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

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ClinicalTrials.gov Identifier: NCT02408068
Recruitment Status : Completed
First Posted : April 3, 2015
Results First Posted : December 15, 2017
Last Update Posted : December 15, 2017
Sponsor:
Collaborator:
Simbec Research
Information provided by (Responsible Party):
Diurnal Limited

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy
Interventions Drug: Dexamethasone
Drug: Chronocort: fasted
Drug: Immediate release hydrocortisone: fasted
Drug: Chronocort: fed
Enrollment 18
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6
Hide 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: Washout Period 1 (7 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 2 (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: Washout Period 2 (7 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 3 (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
Reason Not Completed
Adverse Event             0             0             1             0             0             0
Arm/Group Title All Study Participants
Hide Arm/Group Description All patients received all 3 study treatments in randomised order
Overall Number of Baseline Participants 18
Hide Baseline Analysis Population Description
Cross-over study so all patients received all treatments
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
<=18 years
0
   0.0%
Between 18 and 65 years
18
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants
34.0  (9.73)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants
Female
0
   0.0%
Male
18
 100.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United Kingdom Number Analyzed 18 participants
18
1.Primary Outcome
Title Chronocort Cmax
Time Frame 24 hours
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 18 14
Geometric Least Squares Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
549.49
(17.4%)
708.46
(19.3%)
856.36
(14.6%)
Show Statistical Analysis 1 Hide 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
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LSmean ratio
Estimated Value 77.56
Confidence Interval (2-Sided) 90%
70.89 to 84.86
Estimation Comments [Not Specified]
2.Primary Outcome
Title Comparison of Fed and Fasted Chronocort AUC0-t
Hide 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.)
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 18 14
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h*nmol/L
3229.26
(15.1%)
2980.85
(14.3%)
2466.90
(17.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Chronocort Fed, Chronocort Fasted
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LSmean ratio
Estimated Value 108.33
Confidence Interval (2-Sided) 90%
102.30 to 114.72
Estimation Comments [Not Specified]
3.Primary Outcome
Title Comparison of Fed and Fasted Chronocort Tmax
Hide Description Comparison of Fed and Fasted Chronocort based on the time to achive the maximum concentration of serum cortisol
Time Frame 24 hours
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 18 14
Median (Standard Deviation)
Unit of Measure: hours
6.75  (3.62) 4.5  (1.25) 0.87  (0.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Chronocort Fed, Chronocort Fasted
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 2.25
Confidence Interval (2-Sided) 95%
1.25 to 3.75
Estimation Comments [Not Specified]
4.Primary Outcome
Title Bioavailability of Chronocort® vs Hydrocortisone Tablets - Cmax
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 14 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nmol/L
708.45
(19.3%)
856.36
(14.6%)
549.49
(17.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Chronocort Fasted, Immediate-Release Hydrocortisone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LSmean ratio
Estimated Value 83.27
Confidence Interval (2-Sided) 90%
75.58 to 91.74
Estimation Comments [Not Specified]
5.Primary Outcome
Title Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using AUC0-t
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 14 18
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h*nmol/L
2980.85
(14.3%)
2466.90
(17.1%)
3229.26
(15.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Chronocort Fasted, Immediate-Release Hydrocortisone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LSmean ratio
Estimated Value 118.83
Confidence Interval (2-Sided) 90%
111.58 to 126.54
Estimation Comments [Not Specified]
6.Primary Outcome
Title Bioavailability of Chronocort® vs Hydrocortisone Tablets - Fasted Using Tmax.
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 18 14 18
Median (Standard Deviation)
Unit of Measure: hours
4.5  (1.25) 0.87  (0.81) 6.75  (3.62)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Chronocort Fasted, Immediate-Release Hydrocortisone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 3.5
Confidence Interval (2-Sided) 95%
2.25 to 4.38
Estimation Comments [Not Specified]
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 [Not Specified]
 
Arm/Group Title Chronocort : Fed Chronocort: Fasted Immediate Release Hydrocortisone: Fasted
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide 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 (0.00%)      0/18 (0.00%)      0/17 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Chronocort : Fed Chronocort: Fasted Immediate Release Hydrocortisone: Fasted
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/18 (5.56%)      0/18 (0.00%)      0/17 (0.00%)    
Gastrointestinal disorders       
Abdominal pain upper * 1  1/18 (5.56%)  1 0/18 (0.00%)  0 0/17 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Dyspnoea * 1  1/18 (5.56%)  1 0/18 (0.00%)  0 0/17 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 17.1
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
Layout table for Results Point of Contact information
Name/Title: Dr G Sharma
Organization: Simbec Research Ltd
Phone: 0800 691995
EMail: contact@simbec.com
Layout table for additonal information
Responsible Party: Diurnal Limited
ClinicalTrials.gov Identifier: NCT02408068     History of Changes
Other Study ID Numbers: DIUR-004
First Submitted: March 10, 2015
First Posted: April 3, 2015
Results First Submitted: February 26, 2016
Results First Posted: December 15, 2017
Last Update Posted: December 15, 2017