Adrenal Insufficiency
Conditions
Keywords
Adrenal insufficiency, Primary adrenal insufficiency, Addison's disease, Hydrocortisone, Modified release
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).
Interventions
DRUGhydrocortisone (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
DRUGHydrocortisone, 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.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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, Nsignifies 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. |
| 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. |
| 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. |
| 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 | — |
| 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. |
| 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. |
Participant flow
Pre-assignment details
Study consisted of Part A (cross-over) and Part B (open-label). Of the 64 participants started and completed Part A, 5 participants did not enter Part B (treatment switch=2, withdrawal by participant= 2, nausea and abnormal laboratory value=1), 59 started Part B of the study.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study 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. | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part B - Open Label Period | Did not attend the last visit | 0 | 0 | 1 |
| Part B - Open Label Period | Treatment switch | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study |
|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 13.7 |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 64 | 25 / 64 | 12 / 59 | 16 / 57 | 23 / 59 |
| serious Total, serious adverse events | 6 / 64 | 2 / 64 | 2 / 59 | 4 / 57 | 6 / 59 |
Outcome results
Primary
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.
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
Population: Part A: Intention-To-Treat (ITT) set included all randomised participants who took at least 1 dose of study drug with primary efficacy assessments including all pharmacokinetic (PK) samplings during either treatment period. Here number of participants analysed signifies those who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve From Zero to 24 Hours (AUC0-24h) of Total S-cortisol in Plasma After Multiple Doses During Part A | 3962.0 hour*nanomole per liter | Standard Deviation 1079.6 |
| Hydrocortisone Tablet TID - Part A | 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 | 4879.6 hour*nanomole per liter | Standard Deviation 1194.4 |
p-value: <0.000195% CI: [0.753, 0.862]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 1.11 ratio | Standard Deviation 0.29 |
| Hydrocortisone Tablet TID - Part A | Accumulation Ratio (Rac) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 1.03 ratio | Standard Deviation 0.19 |
p-value: 0.103295% CI: [-0.017, 0.177]Fisher's non-parametric permutation test
Secondary
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, Nsignifies 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
Population: Part A ITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC0-4h (N=61, 61) | 2053.7 hour*nanomole per liter | Standard Deviation 432 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC4-12h (N=61, 61) | 1491.8 hour*nanomole per liter | Standard Deviation 638.9 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC6-12h (N=61, 61) | 808.2 hour*nanomole per liter | Standard Deviation 386.3 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC12-24h (N=61, 61) | 306.2 hour*nanomole per liter | Standard Deviation 305.2 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC0-10h (N=61, 61) | 3388.4 hour*nanomole per liter | Standard Deviation 915 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC4-10h (N=61, 61) | 1334.7 hour*nanomole per liter | Standard Deviation 582.5 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC6-10h (N=61, 61) | 651.1 hour*nanomole per liter | Standard Deviation 322.1 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC10-24h (N=61, 61) | 465.0 hour*nanomole per liter | Standard Deviation 352.2 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC(0-inf) (N=52, 52) | 3972.6 hour*nanomole per liter | Standard Deviation 1125.9 |
