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

Sponsor

Shire (Industry)

Overall Status

Completed

CT.gov ID

NCT00915343

Collaborator

(none)

Enrollment

Arms

17.3

Actual Duration (Months)

Study Details

Study Description

Brief Summary

This is a randomised, controlled, open, two-armed, two-period cross-over, multi-centre phase II/III study to assess the safety, tolerability and pharmacokinetics of once-daily oral modified-release hydrocortisone in comparison to conventional thrice-daily oral hydrocortisone tablets in patients with adrenal insufficiency

Condition or Disease	Intervention/Treatment	Phase
Adrenal Insufficiency	Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg Drug: Hydrocortisone, oral tablet, 10 mg	Phase 2/Phase 3

Detailed Description

Adrenal insufficiency is a disease with more than 80% 1-year mortality before the availability of synthetic glucocorticoids. Current replacement therapy has improved this dramatically, but recent data suggest that outcome is still compromised. Patient receiving replacement therapy with hydrocortisone or cortisone acetate have compromised quality of life, reduced bone mass, increased risk factors for cardiovascular disease and premature mortality that is more than twice the mortality rate in the background population.

Circulating cortisol levels follow a distinct diurnal pattern with high levels in the early morning and low trough values around midnight. Using available formulations for replacement therapy this circadian rhythm is had to mimic and also during the active time of the day high peaks and low troughs occur.

In this trial a newly developed novel dual-, controlled release formulation of hydrocortisone that has in healthy volunteers been able to mimic the circadian pattern of circulating cortisol was studied in patients with primary adrenal insufficiency (Addison's disease).

Study Design

Study Type:

Interventional

Actual Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A, Randomised, Controlled, Two-armed, Two-period Cross-over, Multi-centre Phase II/III Study to Assess the Safety and Pharmacokinetics of Once-daily Oral Modified-release Hydrocortisone in Patients With Adrenal Insufficiency

Actual Study Start Date :

Aug 21, 2007

Actual Primary Completion Date :

Jul 28, 2008

Actual Study Completion Date :

Jan 28, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Novel once daily modified release Test drug: hydrocortisone (modified release), oral tablet, available as 20 mg and 5 mg. The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state	Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state. The dose was the same as patients have had before entering the trial Other Names: DuoCort
Active Comparator: Conventional TID hydrocortisone Reference drug: hydrocortisone, oral tablet, 10 mg. The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM)in the same total daily dose as the experimental drug. The morning dose was administered in the fasting state.	Drug: Hydrocortisone, oral tablet, 10 mg The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM). The morning dose was administered in the fasting state. The total daily dose was the same as in the experimental treatment arm.

Arm

Intervention/Treatment

Experimental: Novel once daily modified release

Test drug: hydrocortisone (modified release), oral tablet, available as 20 mg and 5 mg. The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state

Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg

The modified release hydrocortisone tablet was administered orally o.d. at 8 AM in the fasting state. The dose was the same as patients have had before entering the trial

Other Names:

DuoCort

Active Comparator: Conventional TID hydrocortisone

Reference drug: hydrocortisone, oral tablet, 10 mg. The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM)in the same total daily dose as the experimental drug. The morning dose was administered in the fasting state.

Drug: Hydrocortisone, oral tablet, 10 mg

The reference drug was administered orally thrice daily (at 8 AM, 12 AM and 4 PM). The morning dose was administered in the fasting state. The total daily dose was the same as in the experimental treatment arm.

Outcome Measures

Primary Outcome Measures

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 [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]
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.

