Effect of Slow Release Hydrocortisone on Fed & Fasting Volunteers; Immediate Release on Fasting Only

• Sponsor: Diurnal Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02408068
• Collaborator: Simbec Research (Industry)
• Enrollment: 18
• Arms: 3
• Duration (Months): 1.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Dexamethasone; Drug: Chronocort: fasted; Drug: Immediate release hydrocortisone: fasted; Drug: Chronocort: fed	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Open Label Randomised 3 Period Crossover Study to Evaluate Bioavailability of Modified Release Hydrocortisone (HC) Under Fasting & Fed Conditions & Immediate Release HC Tablets Under Fasting Conditions in Dexamethasone-suppressed Subjects
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Chronocort : fed Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and receive a high fat, high calorie breakfast on the morning of Day 1. Thirty minutes after the start of the breakfast they will receive 20mg of modified release hydrocortisone with 200 millilitres of water, and no further food for 4 hours, water will be allowed from 1 hour after the food. Further dexamethasone doses will be given at 06:00, 12:00, 18:00 and 22:00 hours on Day 1. One baseline pharmacokinetics (PK) sample will be taken starting prior to the dose and then over 24 hours (29 samples).	Drug: Dexamethasone; Dexamethasone used to suppress endogenous cortisol secretion; Drug: Chronocort: fed; single dose of 20mg modified release hydrocortisone in the presence of food; Other Names: modified release hydrocortisone
Active Comparator: Immediate release hydrocortisone: fasted Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and take 20mg immediate release hydrocortisone with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. Further dexamethasone doses will be given at 06:00, 12:00 and 18:00 hours on Day 1. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Drug: Dexamethasone; Dexamethasone used to suppress endogenous cortisol secretion; Drug: Immediate release hydrocortisone: fasted; single dose of 20mg immediate release hydrocortisone in the absence of food; Other Names: Hydrocortisone
Active Comparator: Chronocort: fasted Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and take 20mg modified release hydrocortisone with 200millilitres of water on the morning of Day 1. Water will be allowed 1hr after the dose, but no food for at least 4hrs post dose. Further dexamethasone doses will be given at 06:00, 12:00, 18:00 and 22:00 hours on Day 1. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Drug: Dexamethasone; Dexamethasone used to suppress endogenous cortisol secretion; Drug: Chronocort: fasted; single dose of 20mg modified release hydrocortisone in the absence of food; Other Names: modified release hydrocortisone

Outcome Measures

Primary Outcome Measures

1. Chronocort Cmax [24 hours]

   Comparison of fed and fasted Chronocort Cmax for serum cortisol.

2. 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.

3. 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

4. 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

5. 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

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: Male
• Accepts 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)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Diurnal Limited
• Simbec Research

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Diurnal Limited
• ClinicalTrials.gov Identifier: NCT02408068
• Other Study ID Numbers: DIUR-004
• First Posted: Apr 3, 2015
• Last Update Posted: May 4, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Diurnal Limited: subjects
• Additional relevant MeSH terms: Dexamethasone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate

Study Results

Participant Flow

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6
Arm/Group Description	Chronocort 20mg (fed), Chronocort 20mg (fasted), Hydrocortisone 20mg (fasted)	Chronocort 20mg (fed), Hydrocortisone 20mg (fasted), Chronocort 20mg (fasted)	Chronocort 20mg (fasted), Chronocort 20mg (fed), Hydrocortisone 20mg (fasted)	Chronocort 20mg (fasted), Hydrocortisone 20mg (fasted), Chronocort 20mg (fed)	Hydrocortisone 20mg (fasted), Chronocort 20mg (fed), Chronocort 20mg (fasted)	Hydrocortisone 20mg (fasted), Chronocort 20mg (fasted), Chronocort 20mg (fed)
Period Title: Treatment 1 (1.5 Days)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment 1 (1.5 Days)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment 1 (1.5 Days)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment 1 (1.5 Days)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment 1 (1.5 Days)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	2	3	3	3
NOT COMPLETED	0	0	1	0	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All patients received all 3 study treatments in randomised order
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	18 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.0 (9.73)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	18 100%
Region of Enrollment (participants) [Number]
United Kingdom	18 100%

Outcome Measures

1. Primary Outcome

Title	Chronocort Cmax
Description	Comparison of fed and fasted Chronocort Cmax for serum cortisol.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fed	Chronocort Fasted	Immediate-Release Hydrocortisone
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	18	14
Geometric Least Squares Mean (Geometric Coefficient of Variation) [nmol/L]	549.49 (17.4)	708.46 (19.3)	856.36 (14.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments	Results obtained using a mixed effects ANOVA with fixed effects for study period, sequence, treatment and subject (sequence) (excl. tmax).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LSmean ratio
	Estimated Value	77.56
	Confidence Interval	(2-Sided) 90%; 70.89 to 84.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Comparison of Fed and Fasted Chronocort AUC0-t
Description	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.)

