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Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency (DC 06/02)

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ClinicalTrials.gov Identifier: NCT00915343
Recruitment Status : Completed
First Posted : June 8, 2009
Results First Posted : July 20, 2015
Last Update Posted : July 20, 2015
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Adrenal Insufficiency
Interventions Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg
Drug: Hydrocortisone, oral tablet, 10 mg
Enrollment 64

Recruitment Details  
Pre-assignment Details Study consisted of Part A (cross-over) and Part B (open-label). Of the 64 participants started and completed Part A, 5 participants did not enter Part B (treatment switch=2, withdrawal by participant= 2, nausea and abnormal laboratory value=1), 59 started Part B of the study.
Arm/Group Title Hydrocortisone MR OD Then Hydrocortisone TID - Part A Hydrocortisone TID Then Hydrocortisone MR OD - Part A Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description Participants received novel once daily (OD) hydrocortisone modified release (MR) tablets in the first intervention period then hydrocortisone tablets thrice daily (TID) in the second intervention period, at the same total daily dose of 20 to 40 milligram (mg) for 12 weeks. Participants received hydrocortisone tablets TID in the first intervention period then novel OD hydrocortisone MR tablets in the second intervention period, at the same total daily dose of 20 to 40 mg for 12 weeks. Hydrocortisone MR tablets 20 to 40 mg orally OD for 6 months.
Period Title: Part A - First Intervention Period
Started 32 32 0
Completed 32 32 0
Not Completed 0 0 0
Period Title: Part A - Second Intervention Period
Started 32 32 0
Completed 32 32 0
Not Completed 0 0 0
Period Title: Part B - Open Label Period
Started 0 0 59
Completed 0 0 57
Not Completed 0 0 2
Reason Not Completed
Treatment switch             0             0             1
Did not attend the last visit             0             0             1
Arm/Group Title Entire Study
Hide Arm/Group Description Included all participants randomized to receive hydrocortisone MR tablets orally OD first or hydrocortisone tablets orally TID first; in any of the intervention periods during the 12-week cross-over period of Part A or hydrocortisone MR tablets orally OD during the 6-month open-label period of Part B.
Overall Number of Baseline Participants 63
Hide Baseline Analysis Population Description
Intention-To-Treat (ITT) set included all randomised participants who took at least 1 dose of study drug with assessments of any variables or with primary efficacy assessments including all pharmacokinetic (PK) samplings during any of the treatment periods.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 63 participants
47.3  (13.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants
Female
26
  41.3%
Male
37
  58.7%
1.Primary Outcome
Title Area Under the Concentration Time Curve From Zero to 24 Hours (AUC0-24h) of Total S-cortisol in Plasma After Multiple Doses During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The data for combined arm 1+2 after multiple doses were reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A: Intention-To-Treat (ITT) set included all randomised participants who took at least 1 dose of study drug with primary efficacy assessments including all pharmacokinetic (PK) samplings during either treatment period. Here “number of participants analysed” signifies those who were evaluable for the outcome measure.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: hour*nanomole per liter
3962.0  (1079.6) 4879.6  (1194.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Comparison of log S-cortisol AUC between OD and TID regimens was adjusted for both period effect and subject effect using generalized linear model (GLM) in statistical analysis system (SAS).
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.806
Confidence Interval (2-Sided) 95%
0.753 to 0.862
Estimation Comments The quotient was defined as AUC0-24h for OD treatment divided by AUC0-24h for TID treatment.