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC(24h-inf) (N=52, 52) | 195.3 hour*nanomole per liter | Standard Deviation 568.1 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC10-24h (N=61, 61) | 1058.0 hour*nanomole per liter | Standard Deviation 752.4 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC0-4h (N=61, 61) | 1929.7 hour*nanomole per liter | Standard Deviation 409.9 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC4-10h (N=61, 61) | 1839.0 hour*nanomole per liter | Standard Deviation 599 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC4-12h (N=61, 61) | 2302.5 hour*nanomole per liter | Standard Deviation 669.3 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC(24h-inf) (N=52, 52) | 410.4 hour*nanomole per liter | Standard Deviation 1094 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC6-12h (N=61, 61) | 1607.6 hour*nanomole per liter | Standard Deviation 483.3 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC6-10h (N=61, 61) | 1144.1 hour*nanomole per liter | Standard Deviation 404.6 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC12-24h (N=61, 61) | 576.6 hour*nanomole per liter | Standard Deviation 681.6 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC(0-inf) (N=52, 52) | 5162.8 hour*nanomole per liter | Standard Deviation 1777.2 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve (AUC) Between Specified Timepoints of Total S-cortisol in Plasma After Single and Multiple Dosing During Part A | AUC0-10h (N=61, 61) | 3768.7 hour*nanomole per liter | Standard Deviation 968.5 |
Comparison: AUC0-4hp-value: 0.000295% CI: [1.032, 1.097]ANOVA
Comparison: AUC4-12hp-value: <0.000195% CI: [0.563, 0.675]ANOVA
Comparison: AUC6-12hp-value: <0.000195% CI: [0.424, 0.525]ANOVA
Comparison: AUC12-24hp-value: 0.000395% CI: [0.446, 0.775]ANOVA
Comparison: AUC0-10hp-value: <0.000195% CI: [0.856, 0.935]ANOVA
Comparison: AUC4-10hp-value: <0.000195% CI: [0.632, 0.765]ANOVA
Comparison: AUC6-10hp-value: <0.000195% CI: [0.482, 0.605]ANOVA
Comparison: AUC10-24hp-value: <0.000195% CI: [0.338, 0.504]ANOVA
Comparison: AUC(0-inf)p-value: <0.000195% CI: [0.714, 0.843]ANOVA
Comparison: AUC(24h-inf)p-value: 0.87795% CI: [0.453, 2.521]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve During a Dosing Interval at Steady State Adjusted by Dose (AUCtau/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.048 hour per liter | Standard Deviation 0.016 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve During a Dosing Interval at Steady State Adjusted by Dose (AUCtau/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.061 hour per liter | Standard Deviation 0.017 |
p-value: <0.000195% CI: [0.734, 0.851]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve During a Dosing Interval at Steady State (AUCtau) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 3962.0 hour*nanomole per liter | Standard Deviation 1079.6 |
| Hydrocortisone Tablet TID - Part A | 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 | 4879.6 hour*nanomole per liter | Standard Deviation 1194.4 |
p-value: <0.000195% CI: [0.753, 0.862]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve From Zero to 10 Hours Adjusted by Dose (AUC0-10h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.041 hour per liter | Standard Deviation 0.012 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve From Zero to 10 Hours Adjusted by Dose (AUC0-10h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.046 hour per liter | Standard Deviation 0.013 |
p-value: <0.000195% CI: [0.844, 0.926]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve From Zero to 24 Hours Adjusted by Dose (AUC0-24h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.047 hour per liter | Standard Deviation 0.014 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve From Zero to 24 Hours Adjusted by Dose (AUC0-24h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.060 hour per liter | Standard Deviation 0.018 |
p-value: <0.000195% CI: [0.741, 0.831]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Area Under the Concentration Time Curve From Zero to 4 Hours Adjusted by Dose (AUC0-4h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.025 hour per liter | Standard Deviation 0.005 |
| Hydrocortisone Tablet TID - Part A | Area Under the Concentration Time Curve From Zero to 4 Hours Adjusted by Dose (AUC0-4h/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.024 hour per liter | Standard Deviation 0.006 |
p-value: 0.00295% CI: [1.02, 1.086]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Average Concentration of S-cortisol During the Dosing Interval at Steady State Adjusted by Dose (Css,av/Dose) in Plasma After Single and Multiple Dosing During Part A | 0.002 per liter | Standard Deviation 0.001 |
| Hydrocortisone Tablet TID - Part A | Average Concentration of S-cortisol During the Dosing Interval at Steady State Adjusted by Dose (Css,av/Dose) in Plasma After Single and Multiple Dosing During Part A | 0.003 per liter | Standard Deviation 0.001 |
p-value: <0.000195% CI: [-0.001, 0]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A | 165.1 nanomoles per liter | Standard Deviation 45 |
| Hydrocortisone Tablet TID - Part A | Average Concentration of S-cortisol During the Dosing Interval at Steady State (Css,av) in Plasma After Single and Multiple Dosing During Part A | 203.3 nanomoles per liter | Standard Deviation 49.8 |
p-value: <0.000195% CI: [-50.276, 25.876]Fisher's non-parametric permutation test
Secondary
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.