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fed	Chronocort Fasted	Immediate-Release Hydrocortisone
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	18	14
Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L]	3229.26 (15.1)	2980.85 (14.3)	2466.90 (17.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LSmean ratio
	Estimated Value	108.33
	Confidence Interval	(2-Sided) 90%; 102.30 to 114.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Comparison of Fed and Fasted Chronocort Tmax
Description	Comparison of Fed and Fasted Chronocort based on the time to achive the maximum concentration of serum cortisol
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fed	Chronocort Fasted	Immediate-Release Hydrocortisone
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	18	14
Median (Standard Deviation) [hours]	6.75 (3.62)	4.5 (1.25)	0.87 (0.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.25
	Confidence Interval	(2-Sided) 95%; 1.25 to 3.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fasted	Immediate-Release Hydrocortisone	Chronocort Fed
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	14	18
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	708.45 (19.3)	856.36 (14.6)	549.49 (17.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LSmean ratio
	Estimated Value	83.27
	Confidence Interval	(2-Sided) 90%; 75.58 to 91.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fasted	Immediate-Release Hydrocortisone	Chronocort Fed
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	14	18
Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L]	2980.85 (14.3)	2466.90 (17.1)	3229.26 (15.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LSmean ratio
	Estimated Value	118.83
	Confidence Interval	(2-Sided) 90%; 111.58 to 126.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Chronocort Fasted	Immediate-Release Hydrocortisone	Chronocort Fed
Arm/Group Description	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs, fast overnight, and take 20mg of randomised treatment with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)	Volunteers will be admitted, take dexamethasone to suppress endogenous cortisone at 22.00hrs and subsequently fast overnight. On the morning of Day 1, volunteers will eat a high fat breakfast and take 20mg of randomised treatment with 200 millilitres of water. Water will be allowed 1hr after the study drug is administered. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples)
Measure Participants	18	14	18
Median (Standard Deviation) [hours]	4.5 (1.25)	0.87 (0.81)	6.75 (3.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort Fed, Chronocort Fasted
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; 2.25 to 4.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Each study period is 1.5 days duration, so a total of 4.5 days plus a 7-day washout period between doses
Arm/Group Title	Chronocort : Fed		Chronocort: Fasted		Immediate Release Hydrocortisone: Fasted
Arm/Group Description	Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and receive a high fat, high calorie breakfast on the morning of Day 1. Thirty minutes after the start of the breakfast they will receive 20mg of modified release hydrocortisone with 200 millilitres of water, and no further food for 4 hours, water will be allowed from 1 hour after the food. One baseline pharmacokinetics (PK) sample will be taken starting prior to the dose and then over 24 hours (29 samples). Dexamethasone: Dexamethasone used to suppress endogenous cortisol secretion Chronocort: fed: single dose of 20mg modified release hydrocortisone in the presence of food		Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and take 20mg modified release hydrocortisone with 200millilitres of water on the morning of Day 1. Water will be allowed 1hr after the dose, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples) Dexamethasone: Dexamethasone used to suppress endogenous cortisol secretion Chronocort: fasted: single dose of 20mg modified release hydrocortisone in the absence of food		Volunteers will be admitted, take dexamethasone at 22.00hrs, fast overnight, and take 20mg immediate release hydrocortisone with 200 millilitres of water on the morning of Day 1. Water will be allowed 1hr after the study drug, but no food for at least 4hrs post dose. One baseline pharmacokinetics (PK) sample will be taken prior to the dose, and then afterwards for over a 12 hour period (16 samples) Dexamethasone: Dexamethasone used to suppress endogenous cortisol secretion Immediate release hydrocortisone: fasted: single dose of 20mg immediate release hydrocortisone in the absence of food
All Cause Mortality
	Chronocort : Fed		Chronocort: Fasted		Immediate Release Hydrocortisone: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Chronocort : Fed		Chronocort: Fasted		Immediate Release Hydrocortisone: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Chronocort : Fed		Chronocort: Fasted		Immediate Release Hydrocortisone: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		0/18 (0%)		0/17 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/18 (5.6%)	1	0/18 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/18 (5.6%)	1	0/18 (0%)	0	0/17 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.