2.Secondary Outcome
Title Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated. Cmax1 is the Cmax after first dose of study drug. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
690.7  (109.2) 802.8  (136.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -111.989
Confidence Interval (2-Sided) 95%
-133.980 to 89.999
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated. Cmax2 is the Cmax after second dose of study drug. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 8 8
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
553.8  (170.8) 446.9  (129.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0357
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 110.417
Confidence Interval (2-Sided) 95%
16.755 to 204.078
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A
Hide Description Css,av was calculated as the area under the S-cortisol concentration versus time curve during a dosing interval at steady state (AUCtau) divided by dosing interval (tau). Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
165.1  (45.0) 203.3  (49.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -38.076
Confidence Interval (2-Sided) 95%
-50.276 to 25.876
Estimation Comments [Not Specified]
5.Secondary Outcome
Title First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 62
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
229.0  (169.8) 295.1  (203.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0033
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -65.782
Confidence Interval (2-Sided) 95%
-109.201 to 22.362
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 60 60
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
278.5  (134.9) 426.7  (135.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -148.015
Confidence Interval (2-Sided) 95%
-189.469 to -106.561
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 60 60
Mean (Standard Deviation)
Unit of Measure: nanomoles per liter
214.1  (106.8) 322.4  (110.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -108.306
Confidence Interval (2-Sided) 95%
-140.193 to -76.420
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Tmax is the time after administration of a drug when the maximum plasma concentration in the body is reached. Tmax1 is the Tmax after first dose of study drug. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Median (Full Range)
Unit of Measure: hours
1.00
(0.38 to 5.00)
0.750
(0.292 to 2.750)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0214
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 0.270
Confidence Interval (2-Sided) 95%
0.028 to 0.512
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Tmax is the time after administration of a drug when the maximum plasma concentration in the body is reached. Tmax2 is the Tmax after second dose of study drug. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 8 8
Median (Full Range)
Unit of Measure: hours
5.00
(3.50 to 6.00)
6.00
(5.00 to 6.00)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0714
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -1.042
Confidence Interval (2-Sided) 95%
-2.098 to 0.015
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 62
Median (Full Range)
Unit of Measure: hours
0.229
(0.000 to 0.625)
0.208
(0.000 to 0.500)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6687
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.007
Confidence Interval (2-Sided) 95%
-0.038 to 0.024
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 62
Median (Full Range)
Unit of Measure: hours
0.250
(0.000 to 0.750)
0.167
(0.063 to 0.563)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0280
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 0.049
Confidence Interval (2-Sided) 95%
0.006 to 0.093
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Drug Concentration Half-Life From 5 to 24 Hours (t1/2[5-24h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description t1/2[5-24h] is the time taken for the blood plasma concentration of a drug to halve from 5 to 24 hours. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 17 17
Mean (Standard Deviation)
Unit of Measure: hours
7.32  (9.32) 1.84  (0.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 5.509
Confidence Interval (2-Sided) 95%
0.751 to 10.268
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Drug Concentration Half-Life From 5 to 14 Hours (t1/2[5-14h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description t1/2[5-14h] is the time taken for the blood plasma concentration of a drug to halve from 5 to 14 hours. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 52 52
Mean (Standard Deviation)
Unit of Measure: hours
4.60  (5.82) 18.4  (24.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -13.800
Confidence Interval (2-Sided) 95%
-20.533 to -7.067
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. AUC between specified timepoints included AUC0-4h, AUC4-12h, AUC6-12h, AUC12-24h, AUC0-10h, AUC4-10h, AUC6-10h, AUC10-24h, AUC(0-inf), AUC(24h-inf). Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported. Here, "N"signifies the number of participants evaluable for this outcome.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 63 63