Time frame: Baseline (week 0), Week 12
Population: ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 12 Weeks in Diurnal Fatigue Questionnaire for Day Average of Once Daily Therapy - Part A | -3.1 scores on a scale | Standard Deviation 12.1 |
p-value: 0.97Wilcoxon Signed Rank test
Secondary
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.
Time frame: Baseline (week 0), month 6
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 6 Months in Diurnal Fatigue Questionnaire for Day Average- Part B | -0.180 scores on a scale | Standard Deviation 7.943 |
p-value: 0.2624Wilcoxon Signed Rank test
Secondary
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.
Time frame: Baseline (week 0), month 6
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score - Part B | -1.09 scores on a scale | Standard Deviation 12.49 |
p-value: 0.5982Wilcoxon Signed Rank test
Secondary
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.
Time frame: Baseline (week 0), month 6
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores- Part B | -0.739 scores on a scale | Standard Deviation 9.687 |
p-value: 0.8676Wilcoxon Signed Rank test
Secondary
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.
Time frame: Baseline (week 0), month 6
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score - Part B | Mental component | -0.896 scores on a scale | Standard Deviation 5.913 |
| Hydrocortisone MR Tablet OD - Part A | Change From Baseline to 6 Months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score - Part B | Physical component | 0.390 scores on a scale | Standard Deviation 4.374 |
Comparison: Change From Baseline to 6 months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical Component Scorep-value: 0.8418Wilcoxon Signed Rank
Comparison: Change From Baseline to 6 months in Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Mental Component Scorep-value: 0.355Wilcoxon Signed Rank test
Secondary
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.
Time frame: 12 weeks
Population: Part A ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A | Patient | 4.28 scores on a scale | Standard Deviation 0.74 |
| Hydrocortisone MR Tablet OD - Part A | Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A | Investigator | 4.26 scores on a scale | Standard Deviation 0.73 |
| Hydrocortisone Tablet TID - Part A | Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A | Patient | 4.36 scores on a scale | Standard Deviation 0.73 |
| Hydrocortisone Tablet TID - Part A | Comparison of Overall Patient Tolerability Score Between Once Daily and Thrice Daily Therapy, Assessed by Patient and Investigator - Part A | Investigator | 4.33 scores on a scale | Standard Deviation 0.73 |
Comparison: Patientp-value: 0.376795% CI: [-0.25, 0.094]Fisher's test
Comparison: Investigatorp-value: 0.462595% CI: [-0.235, 0.107]Fisher's test
Secondary
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.
Time frame: 12 weeks
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A | 22.6 scores on a scale | Standard Deviation 25.4 |
| Hydrocortisone Tablet TID - Part A | Comparison of Quality of Life (QoL) Assessed by Fatigue Impact Scale (FIS) Total Score Between Once Daily and Thrice Daily Therapy - Part A | 26.4 scores on a scale | Standard Deviation 30.3 |
p-value: 0.0823Fisher's
Secondary
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.
Time frame: 12 weeks
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A | 110.5 scores on a scale | Standard Deviation 14 |
| Hydrocortisone Tablet TID - Part A | Comparison of Quality of Life (QoL) Assessed by Psychological General Well Being (PGWB) Total Scores Between Once Daily and Thrice Daily Therapy- Part A | 107.7 scores on a scale | Standard Deviation 17.3 |
p-value: 0.0632Fisher's test
Secondary
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.
Time frame: 12 weeks
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A | Physical component | 49.3 scores on a scale | Standard Deviation 9.1 |
| Hydrocortisone MR Tablet OD - Part A | Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A | Mental component | 51.1 scores on a scale | Standard Deviation 7.3 |
| Hydrocortisone Tablet TID - Part A | Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A | Physical component | 50.0 scores on a scale | Standard Deviation 9.9 |
| Hydrocortisone Tablet TID - Part A | Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical and Mental Component Score Between Once Daily and Thrice Daily Therapy- Part A | Mental component | 49.8 scores on a scale | Standard Deviation 9.3 |
Comparison: Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Physical Component Scorep-value: 0.3332Fisher's test
Comparison: Comparison of Quality of Life (QoL) Assessed by Short Form-36 Survey (SF-36) For Mental Component Scorep-value: 0.3405Fisher's test
Secondary
Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A
Time frame: 12 weeks
Population: Part A Safety population consisted of all randomised patients who took at least one dose of study medication. Safety population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A | 385.7 nanomoles per 24 hours | Standard Deviation 178.8 |
| Hydrocortisone Tablet TID - Part A | Comparison on 24-hour Urinary Free Cortisol Between Once Daily and Thrice Daily Therapy-Part A | 425.9 nanomoles per 24 hours | Standard Deviation 278.8 |
p-value: 0.0034Wilcoxon Signed Rank test
Secondary
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).