Secondary Outcome Measures

Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A [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]
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.
First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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 to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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 to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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 to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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 to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
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 [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]
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.
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 [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]
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.
Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
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 [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]
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.
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 [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]
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.
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 [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]
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.
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 [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]
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.
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 [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]
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.
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 [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]
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.
Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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 to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A [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]
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.
Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A [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]
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.
Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A [12 weeks]
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".
Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B [Baseline (week 0), month 6]
Patient tolerability questionnaire was assessed by both patient and investigator, the responses were as follows: improvement, no change, worsening and were reported.
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 [12 weeks]
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.
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 [Baseline (week 0), month 6]
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.
Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A [12 weeks]
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.
Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B [Baseline (week 0), month 6]
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.
Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A [12 weeks]
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.
Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B [Baseline (week 0), month 6]
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.
Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A [Baseline (week 0), Week 12]
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.
Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B [Baseline (week 0), month 6]
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.
Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A [Weeks 4 up to 28]
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).
Participant Compliance- Part B [Up to Month 6 follow-up]
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).
Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A [Weeks 16 up to 28]
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.
Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A [12 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Previously diagnosed (e.g. more than 6 months ago) primary adrenal insufficiency with a stable daily glucocorticoid substitution dose for at least 3 months prior to study entry
Signed informed consent to participate in the study.

Exclusion Criteria:

Clinical or laboratory signs of significant cerebral, cardiovascular, respiratory, Hepatobiliary, pancreatic disease
Clinically significant renal dysfunction
Clinical or laboratory signs of significant gastrointestinal emptying or motility disease
Any medication with agents which could interfere with hydrocortisone kinetics
Pregnant or lactating women
Regular dehydroepiandrosterone (DHEA) medication for the past 4 weeks
Oral oestrogen medication for the past 4 weeks
Deranged mineralocorticoid status

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Shire

Investigators

Study Director: Maria Forss, MSc BA, DuoCort AB
Principal Investigator: Anna G Nilsson, MD, PhD, Sahlgrenska Academy, Gothenburg University

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Shire

ClinicalTrials.gov Identifier:

NCT00915343

Other Study ID Numbers:

DC 06/02
104-07
2006-007084-89

First Posted:

Jun 8, 2009

Last Update Posted:

Nov 24, 2020

Last Verified:

Nov 1, 2020

Keywords provided by Shire

Adrenal insufficiency

Primary adrenal insufficiency

Addison's disease

Hydrocortisone

Modified release

Additional relevant MeSH terms:

Adrenal Insufficiency

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	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)
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 - First Intervention Period
STARTED	32	32	0
COMPLETED	32	32	0
NOT COMPLETED	0	0	0
Period Title: Part A - First Intervention Period
STARTED	0	0	59
COMPLETED	0	0	57
NOT COMPLETED	0	0	2

Baseline Characteristics

Arm/Group Title	Entire Study
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 Participants	63
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.3 (13.7)
Sex: Female, Male (Count of Participants)
Female	26 41.3%
Male	37 58.7%

Outcome Measures

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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [hour*nanomole per liter]	3962.0 (1079.6)	4879.6 (1194.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

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

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.806
	Confidence Interval	(2-Sided) 95% 0.753 to 0.862
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Mean (Standard Deviation) [nanomoles per liter]	690.7 (109.2)	802.8 (136.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-111.989
	Confidence Interval	(2-Sided) 95% -133.980 to 89.999
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	8	8
Mean (Standard Deviation) [nanomoles per liter]	553.8 (170.8)	446.9 (129.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0357
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	110.417
	Confidence Interval	(2-Sided) 95% 16.755 to 204.078
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [nanomoles per liter]	165.1 (45.0)	203.3 (49.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-38.076
	Confidence Interval	(2-Sided) 95% -50.276 to 25.876
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	62	62
Mean (Standard Deviation) [nanomoles per liter]	229.0 (169.8)	295.1 (203.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-65.782
	Confidence Interval	(2-Sided) 95% -109.201 to 22.362
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	60	60
Mean (Standard Deviation) [nanomoles per liter]	278.5 (134.9)	426.7 (135.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-148.015
	Confidence Interval	(2-Sided) 95% -189.469 to -106.561
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	60	60
Mean (Standard Deviation) [nanomoles per liter]	214.1 (106.8)	322.4 (110.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-108.306
	Confidence Interval	(2-Sided) 95% -140.193 to -76.420
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Median (Full Range) [hours]	1.00	0.750

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0214
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	0.270
	Confidence Interval	(2-Sided) 95% 0.028 to 0.512
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	8	8
Median (Full Range) [hours]	5.00	6.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0714
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-1.042
	Confidence Interval	(2-Sided) 95% -2.098 to 0.015
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	62	62
Median (Full Range) [hours]	0.229	0.208