Mean (Standard Deviation)
Unit of Measure: hour*nanomole per liter
AUC0-4h (N=61, 61) 2053.7  (432.0) 1929.7  (409.9)
AUC4-12h (N=61, 61) 1491.8  (638.9) 2302.5  (669.3)
AUC6-12h (N=61, 61) 808.2  (386.3) 1607.6  (483.3)
AUC12-24h (N=61, 61) 306.2  (305.2) 576.6  (681.6)
AUC0-10h (N=61, 61) 3388.4  (915.0) 3768.7  (968.5)
AUC4-10h (N=61, 61) 1334.7  (582.5) 1839.0  (599.0)
AUC6-10h (N=61, 61) 651.1  (322.1) 1144.1  (404.6)
AUC10-24h (N=61, 61) 465.0  (352.2) 1058.0  (752.4)
AUC(0-inf) (N=52, 52) 3972.6  (1125.9) 5162.8  (1777.2)
AUC(24h-inf) (N=52, 52) 195.3  (568.1) 410.4  (1094.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC0-4h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 1.064
Confidence Interval (2-Sided) 95%
1.032 to 1.097
Estimation Comments The quotient was defined as AUC0-4h for OD treatment divided by AUC0-4h for TID treatment.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC4-12h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.617
Confidence Interval (2-Sided) 95%
0.563 to 0.675
Estimation Comments The quotient was defined as AUC4-12h for OD treatment divided by AUC4-12h for TID treatment.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC6-12h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.472
Confidence Interval (2-Sided) 95%
0.424 to 0.525
Estimation Comments The quotient was defined as AUC6-12h for OD treatment divided by AUC6-12h for TID treatment.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC12-24h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.588
Confidence Interval (2-Sided) 95%
0.446 to 0.775
Estimation Comments The quotient was defined as AUC12-24h for OD treatment divided by AUC12-24h for TID treatment.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC0-10h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.894
Confidence Interval (2-Sided) 95%
0.856 to 0.935
Estimation Comments The quotient was defined as AUC0-10h for OD treatment divided by AUC0-10h for TID treatment.
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC4-10h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.695
Confidence Interval (2-Sided) 95%
0.632 to 0.765
Estimation Comments The quotient was defined as AUC4-10h for OD treatment divided by AUC4-10h for TID treatment.
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC6-10h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.540
Confidence Interval (2-Sided) 95%
0.482 to 0.605
Estimation Comments The quotient was defined as AUC6-10h for OD treatment divided by AUC6-10h for TID treatment.
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC10-24h
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.412
Confidence Interval (2-Sided) 95%
0.338 to 0.504
Estimation Comments The quotient was defined as AUC10-24h for OD treatment divided by AUC10-24h for TID treatment.
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC(0-inf)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.776
Confidence Interval (2-Sided) 95%
0.714 to 0.843
Estimation Comments The quotient was defined as AUC(0-inf) for OD treatment divided by AUC(0-inf) for TID treatment.
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments AUC(24h-inf)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8770
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 1.069
Confidence Interval (2-Sided) 95%
0.453 to 2.521
Estimation Comments The quotient was defined as AUC(24h-inf) for OD treatment divided by AUC(24h-inf) for TID treatment.
15.Secondary Outcome
Title Area Under the Concentration Time Curve During a Dosing Interval at Steady State (AUCtau) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. AUCtau is defined as AUC during a dosing interval at steady state. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: hour*nanomole per liter
3962.0  (1079.6) 4879.6  (1194.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.806
Confidence Interval (2-Sided) 95%
0.753 to 0.862
Estimation Comments The quotient was defined as AUCtau for OD treatment divided by AUCtau for TID treatment.
16.Secondary Outcome
Title Area Under the Concentration Time Curve During a Dosing Interval at Steady State Adjusted by Dose (AUCtau/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 14 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: hour per liter
0.048  (0.016) 0.061  (0.017)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.790
Confidence Interval (2-Sided) 95%
0.734 to 0.851
Estimation Comments The quotient was defined as AUCtau/dose for OD treatment divided by AUCtau/dose for TID treatment.
17.Secondary Outcome
Title Area Under the Concentration Time Curve From Zero to 24 Hours Adjusted by Dose (AUC0-24h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: hour per liter
0.047  (0.014) 0.060  (0.018)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.785
Confidence Interval (2-Sided) 95%
0.741 to 0.831
Estimation Comments The quotient was defined as AUC0-24h/dose for OD treatment divided by AUC0-24h/dose for TID treatment.
