Trial Outcomes & Findings for Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency (NCT NCT00915343)

NCT ID: NCT00915343

Last Updated: 2020-11-24

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 64 participants
• Primary outcome timeframe: 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
• Results posted on: 2020-11-24

Participant Flow

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.

Participant milestones

Measure	Hydrocortisone MR OD Then Hydrocortisone TID - Part A 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.	Hydrocortisone TID Then Hydrocortisone MR OD - Part A 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 Tablet OD - Part B (All 6 Months) Hydrocortisone MR tablets 20 to 40 mg orally OD for 6 months.
Part A - First Intervention Period STARTED	32	32	0
Part A - First Intervention Period COMPLETED	32	32	0
Part A - First Intervention Period NOT COMPLETED	0	0	0
Part A - Second Intervention Period STARTED	32	32	0
Part A - Second Intervention Period COMPLETED	32	32	0
Part A - Second Intervention Period NOT COMPLETED	0	0	0
Part B - Open Label Period STARTED	0	0	59
Part B - Open Label Period COMPLETED	0	0	57
Part B - Open Label Period NOT COMPLETED	0	0	2

Reasons for withdrawal

Measure	Hydrocortisone MR OD Then Hydrocortisone TID - Part A 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.	Hydrocortisone TID Then Hydrocortisone MR OD - Part A 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 Tablet OD - Part B (All 6 Months) Hydrocortisone MR tablets 20 to 40 mg orally OD for 6 months.
Part B - Open Label Period Treatment switch	0	0	1
Part B - Open Label Period Did not attend the last visit	0	0	1

Baseline Characteristics

Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency

Baseline characteristics by cohort

Measure	Entire Study n=63 Participants 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.
Age, Continuous	47.3 years STANDARD_DEVIATION 13.7 • n=93 Participants
Sex: Female, Male Female	26 Participants n=93 Participants
Sex: Female, Male Male	37 Participants n=93 Participants

PRIMARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	3962.0 hour*nanomole per liter Standard Deviation 1079.6	4879.6 hour*nanomole per liter Standard Deviation 1194.4

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	690.7 nanomoles per liter Standard Deviation 109.2	802.8 nanomoles per liter Standard Deviation 136.2

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=8 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=8 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	553.8 nanomoles per liter Standard Deviation 170.8	446.9 nanomoles per liter Standard Deviation 129.3

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A	165.1 nanomoles per liter Standard Deviation 45.0	203.3 nanomoles per liter Standard Deviation 49.8

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=62 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	229.0 nanomoles per liter Standard Deviation 169.8	295.1 nanomoles per liter Standard Deviation 203.2

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=60 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=60 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	278.5 nanomoles per liter Standard Deviation 134.9	426.7 nanomoles per liter Standard Deviation 135.2

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=60 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=60 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	214.1 nanomoles per liter Standard Deviation 106.8	322.4 nanomoles per liter Standard Deviation 110.0

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	1.00 hours Interval 0.38 to 5.0	0.750 hours Interval 0.292 to 2.75

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=8 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=8 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	5.00 hours Interval 3.5 to 6.0	6.00 hours Interval 5.0 to 6.0

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=62 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	0.229 hours Interval 0.0 to 0.625	0.208 hours Interval 0.0 to 0.5

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=62 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	0.250 hours Interval 0.0 to 0.75	0.167 hours Interval 0.063 to 0.563

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=17 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=17 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	7.32 hours Standard Deviation 9.32	1.84 hours Standard Deviation 0.93

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=52 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=52 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	4.60 hours Standard Deviation 5.82	18.4 hours Standard Deviation 24.5