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.6687
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 95% -0.038 to 0.024
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	62	62
Median (Full Range) [hours]	0.250	0.167

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0280
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	0.049
	Confidence Interval	(2-Sided) 95% 0.006 to 0.093
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	17	17
Mean (Standard Deviation) [hours]	7.32 (9.32)	1.84 (0.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	5.509
	Confidence Interval	(2-Sided) 95% 0.751 to 10.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	52	52
Mean (Standard Deviation) [hours]	4.60 (5.82)	18.4 (24.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-13.800
	Confidence Interval	(2-Sided) 95% -20.533 to -7.067
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

Analysis Population Description
Part A ITT population.

Arm/Group Title	Hydrocortisone MR Tablet OD - Part A	Hydrocortisone Tablet TID - Part A
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.
Measure Participants	63	63
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)

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	1.064
	Confidence Interval	(2-Sided) 95% 1.032 to 1.097
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC0-4h for OD treatment divided by AUC0-4h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.617
	Confidence Interval	(2-Sided) 95% 0.563 to 0.675
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC4-12h for OD treatment divided by AUC4-12h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.472
	Confidence Interval	(2-Sided) 95% 0.424 to 0.525
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC6-12h for OD treatment divided by AUC6-12h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.588
	Confidence Interval	(2-Sided) 95% 0.446 to 0.775
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC12-24h for OD treatment divided by AUC12-24h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.894
	Confidence Interval	(2-Sided) 95% 0.856 to 0.935
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC0-10h for OD treatment divided by AUC0-10h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.695
	Confidence Interval	(2-Sided) 95% 0.632 to 0.765
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC4-10h for OD treatment divided by AUC4-10h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.540
	Confidence Interval	(2-Sided) 95% 0.482 to 0.605
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC6-10h for OD treatment divided by AUC6-10h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.412
	Confidence Interval	(2-Sided) 95% 0.338 to 0.504
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC10-24h for OD treatment divided by AUC10-24h for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.776
	Confidence Interval	(2-Sided) 95% 0.714 to 0.843
	Parameter Dispersion	Type: Value:
	Estimation Comments	The quotient was defined as AUC(0-inf) for OD treatment divided by AUC(0-inf) for TID treatment.

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.8770
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	1.069
	Confidence Interval	(2-Sided) 95% 0.453 to 2.521
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [hour*nanomole per liter]	3962.0 (1079.6)	4879.6 (1194.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.806
	Confidence Interval	(2-Sided) 95% 0.753 to 0.862
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [hour per liter]	0.048 (0.016)	0.061 (0.017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.790
	Confidence Interval	(2-Sided) 95% 0.734 to 0.851
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Mean (Standard Deviation) [hour per liter]	0.047 (0.014)	0.060 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.785
	Confidence Interval	(2-Sided) 95% 0.741 to 0.831
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Mean (Standard Deviation) [hour per liter]	0.041 (0.012)	0.046 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.885
	Confidence Interval	(2-Sided) 95% 0.844 to 0.926
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Mean (Standard Deviation) [hour per liter]	0.025 (0.005)	0.024 (0.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	1.053
	Confidence Interval	(2-Sided) 95% 1.020 to 1.086
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [per liter]	0.002 (0.001)	0.003 (0.001)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.001
	Confidence Interval	(2-Sided) 95% -0.001 to -0.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Mean (Standard Deviation) [per liter]	0.008 (0.002)	0.010 (0.002)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.001
	Confidence Interval	(2-Sided) 95% -0.002 to -0.001
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	62	62
Mean (Standard Deviation) [(hour per nanomole)*10^6]	2.26 (1.69)	2.32 (1.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.7827
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.055
	Confidence Interval	(2-Sided) 95% -0.444 to 0.334
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	62	62
Mean (Standard Deviation) [per liter]	0.003 (0.002)	0.004 (0.002)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.001
	Confidence Interval	(2-Sided) 95% -0.001 to -0.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	52	52
Mean (Standard Deviation) [percentage of AUC]	10.1 (7.9)	9.26 (12.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	6.098
	Confidence Interval	(2-Sided) 95% 2.940 to 12.646
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	59	59
Mean (Standard Deviation) [percentage of fluctuation]	429.7 (117.3)	396.2 (99.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0396
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	33.532
	Confidence Interval	(2-Sided) 95% 1.734 to 65.329
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
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

