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state by Cmax |
| Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t | 24 hours | To evaluate the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state using area under the curve |
| Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax. | 24 hours | To evaluate the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state using Tmax. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All patients received all 3 study treatments in randomised order | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment 3 (1.5 Days) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
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 | 18 Participants |
| Age, Continuous | 34.0 years STANDARD_DEVIATION 9.73 |
| Region of Enrollment United Kingdom | 18 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 18 | 0 / 18 | 0 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 17 |
Outcome results
Primary
Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax
Evaluation of the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state by Cmax
Time frame: 24 hours
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax | 708.45 nmol/L | Geometric Coefficient of Variation 19.3 |
| Chronocort Fasted | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax | 856.36 nmol/L | Geometric Coefficient of Variation 14.6 |
| Immediate-Release Hydrocortisone | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax | 549.49 nmol/L | Geometric Coefficient of Variation 17.4 |
90% CI: [75.58, 91.74]
Primary
Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t
To evaluate the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state using area under the curve
Time frame: 24 hours
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t | 2980.85 h*nmol/L | Geometric Coefficient of Variation 14.3 |
| Chronocort Fasted | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t | 2466.90 h*nmol/L | Geometric Coefficient of Variation 17.1 |
| Immediate-Release Hydrocortisone | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t | 3229.26 h*nmol/L | Geometric Coefficient of Variation 15.1 |
90% CI: [111.58, 126.54]
Primary
Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax.
To evaluate the relative bioavailability of Chronocort® and immediate release hydrocortisone at a single dose of 20 mg in the fasted state using Tmax.
Time frame: 24 hours
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax. | 4.5 hours | Standard Deviation 1.25 |
| Chronocort Fasted | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax. | 0.87 hours | Standard Deviation 0.81 |
| Immediate-Release Hydrocortisone | Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax. | 6.75 hours | Standard Deviation 3.62 |
p-value: 0.001495% CI: [2.25, 4.38]Wilcoxon (Mann-Whitney)
Primary
Chronocort Cmax
Comparison of fed and fasted Chronocort Cmax for serum cortisol.
Time frame: 24 hours
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Chronocort Cmax | 549.49 nmol/L | Geometric Coefficient of Variation 17.4 |
| Chronocort Fasted | Chronocort Cmax | 708.46 nmol/L | Geometric Coefficient of Variation 19.3 |
| Immediate-Release Hydrocortisone | Chronocort Cmax | 856.36 nmol/L | Geometric Coefficient of Variation 14.6 |
Comparison: Results obtained using a mixed effects ANOVA with fixed effects for study period, sequence, treatment and subject (sequence) (excl. tmax).90% CI: [70.89, 84.86]ANOVA
Primary
Comparison of Fed and Fasted Chronocort AUC0-t
Area under the curve from 0 to 24 hours for serum cortisol. Please note that the AUC0-t will be presented as a single figure (geometric mean) to represent exposure over time. N.B., the sampling points for Hydrocortisone are as follows: 0h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h and 12h post-dose. However, the results for Hydrocortisone will not be incorporated into the analysis for this outcome measure.
Time frame: 24 hours (at 0h, then 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, 13h, 14h, 15h, 16h, 18h, 20h, 22h and 24h post-dose.)
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Comparison of Fed and Fasted Chronocort AUC0-t | 3229.26 h*nmol/L | Geometric Coefficient of Variation 15.1 |
| Chronocort Fasted | Comparison of Fed and Fasted Chronocort AUC0-t | 2980.85 h*nmol/L | Geometric Coefficient of Variation 14.3 |
| Immediate-Release Hydrocortisone | Comparison of Fed and Fasted Chronocort AUC0-t | 2466.90 h*nmol/L | Geometric Coefficient of Variation 17.1 |
90% CI: [102.3, 114.72]ANOVA
Primary
Comparison of Fed and Fasted Chronocort Tmax
Comparison of Fed and Fasted Chronocort based on the time to achive the maximum concentration of serum cortisol
Time frame: 24 hours
Population: PK population: All randomised subjects who had sufficient plasma concentration by time profiles for 2 adequate treatments and who did not violate the protocol in such a way that could invalidate or bias the results (major protocol violators).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Chronocort Fed | Comparison of Fed and Fasted Chronocort Tmax | 6.75 hours | Standard Deviation 3.62 |
| Chronocort Fasted | Comparison of Fed and Fasted Chronocort Tmax | 4.5 hours | Standard Deviation 1.25 |
| Immediate-Release Hydrocortisone | Comparison of Fed and Fasted Chronocort Tmax | 0.87 hours | Standard Deviation 0.81 |
p-value: 0.000595% CI: [1.25, 3.75]Wilcoxon (Mann-Whitney)