18.Secondary Outcome
Title Area Under the Concentration Time Curve From Zero to 10 Hours Adjusted by Dose (AUC0-10h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: hour per liter
0.041  (0.012) 0.046  (0.013)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.885
Confidence Interval (2-Sided) 95%
0.844 to 0.926
Estimation Comments The quotient was defined as AUC0-10h/dose for OD treatment divided by AUC0-10h/dose for TID treatment.
19.Secondary Outcome
Title Area Under the Concentration Time Curve From Zero to 4 Hours Adjusted by Dose (AUC0-4h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: hour per liter
0.025  (0.005) 0.024  (0.006)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 1.053
Confidence Interval (2-Sided) 95%
1.020 to 1.086
Estimation Comments The quotient was defined as AUC0-4h/dose for OD treatment divided by AUC0-4h/dose for TID treatment.
20.Secondary Outcome
Title Average Concentration of S-cortisol During the Dosing Interval at Steady State Adjusted by Dose (Css,av/Dose) in Plasma After Single and Multiple Dosing During Part A
Hide Description Css,av was calculated as the area under the S-cortisol concentration versus time curve during a dosing interval at steady state (AUCtau) divided by dosing interval (tau). Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: per liter
0.002  (0.001) 0.003  (0.001)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.001 to -0.000
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated. Cmax1 is the Cmax after first dose of study drug. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: per liter
0.008  (0.002) 0.010  (0.002)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.002 to -0.001
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 62
Mean (Standard Deviation)
Unit of Measure: (hour per nanomole)*10^6
2.26  (1.69) 2.32  (1.43)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7827
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.055
Confidence Interval (2-Sided) 95%
-0.444 to 0.334
Estimation Comments [Not Specified]
23.Secondary Outcome
Title First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 62
Mean (Standard Deviation)
Unit of Measure: per liter
0.003  (0.002) 0.004  (0.002)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.001 to -0.000
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description The percentage of AUC0-inf that is due to extrapolation from Tlast to infinity (AUC%Extrapolation) was calculated by using the formula AUC%extrapolation = 100*(AUC0-inf minus AUC0-t)/AUC0-inf. The function of this parameter was to provide information about what percentage of the theoretical curve (AUC0-inf) was possible to determine experimentally (AUC0-t). Therefore, on average, it is expected that the residual area (AUCextrapolation) is not greater than 20%. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 52 52
Mean (Standard Deviation)
Unit of Measure: percentage of AUC
10.1  (7.9) 9.26  (12.74)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 6.098
Confidence Interval (2-Sided) 95%
2.940 to 12.646
Estimation Comments The quotient was defined as AUC Extrapolation for OD treatment divided by AUC Extrapolation for TID treatment.
25.Secondary Outcome
Title Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A
Hide Description Percentage of fluctuation was calculated by using formula 100*(Cmax-minimum plasma concentration [Cmin])/Cavg,ss. It was peak trough fluctuation within one dosing interval at steady state. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 59 59
Mean (Standard Deviation)
Unit of Measure: percentage of fluctuation
429.7  (117.3) 396.2  (99.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0396
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 33.532
Confidence Interval (2-Sided) 95%
1.734 to 65.329
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
Hide Description The Rac was calculated as area under the S-cortisol concentration versus time curve during a dosing interval at steady state (AUCtau) on Day 28 divided by AUC0-24h on Day 1. Participants in Arm 1 underwent standardised in-house PK sampling during 24 hours in order to assess single-dose PK of OD or TID regimen at the start of each study treatment period while participants in Arm 2 had a reduced PK sampling scheme of single dose PK on Days 1-2 and returned for multiple-dose PK sampling on Days 7-8. The average of single and multiple dosing for combined arm 1+2 was reported.