Outcome Measure Data

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
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.
Measure Participants	55	55
Mean (Standard Deviation) [ratio]	1.11 (0.29)	1.03 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1032
	Comments
	Method	Fisher's non-parametric permutation test
	Comments

Method of Estimation	Estimation Parameter	Period-adjusted quotient
	Estimated Value	0.080
	Confidence Interval	(2-Sided) 95% -0.017 to 0.177
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A
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

Outcome Measure Data

Analysis Population Description
Part A ITT population

Arm/Group Title	Hydrocortisone MR Tablet OD - Part A	Hydrocortisone Tablet TID - Part A
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.
Measure Participants	63	63
Patient	4.28 (0.74)	4.36 (0.73)
Investigator	4.26 (0.73)	4.33 (0.73)

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3767
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.4625
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	56
Improvement (Patient)	10.7 17%
Improvement (Investigator)	14.0 22.2%
No change (Patient)	73.2 116.2%
No change (Investigator)	70.0 111.1%
Worsening (Patient)	16.1 25.6%
Worsening (Investigator)	16.0 25.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments	Patient
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.6072
	Comments
	Method	Sign test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments	Investigator
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Sign test
	Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	61	61
Physical component	49.3 (9.1)	50.0 (9.9)
Mental component	51.1 (7.3)	49.8 (9.3)

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3332
	Comments
	Method	Fisher's test
	Comments	Fisher's non-parametric two-sample permutation test

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3405
	Comments
	Method	Fisher's test
	Comments	Fisher's non-parametric two-sample permutation test

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	0.9
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	54
Physical component	0.390 (4.374)
Mental component	-0.896 (5.913)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.8418
	Comments
	Method	Wilcoxon Signed Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	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 (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.3550
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	62	61
Mean (Standard Deviation) [scores on a scale]	22.6 (25.4)	26.4 (30.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0823
	Comments
	Method	Fisher's
	Comments	Fisher's non-parametric two-sample permutation test

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	56
Mean (Standard Deviation) [scores on a scale]	-1.09 (12.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.5982
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

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
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

Outcome Measure Data

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
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.
Measure Participants	62	61
Mean (Standard Deviation) [scores on a scale]	110.5 (14.0)	107.7 (17.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0632
	Comments
	Method	Fisher's test
	Comments	Fisher's non-parametric two-sample permutation test

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	2.3
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	55
Mean (Standard Deviation) [scores on a scale]	-0.739 (9.687)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.8676
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

35. Secondary Outcome

Title	Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A
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

Outcome Measure Data

Analysis Population Description
ITT population with participants evaluable for this outcome.

Arm/Group Title	Hydrocortisone MR Tablet OD - Part A
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.
Measure Participants	47
Mean (Standard Deviation) [scores on a scale]	-3.1 (12.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.9700
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

36. Secondary Outcome

Title	Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	44
Mean (Standard Deviation) [scores on a scale]	-0.180 (7.943)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.2624
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

37. Secondary Outcome

Title	Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A
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

Outcome Measure Data

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
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.
Measure Participants	58	58
Mean (Standard Deviation) [percentage use]	104.8 (7.5)	103.1 (13.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	1.28
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

38. Secondary Outcome

Title	Participant Compliance- Part B
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

Outcome Measure Data

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)
Arm/Group Description	Hydrocortisone MR tablets 20 to 40 mg orally OD during the entire 6-month period of Part B.
Measure Participants	58
Mean (Standard Deviation) [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
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

Outcome Measure Data

Analysis Population Description
Part A ITT population

Arm/Group Title	Hydrocortisone OD Versus TID
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.
Measure Participants	63
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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Sign test
	Comments

