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)
18
3
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
  • 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
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    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
    Adverse Event Reporting Description
    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.

    Results Point of Contact

    Name/Title Dr G Sharma
    Organization Simbec Research Ltd
    Phone 0800 691995
    Email contact@simbec.com
    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