Time Frame Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 55 55
Mean (Standard Deviation)
Unit of Measure: ratio
1.11  (0.29) 1.03  (0.19)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1032
Comments [Not Specified]
Method Fisher's non-parametric permutation test
Comments [Not Specified]
Method of Estimation Estimation Parameter Period-adjusted quotient
Estimated Value 0.080
Confidence Interval (2-Sided) 95%
-0.017 to 0.177
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator – Part A
Hide Description

Overall patient tolerability score assessed by patient and investigator, ranged from 1 (feeling poor on treatment) to 5 (feeling very well on treatment). The average total score ranges from 1 to 5 with a higher score representing better tolerability of the treatment.

Questionnaire assessed by patient were "I have been very poorly on the treatment", "I haven’t been very well (or less well) on the treatment", "I have been acceptably well on the treatment", "I have been well on the treatment" and "I have been very well on the treatment". Questionnaire assessed by investigator were "The patient has been feeling very poorly on the treatment", "The patient has not tolerated the treatment well", "The patient has tolerated the treatment less well", "The patient has tolerated the treatment well" and "The patient has tolerated the treatment very well".

Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 63 63
Mean (Standard Deviation)
Unit of Measure: scores on a scale
Patient 4.28  (0.74) 4.36  (0.73)
Investigator 4.26  (0.73) 4.33  (0.73)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments Patient
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3767
Comments [Not Specified]
Method Fisher’s test
Comments Fisher’s non
Method of Estimation Estimation Parameter least square mean
Estimated Value -0.078
Confidence Interval (2-Sided) 95%
-0.250 to 0.094
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments Investigator
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4625
Comments [Not Specified]
Method Fisher’s test
Comments Fisher’s non
Method of Estimation Estimation Parameter least square mean
Estimated Value -0.064
Confidence Interval (2-Sided) 95%
-0.235 to 0.107
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator – Part B
Hide Description Patient tolerability questionnaire was assessed by both patient and investigator, the responses were as follows: improvement, no change, worsening and were reported.
Time Frame Baseline (week 0), month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 56
Measure Type: Number
Unit of Measure: percentage of participants
Improvement (Patient) 10.7
Improvement (Investigator) 14.0
No change (Patient) 73.2
No change (Investigator) 70.0
Worsening (Patient) 16.1
Worsening (Investigator) 16.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments Patient
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6072
Comments [Not Specified]
Method Sign test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments Investigator
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method Sign test
Comments [Not Specified]
29.Secondary Outcome
Title Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A
Hide Description The SF-36 was a questionnaire used to assess physical functioning and is made up of eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Transforming and standardizing these domains lead to the calculation of the physical and mental component summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A higher value corresponds to better well-being.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 61 61
Mean (Standard Deviation)
Unit of Measure: scores on a scale
Physical component 49.3  (9.1) 50.0  (9.9)
Mental component 51.1  (7.3) 49.8  (9.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical Component Score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3332
Comments [Not Specified]
Method Fisher’s test
Comments Fisher’s non-parametric two-sample permutation test
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.6
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Mental Component Score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3405
Comments [Not Specified]
Method Fisher’s test
Comments Fisher’s non-parametric two-sample permutation test
Method of Estimation Estimation Parameter Mean difference
Estimated Value 0.9
Estimation Comments [Not Specified]
30.Secondary Outcome
Title Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score - Part B
Hide Description The SF-36 was a questionnaire used to assess physical functioning and is made up of eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Transforming and standardizing these domains lead to the calculation of the physical and mental component summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A higher value in the SF-36 questionnaire corresponds to better well-being.
Time Frame Baseline (week 0), month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 54
Mean (Standard Deviation)
Unit of Measure: scores on a scale
Physical component 0.390  (4.374)
Mental component -0.896  (5.913)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments Change From Baseline to 6 months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical Component Score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8418
Comments [Not Specified]
Method Wilcoxon Signed Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments Change From Baseline to 6 months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Mental Component Score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3550
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
31.Secondary Outcome
Title Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A
Hide Description FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in participants. It consisted of 40 statements that measure fatigue in 3 areas: physical, cognitive, and psychosocial. This 40-item scale evaluates the construct of perceived impact of fatigue on everyday life. Respondents rated each statement using a 5-point Likert-type scale ranging from 0 (no problem) to 4 (extreme problem). A total score ranged from 0 to 160. A lower value corresponds to better well-being.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 61
Mean (Standard Deviation)
Unit of Measure: scores on a scale
22.6  (25.4) 26.4  (30.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0823
Comments [Not Specified]
Method Fisher’s
Comments Fisher’s non-parametric two-sample permutation test
Method of Estimation Estimation Parameter Mean difference
Estimated Value -2.9
Estimation Comments [Not Specified]
32.Secondary Outcome
Title Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B
Hide Description FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in participants. It consisted of 40 statements that measure fatigue in 3 areas: physical, cognitive, and psychosocial. This 40-item scale evaluates the construct of perceived impact of fatigue on everyday life. Respondents rated each statement using a 5-point Likert-type scale ranging from 0 (no problem) to 4 (extreme problem). A total score ranged from 0 to 160. A lower value corresponds to better well-being.
Time Frame Baseline (week 0), month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 56
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-1.09  (12.49)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5982
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
33.Secondary Outcome
Title Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A
Hide Description The PGWB consists of 22 self-administered items rated on a scale from 1 (worst level of well-being) to 6 (maximum level of well-being) with a total score ranging from 22 to 132. A higher score represents better well-being.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 62 61
Mean (Standard Deviation)
Unit of Measure: scores on a scale
110.5  (14.0) 107.7  (17.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0632
Comments [Not Specified]
Method Fisher’s test
Comments Fisher’s non-parametric two-sample permutation test
Method of Estimation Estimation Parameter Mean difference
Estimated Value 2.3
Estimation Comments [Not Specified]
34.Secondary Outcome
Title Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B
Hide Description The PGWB consists of 22 self-administered items rated on a scale from 1 (worst level of well-being) to 6 (maximum level of well-being) with a total score ranging from 22 to 132. A higher score represents better well-being.
Time Frame Baseline (week 0), month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 55
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.739  (9.687)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8676
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
35.Secondary Outcome
Title Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A
Hide Description Diurnal fatigue was assessed at 8 ante meridian (AM), at 12 AM and at 4 post meridian (PM) by a visual analogue scale (VAS) based on 8 domains (energy, relaxed, less alert, moody, mental fatigue, intellectually slow, difficulty focusing, physical activity). Mean values were calculated for the morning (8 AM), the day (12 AM), the evening (4 PM) and mean per day (mean of 8 AM, 12 AM and 4 PM) were analyzed with score range from 0 to 100. A lower value corresponds to better well-being.
Time Frame Baseline (week 0), Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A
Hide Arm/Group Description:
During the 4-week run-in period prior to the first intervention period during Part A, participants on a twice-a-day (BID) regimen were transferred to a thrice-a-day (TID) regimen while maintaining the same total daily hydrocortisone dose. In the first and second intervention periods during Part A, participants were randomised to novel once daily (OD) treatment with hydrocortisone modified release (MR) tablets 20 to 40 milligram (mg) orally and the treatment continued for 12 weeks and returned every 4 weeks for study drug dispensation.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-3.1  (12.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9700
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
36.Secondary Outcome
Title Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B
Hide Description Diurnal fatigue scores (Visual Analog Scale [VAS] scores of energy, relaxed, less alert, moody, mental fatigue, intellectually slow, difficulty focusing, physical activity) were analyzed with score range from 0 to 100. A lower value corresponds to better well-being.
Time Frame Baseline (week 0), month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 44
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.180  (7.943)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2624
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
37.Secondary Outcome
Title Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A
Hide Description Compliance was calculated as actual consumption/expected consumption Compliance = (Number of dispensed tablets – Number of returned tablets)/(Number of days during the study period x daily Number of hydrocortisone tablets when taking the ordinary daily dose).