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=63 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=63 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC0-4h (N=61, 61)	2053.7 hour*nanomole per liter Standard Deviation 432.0	1929.7 hour*nanomole per liter Standard Deviation 409.9
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC4-12h (N=61, 61)	1491.8 hour*nanomole per liter Standard Deviation 638.9	2302.5 hour*nanomole per liter Standard Deviation 669.3
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC6-12h (N=61, 61)	808.2 hour*nanomole per liter Standard Deviation 386.3	1607.6 hour*nanomole per liter Standard Deviation 483.3
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC12-24h (N=61, 61)	306.2 hour*nanomole per liter Standard Deviation 305.2	576.6 hour*nanomole per liter Standard Deviation 681.6
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC0-10h (N=61, 61)	3388.4 hour*nanomole per liter Standard Deviation 915.0	3768.7 hour*nanomole per liter Standard Deviation 968.5
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC4-10h (N=61, 61)	1334.7 hour*nanomole per liter Standard Deviation 582.5	1839.0 hour*nanomole per liter Standard Deviation 599.0
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC6-10h (N=61, 61)	651.1 hour*nanomole per liter Standard Deviation 322.1	1144.1 hour*nanomole per liter Standard Deviation 404.6
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC10-24h (N=61, 61)	465.0 hour*nanomole per liter Standard Deviation 352.2	1058.0 hour*nanomole per liter Standard Deviation 752.4
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC(0-inf) (N=52, 52)	3972.6 hour*nanomole per liter Standard Deviation 1125.9	5162.8 hour*nanomole per liter Standard Deviation 1777.2
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A AUC(24h-inf) (N=52, 52)	195.3 hour*nanomole per liter Standard Deviation 568.1	410.4 hour*nanomole per liter Standard Deviation 1094.0

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	3962.0 hour*nanomole per liter Standard Deviation 1079.6	4879.6 hour*nanomole per liter Standard Deviation 1194.4

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	0.048 hour per liter Standard Deviation 0.016	0.061 hour per liter Standard Deviation 0.017

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	0.047 hour per liter Standard Deviation 0.014	0.060 hour per liter Standard Deviation 0.018

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	0.041 hour per liter Standard Deviation 0.012	0.046 hour per liter Standard Deviation 0.013

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	0.025 hour per liter Standard Deviation 0.005	0.024 hour per liter Standard Deviation 0.006

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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	0.002 per liter Standard Deviation 0.001	0.003 per liter Standard Deviation 0.001

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	0.008 per liter Standard Deviation 0.002	0.010 per liter Standard Deviation 0.002

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=62 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	2.26 (hour per nanomole)*10^6 Standard Deviation 1.69	2.32 (hour per nanomole)*10^6 Standard Deviation 1.43

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=62 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	0.003 per liter Standard Deviation 0.002	0.004 per liter Standard Deviation 0.002

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=52 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=52 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A	10.1 percentage of AUC Standard Deviation 7.9	9.26 percentage of AUC Standard Deviation 12.74

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=59 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=59 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A	429.7 percentage of fluctuation Standard Deviation 117.3	396.2 percentage of fluctuation Standard Deviation 99.0

SECONDARY outcome

Timeframe: 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

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=55 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=55 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A	1.11 ratio Standard Deviation 0.29	1.03 ratio Standard Deviation 0.19

SECONDARY outcome

Timeframe: 12 weeks

Population: Part A ITT population

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".

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=63 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=63 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A Patient	4.28 scores on a scale Standard Deviation 0.74	4.36 scores on a scale Standard Deviation 0.73
Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A Investigator	4.26 scores on a scale Standard Deviation 0.73	4.33 scores on a scale Standard Deviation 0.73

SECONDARY outcome

Timeframe: Baseline (week 0), month 6

Population: Part B ITT population with participants evaluable for this outcome.

Patient tolerability questionnaire was assessed by both patient and investigator, the responses were as follows: improvement, no change, worsening and were reported.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=56 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B No change (Investigator)	70.0 percentage of participants	—
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B Improvement (Patient)	10.7 percentage of participants	—
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B Improvement (Investigator)	14.0 percentage of participants	—
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B No change (Patient)	73.2 percentage of participants	—
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B Worsening (Patient)	16.1 percentage of participants	—
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B Worsening (Investigator)	16.0 percentage of participants	—

SECONDARY outcome

Timeframe: 12 weeks

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=61 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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 Physical component	49.3 scores on a scale Standard Deviation 9.1	50.0 scores on a scale Standard Deviation 9.9
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 Mental component	51.1 scores on a scale Standard Deviation 7.3	49.8 scores on a scale Standard Deviation 9.3

SECONDARY outcome

Timeframe: Baseline (week 0), month 6

Population: Part B ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=54 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
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 Physical component	0.390 scores on a scale Standard Deviation 4.374	—
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 Mental component	-0.896 scores on a scale Standard Deviation 5.913	—

SECONDARY outcome

Timeframe: 12 weeks

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A	22.6 scores on a scale Standard Deviation 25.4	26.4 scores on a scale Standard Deviation 30.3