40. Secondary Outcome

Title	Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A
Description
Time Frame	12 weeks

Outcome Measure Data

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
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.
Measure Participants	36	37
Mean (Standard Deviation) [nanomoles per 24 hours]	385.7 (178.8)	425.9 (278.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydrocortisone MR Tablet OD - Part A, Hydrocortisone Tablet TID - Part A
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0034
	Comments
	Method	Wilcoxon Signed Rank test
	Comments

Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-272.3
	Confidence Interval	(2-Sided) % to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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)
Time Frame	Part A (24 weeks) and Part B (6 months)
Adverse Event Reporting Description

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)
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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (9.4%)		2/64 (3.1%)		2/59 (3.4%)		4/57 (7%)		6/59 (10.2%)
Gastrointestinal disorders
Pancreatitis acute	0/64 (0%)	0	0/64 (0%)	0	0/59 (0%)	0	1/57 (1.8%)	1	1/59 (1.7%)	1
Hepatobiliary disorders
Cholelithiasis	0/64 (0%)	0	0/64 (0%)	0	0/59 (0%)	0	1/57 (1.8%)	1	1/59 (1.7%)	1
Infections and infestations
Gastroenteritis	4/64 (6.3%)	4	2/64 (3.1%)	2	1/59 (1.7%)	1	0/57 (0%)	0	1/59 (1.7%)	1
Influenza	1/64 (1.6%)	1	0/64 (0%)	0	0/59 (0%)	0	0/57 (0%)	0	0/59 (0%)	0
Pneumonia	1/64 (1.6%)	1	0/64 (0%)	0	0/59 (0%)	0	0/57 (0%)	0	0/59 (0%)	0
Varicella	0/64 (0%)	0	0/64 (0%)	0	0/59 (0%)	0	1/57 (1.8%)	1	1/59 (1.7%)	1
Renal and urinary disorders
Nephrolithiasis	0/64 (0%)	0	0/64 (0%)	0	1/59 (1.7%)	1	0/57 (0%)	0	1/59 (1.7%)	1
Surgical and medical procedures
Surgical and medical procedures	0/64 (0%)	0	0/64 (0%)	0	0/59 (0%)	0	1/57 (1.8%)	1	1/59 (1.7%)	1
Other (Not Including 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	29/64 (45.3%)		25/64 (39.1%)		12/59 (20.3%)		16/57 (28.1%)		23/59 (39%)
Gastrointestinal disorders
Diarrhoea	1/64 (1.6%)	1	0/64 (0%)	0	0/59 (0%)	0	4/57 (7%)	5	4/59 (6.8%)	5
General disorders
Fatigue	8/64 (12.5%)	10	3/64 (4.7%)	3	4/59 (6.8%)	4	2/57 (3.5%)	2	6/59 (10.2%)	6
Infections and infestations
Gastroenteritis	8/64 (12.5%)	9	2/64 (3.1%)	2	4/59 (6.8%)	4	0/57 (0%)	0	4/59 (6.8%)	4
Influenza	8/64 (12.5%)	8	2/64 (3.1%)	2	1/59 (1.7%)	1	4/57 (7%)	4	5/59 (8.5%)	5
Nasopharyngitis	7/64 (10.9%)	9	15/64 (23.4%)	16	1/59 (1.7%)	1	6/57 (10.5%)	6	7/59 (11.9%)	7
Investigations
Blood thyroid stimulating hormone increased	1/64 (1.6%)	1	3/64 (4.7%)	3	2/59 (3.4%)	2	1/57 (1.8%)	1	3/59 (5.1%)	3
Nervous system disorders
Headache	2/64 (3.1%)	4	5/64 (7.8%)	7	1/59 (1.7%)	1	1/57 (1.8%)	1	2/59 (3.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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
Email	clinicaltransparency@shire.com

Responsible Party:

Shire

ClinicalTrials.gov Identifier:

NCT00915343

Other Study ID Numbers:

DC 06/02
104-07
2006-007084-89

First Posted:

Jun 8, 2009

Last Update Posted:

Nov 24, 2020

Last Verified:

Nov 1, 2020