Time Frame Weeks 4 up to 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 58 58
Mean (Standard Deviation)
Unit of Measure: percentage use
104.8  (7.5) 103.1  (13.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value 1.28
Estimation Comments [Not Specified]
38.Secondary Outcome
Title Participant Compliance- Part B
Hide Description Compliance was calculated as actual consumption/expected consumption Compliance = (Number of dispensed tablets – Number of returned tablets)/(Number of days during the study period x daily Number of hydrocortisone tablets when taking the ordinary daily dose).
Time Frame Up to Month 6 follow-up
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part B ITT population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Overall Number of Participants Analyzed 58
Mean (Standard Deviation)
Unit of Measure: percentage use
102.3  (12.8)
39.Secondary Outcome
Title Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A
Hide Description

Participant Preference Questionnaire consisted of the following set of questions:

1. How large was the benefit with OD compared to TID and the responses were recorded as considerably poorer, somewhat poorer, comparable, large, very large; 2. How strongly concur with the following statement: I prefer novel OD to conventional TID and the responses were recorded as strongly disagree, disagree, neutral, strongly, very strongly; 3. How strongly concur with the following statement: I prefer conventional TID to novel OD and the responses were recorded as strongly disagree, disagree, neutral, strongly, very strongly.

Time Frame Weeks 16 up to 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A ITT population
Arm/Group Title Hydrocortisone OD Versus TID
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study. Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 63
Measure Type: Number
Unit of Measure: percentage of preference
Benefit compared OD to TID: Considerably poorer 3.8
Benefit compared OD to TID: Somewhat poorer 5.7
Benefit compared OD to TID: Comparable 5.7
Benefit compared OD to TID: Large 20.8
Benefit compared OD to TID: Very large 64.2
Prefer OD to TID: Strongly disagree 3.7
Prefer OD to TID: Disagree 3.7
Prefer OD to TID: Neutral 5.6
Prefer OD to TID: Strongly 25.9
Prefer OD to TID: Very strongly 61.1
Prefer TID to OD: Strongly disagree 39.6
Prefer TID to OD: Disagree 35.4
Prefer TID to OD: Neutral 12.5
Prefer TID to OD: Strongly 4.2
Prefer TID to OD: Very strongly 8.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone OD Versus TID
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Sign test
Comments [Not Specified]
40.Secondary Outcome
Title Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A
Hide Description [Not Specified]
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part A Safety population consisted of all randomised patients who took at least one dose of study medication. Safety population with participants evaluable for this outcome.
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A
Hide Arm/Group Description:
Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.
Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Overall Number of Participants Analyzed 36 37
Mean (Standard Deviation)
Unit of Measure: nanomoles per 24 hours
385.7  (178.8) 425.9  (278.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0034
Comments [Not Specified]
Method Wilcoxon Signed Rank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -272.3
Estimation Comments [Not Specified]
Time Frame Part A (24 weeks) and Part B (6 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A Hydrocortisone MR Tablet OD - Part B (First 3 Months) Hydrocortisone MR Tablet OD - Part B (Second 3 Months) Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Hide Arm/Group Description Hydrocortisone modified release (MR) tablets 20 to 40 mg orally, once daily (OD) during the 12-week period of Part A. Hydrocortisone tablets 20 to 40 mg orally, thrice daily (TID) during the 12-week period of Part A. Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the first 3 months of Part B (6 months). Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the second 3 months of Part B (6 months). Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the entire 6-month period of Part B.