SECONDARY outcome

Timeframe: Baseline (week 0), month 6

Population: Part B ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=56 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B	-1.09 scores on a scale Standard Deviation 12.49	—

SECONDARY outcome

Timeframe: 12 weeks

Population: Part A ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=62 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=61 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A	110.5 scores on a scale Standard Deviation 14.0	107.7 scores on a scale Standard Deviation 17.3

SECONDARY outcome

Timeframe: Baseline (week 0), month 6

Population: Part B ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=55 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B	-0.739 scores on a scale Standard Deviation 9.687	—

SECONDARY outcome

Timeframe: Baseline (week 0), Week 12

Population: ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=47 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A	-3.1 scores on a scale Standard Deviation 12.1	—

SECONDARY outcome

Timeframe: Baseline (week 0), month 6

Population: Part B ITT population with participants evaluable for this outcome.

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=44 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B	-0.180 scores on a scale Standard Deviation 7.943	—

SECONDARY outcome

Timeframe: Weeks 4 up to 28

Population: Part A ITT population with participants evaluable for this outcome.

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).

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=58 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=58 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A	104.8 percentage use Standard Deviation 7.5	103.1 percentage use Standard Deviation 13.2

SECONDARY outcome

Timeframe: Up to Month 6 follow-up

Population: Part B ITT population with participants evaluable for this outcome.

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).

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=58 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Participant Compliance- Part B	102.3 percentage use Standard Deviation 12.8	—

SECONDARY outcome

Timeframe: Weeks 16 up to 28

Population: Part A ITT population

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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=63 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Benefit compared OD to TID: Considerably poorer	3.8 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Benefit compared OD to TID: Somewhat poorer	5.7 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Benefit compared OD to TID: Comparable	5.7 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Benefit compared OD to TID: Large	20.8 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Benefit compared OD to TID: Very large	64.2 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer OD to TID: Strongly disagree	3.7 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer OD to TID: Disagree	3.7 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer OD to TID: Neutral	5.6 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer OD to TID: Strongly	25.9 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer OD to TID: Very strongly	61.1 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer TID to OD: Strongly disagree	39.6 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer TID to OD: Disagree	35.4 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer TID to OD: Neutral	12.5 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer TID to OD: Strongly	4.2 percentage of preference	—
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A Prefer TID to OD: Very strongly	8.3 percentage of preference	—

SECONDARY outcome

Timeframe: 12 weeks

Population: 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.

Outcome measures

Measure	Hydrocortisone MR Tablet OD - Part A n=36 Participants Hydrocortisone MR tablets 20 to 40 mg orally OD during Part A of the study.	Hydrocortisone Tablet TID - Part A n=37 Participants Hydrocortisone tablets 20 to 40 mg orally TID during Part A of the study.
Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A	385.7 nanomoles per 24 hours Standard Deviation 178.8	425.9 nanomoles per 24 hours Standard Deviation 278.8

Adverse Events

Hydrocortisone MR Tablet OD - Part A

Serious events: 6 serious events

Other events: 29 other events

Deaths: 0 deaths

Hydrocortisone Tablet TID - Part A

Serious events: 2 serious events

Other events: 25 other events

Deaths: 0 deaths

Hydrocortisone MR Tablet OD - Part B (First 3 Months)

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Hydrocortisone MR Tablet OD - Part B (Second 3 Months)

Serious events: 4 serious events

Other events: 16 other events

Deaths: 0 deaths

Hydrocortisone MR Tablet OD - Part B (All 6 Months)

Serious events: 6 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Measure	Hydrocortisone MR Tablet OD - Part A n=64 participants at risk Hydrocortisone modified release (MR) tablets 20 to 40 mg orally, once daily (OD) during the 12-week period of Part A.	Hydrocortisone Tablet TID - Part A n=64 participants at risk Hydrocortisone tablets 20 to 40 mg orally, thrice daily (TID) during the 12-week period of Part A.	Hydrocortisone MR Tablet OD - Part B (First 3 Months) n=59 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the first 3 months of Part B (6 months).	Hydrocortisone MR Tablet OD - Part B (Second 3 Months) n=57 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the second 3 months of Part B (6 months).	Hydrocortisone MR Tablet OD - Part B (All 6 Months) n=59 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the entire 6-month period of Part B.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)
Hepatobiliary disorders Cholelithiasis	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Gastroenteritis	6.2% 4/64 • Number of events 4 • Part A (24 weeks) and Part B (6 months)	3.1% 2/64 • Number of events 2 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	0.00% 0/57 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Influenza	1.6% 1/64 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	0.00% 0/57 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Pneumonia	1.6% 1/64 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	0.00% 0/57 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Varicella	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)
Renal and urinary disorders Nephrolithiasis	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	0.00% 0/57 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)
Surgical and medical procedures Surgical and medical procedures	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)

