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

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

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

Study Overview

• Status: Completed
• Conditions: Adrenal Insufficiency
• Intervention / Treatment: Drug: hydrocortisone (modified release), oral tablet 20 and 5 mg; Drug: Hydrocortisone, oral tablet, 10 mg

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 Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	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

Secondary Outcome Measures

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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. 2006 Dec;91(12):4849-53. doi: 10.1210/jc.2006-0076. Epub 2006 Sep 12.
• Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Jul;161(1):119-30. doi: 10.1530/EJE-09-0170. Epub 2009 Apr 21.
• Lennernas H, Skrtic S, Johannsson G. Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors. Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):749-58. doi: 10.1517/17425255.4.6.749.
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Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2007
• Primary Completion (Actual): July 28, 2008
• Study Completion (Actual): January 28, 2009

Study Registration Dates

• First Submitted: June 5, 2009
• First Submitted That Met QC Criteria: June 5, 2009
• First Posted (Estimate): June 8, 2009

Study Record Updates

• Last Update Posted (Actual): November 24, 2020
• Last Update Submitted That Met QC Criteria: November 9, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Hydrocortisone; Adrenal insufficiency; Modified release; Primary adrenal insufficiency; Addison's disease
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: DC 06/02; 104-07; 2006-007084-89 (EudraCT Number)