All-Cause Mortality
Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A Hydrocortisone MR Tablet OD - Part B (First 3 Months) Hydrocortisone MR Tablet OD - Part B (Second 3 Months) Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A Hydrocortisone MR Tablet OD - Part B (First 3 Months) Hydrocortisone MR Tablet OD - Part B (Second 3 Months) Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/64 (9.38%)      2/64 (3.13%)      2/59 (3.39%)      4/57 (7.02%)      6/59 (10.17%)    
Gastrointestinal disorders           
Pancreatitis acute * 1  0/64 (0.00%)  0 0/64 (0.00%)  0 0/59 (0.00%)  0 1/57 (1.75%)  1 1/59 (1.69%)  1
Hepatobiliary disorders           
Cholelithiasis * 1  0/64 (0.00%)  0 0/64 (0.00%)  0 0/59 (0.00%)  0 1/57 (1.75%)  1 1/59 (1.69%)  1
Infections and infestations           
Gastroenteritis * 1  4/64 (6.25%)  4 2/64 (3.13%)  2 1/59 (1.69%)  1 0/57 (0.00%)  0 1/59 (1.69%)  1
Influenza * 1  1/64 (1.56%)  1 0/64 (0.00%)  0 0/59 (0.00%)  0 0/57 (0.00%)  0 0/59 (0.00%)  0
Pneumonia * 1  1/64 (1.56%)  1 0/64 (0.00%)  0 0/59 (0.00%)  0 0/57 (0.00%)  0 0/59 (0.00%)  0
Varicella * 1  0/64 (0.00%)  0 0/64 (0.00%)  0 0/59 (0.00%)  0 1/57 (1.75%)  1 1/59 (1.69%)  1
Renal and urinary disorders           
Nephrolithiasis * 1  0/64 (0.00%)  0 0/64 (0.00%)  0 1/59 (1.69%)  1 0/57 (0.00%)  0 1/59 (1.69%)  1
Surgical and medical procedures           
Surgical and medical procedures * 1  0/64 (0.00%)  0 0/64 (0.00%)  0 0/59 (0.00%)  0 1/57 (1.75%)  1 1/59 (1.69%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Hydrocortisone MR Tablet OD - Part A Hydrocortisone Tablet TID - Part A Hydrocortisone MR Tablet OD - Part B (First 3 Months) Hydrocortisone MR Tablet OD - Part B (Second 3 Months) Hydrocortisone MR Tablet OD - Part B (All 6 Months)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   29/64 (45.31%)      25/64 (39.06%)      12/59 (20.34%)      16/57 (28.07%)      23/59 (38.98%)    
Gastrointestinal disorders           
Diarrhoea * 1  1/64 (1.56%)  1 0/64 (0.00%)  0 0/59 (0.00%)  0 4/57 (7.02%)  5 4/59 (6.78%)  5
General disorders           
Fatigue * 1  8/64 (12.50%)  10 3/64 (4.69%)  3 4/59 (6.78%)  4 2/57 (3.51%)  2 6/59 (10.17%)  6
Infections and infestations           
Gastroenteritis * 1  8/64 (12.50%)  9 2/64 (3.13%)  2 4/59 (6.78%)  4 0/57 (0.00%)  0 4/59 (6.78%)  4
Influenza * 1  8/64 (12.50%)  8 2/64 (3.13%)  2 1/59 (1.69%)  1 4/57 (7.02%)  4 5/59 (8.47%)  5
Nasopharyngitis * 1  7/64 (10.94%)  9 15/64 (23.44%)  16 1/59 (1.69%)  1 6/57 (10.53%)  6 7/59 (11.86%)  7
Investigations           
Blood thyroid stimulating hormone increased * 1  1/64 (1.56%)  1 3/64 (4.69%)  3 2/59 (3.39%)  2 1/57 (1.75%)  1 3/59 (5.08%)  3
Nervous system disorders           
Headache * 1  2/64 (3.13%)  4 5/64 (7.81%)  7 1/59 (1.69%)  1 1/57 (1.75%)  1 2/59 (3.39%)  2
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
If a multicentre publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicentre Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Results Point of Contact
Name/Title: Study Physician
Organization: Shire
Phone: 1866-842-5335
Publications:
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00915343     History of Changes
Other Study ID Numbers: EudraCT: 2006-0007084-89
104-07
First Submitted: June 5, 2009
First Posted: June 8, 2009
Results First Submitted: June 8, 2015
Results First Posted: July 20, 2015
Last Update Posted: July 20, 2015