Other adverse events

Measure	Hydrocortisone MR Tablet OD - Part A n=64 participants at risk Hydrocortisone modified release (MR) tablets 20 to 40 mg orally, once daily (OD) during the 12-week period of Part A.	Hydrocortisone Tablet TID - Part A n=64 participants at risk Hydrocortisone tablets 20 to 40 mg orally, thrice daily (TID) during the 12-week period of Part A.	Hydrocortisone MR Tablet OD - Part B (First 3 Months) n=59 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the first 3 months of Part B (6 months).	Hydrocortisone MR Tablet OD - Part B (Second 3 Months) n=57 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the second 3 months of Part B (6 months).	Hydrocortisone MR Tablet OD - Part B (All 6 Months) n=59 participants at risk Hydrocortisone MR tablets 20 to 40 mg orally, once daily (OD) during the entire 6-month period of Part B.
Gastrointestinal disorders Diarrhoea	1.6% 1/64 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	0.00% 0/64 • Part A (24 weeks) and Part B (6 months)	0.00% 0/59 • Part A (24 weeks) and Part B (6 months)	7.0% 4/57 • Number of events 5 • Part A (24 weeks) and Part B (6 months)	6.8% 4/59 • Number of events 5 • Part A (24 weeks) and Part B (6 months)
General disorders Fatigue	12.5% 8/64 • Number of events 10 • Part A (24 weeks) and Part B (6 months)	4.7% 3/64 • Number of events 3 • Part A (24 weeks) and Part B (6 months)	6.8% 4/59 • Number of events 4 • Part A (24 weeks) and Part B (6 months)	3.5% 2/57 • Number of events 2 • Part A (24 weeks) and Part B (6 months)	10.2% 6/59 • Number of events 6 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Gastroenteritis	12.5% 8/64 • Number of events 9 • Part A (24 weeks) and Part B (6 months)	3.1% 2/64 • Number of events 2 • Part A (24 weeks) and Part B (6 months)	6.8% 4/59 • Number of events 4 • Part A (24 weeks) and Part B (6 months)	0.00% 0/57 • Part A (24 weeks) and Part B (6 months)	6.8% 4/59 • Number of events 4 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Influenza	12.5% 8/64 • Number of events 8 • Part A (24 weeks) and Part B (6 months)	3.1% 2/64 • Number of events 2 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	7.0% 4/57 • Number of events 4 • Part A (24 weeks) and Part B (6 months)	8.5% 5/59 • Number of events 5 • Part A (24 weeks) and Part B (6 months)
Infections and infestations Nasopharyngitis	10.9% 7/64 • Number of events 9 • Part A (24 weeks) and Part B (6 months)	23.4% 15/64 • Number of events 16 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	10.5% 6/57 • Number of events 6 • Part A (24 weeks) and Part B (6 months)	11.9% 7/59 • Number of events 7 • Part A (24 weeks) and Part B (6 months)
Investigations Blood thyroid stimulating hormone increased	1.6% 1/64 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	4.7% 3/64 • Number of events 3 • Part A (24 weeks) and Part B (6 months)	3.4% 2/59 • Number of events 2 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	5.1% 3/59 • Number of events 3 • Part A (24 weeks) and Part B (6 months)
Nervous system disorders Headache	3.1% 2/64 • Number of events 4 • Part A (24 weeks) and Part B (6 months)	7.8% 5/64 • Number of events 7 • Part A (24 weeks) and Part B (6 months)	1.7% 1/59 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	1.8% 1/57 • Number of events 1 • Part A (24 weeks) and Part B (6 months)	3.4% 2/59 • Number of events 2 • Part A (24 weeks) and Part B (6 months)

Additional Information

Study Physician

Shire

Phone: 1866-842-5335

Email: clinicaltransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER