Clinical trial NCT00915343: Once-daily Oral Modified Release Hydrocortisone in Patients With Adrenal Insufficiency
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Adrenal Insufficiency
Keywords: Adrenal insufficiency
Primary adrenal insufficiency
Addison's disease
Hydrocortisone
Modified release
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-06-08
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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

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).

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
Secondary outcomes:
measure: Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: 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
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A
timeFrame: Arm 1: Week 4, Week 16, Week 16 + 1 day, Week 28; Arm 2: Week 4, Week 4 + 7 days, Week 16, Week 16 + 7 days
measure: Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A
timeFrame: 12 weeks
measure: Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B
timeFrame: Baseline (week 0), month 6
measure: 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
timeFrame: 12 weeks
measure: 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
timeFrame: Baseline (week 0), month 6
measure: Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A
timeFrame: 12 weeks
measure: Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B
timeFrame: Baseline (week 0), month 6
measure: Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A
timeFrame: 12 weeks
measure: Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B
timeFrame: Baseline (week 0), month 6
measure: Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A
timeFrame: Baseline (week 0), Week 12
measure: Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B
timeFrame: Baseline (week 0), month 6
measure: Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A
timeFrame: Weeks 4 up to 28
measure: Participant Compliance- Part B
timeFrame: Up to Month 6 follow-up
measure: Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A
timeFrame: Weeks 16 up to 28
measure: Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A
timeFrame: 12 weeks
Other outcomes:
Locations:
Study officials:
affiliation: DuoCort AB
name: Maria Forss, MSc BA
role: STUDY_DIRECTOR
affiliation: Göteborg University
name: Anna G Nilsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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