Time frame: Weeks 4 up to 28
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A | 104.8 percentage use | Standard Deviation 7.5 |
| Hydrocortisone Tablet TID - Part A | Comparison on Participant Compliance Between Once Daily and Thrice Daily Therapy - Part A | 103.1 percentage use | Standard Deviation 13.2 |
Secondary
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.
Time frame: Weeks 16 up to 28
Population: Part A ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Benefit compared OD to TID: Considerably poorer | 3.8 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Benefit compared OD to TID: Somewhat poorer | 5.7 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Benefit compared OD to TID: Comparable | 5.7 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Benefit compared OD to TID: Large | 20.8 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Benefit compared OD to TID: Very large | 64.2 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer OD to TID: Strongly disagree | 3.7 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer OD to TID: Disagree | 3.7 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer OD to TID: Neutral | 5.6 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer OD to TID: Strongly | 25.9 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer OD to TID: Very strongly | 61.1 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer TID to OD: Strongly disagree | 39.6 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer TID to OD: Disagree | 35.4 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer TID to OD: Neutral | 12.5 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer TID to OD: Strongly | 4.2 percentage of preference |
| Hydrocortisone MR Tablet OD - Part A | Comparison on Participant Preference by Questionnaire Between Once Daily and Thrice Daily Therapy-Part A | Prefer TID to OD: Very strongly | 8.3 percentage of preference |
p-value: <0.0001Sign test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 278.5 nanomoles per liter | Standard Deviation 134.9 |
| Hydrocortisone Tablet TID - Part A | Concentration at 6 Hours (C6h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 426.7 nanomoles per liter | Standard Deviation 135.2 |
p-value: <0.000195% CI: [-189.469, -106.561]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 214.1 nanomoles per liter | Standard Deviation 106.8 |
| Hydrocortisone Tablet TID - Part A | Concentration at 7 Hours (C7h) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 322.4 nanomoles per liter | Standard Deviation 110 |
p-value: <0.000195% CI: [-140.193, -76.42]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Drug Concentration Half-Life From 5 to 14 Hours (t1/2[5-14h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 4.60 hours | Standard Deviation 5.82 |
| Hydrocortisone Tablet TID - Part A | 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 | 18.4 hours | Standard Deviation 24.5 |
p-value: <0.000195% CI: [-20.533, -7.067]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Drug Concentration Half-Life From 5 to 24 Hours (t1/2[5-24h]) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 7.32 hours | Standard Deviation 9.32 |
| Hydrocortisone Tablet TID - Part A | 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 | 1.84 hours | Standard Deviation 0.93 |
p-value: 0.000395% CI: [0.751, 10.268]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.003 per liter | Standard Deviation 0.002 |
| Hydrocortisone Tablet TID - Part A | First Detectable Concentration Adjusted by Dose (Cfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.004 per liter | Standard Deviation 0.002 |
p-value: 0.001595% CI: [-0.001, 0]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 229.0 nanomoles per liter | Standard Deviation 169.8 |
| Hydrocortisone Tablet TID - Part A | First Detectable Concentration (Cfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 295.1 nanomoles per liter | Standard Deviation 203.2 |
p-value: 0.003395% CI: [-109.201, 22.362]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.008 per liter | Standard Deviation 0.002 |
| Hydrocortisone Tablet TID - Part A | Maximal Concentration Adjusted by Dose (Cmax1/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.010 per liter | Standard Deviation 0.002 |
p-value: <0.000195% CI: [-0.002, -0.001]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 690.7 nanomoles per liter | Standard Deviation 109.2 |
| Hydrocortisone Tablet TID - Part A | Maximal Concentration (Cmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 802.8 nanomoles per liter | Standard Deviation 136.2 |
p-value: <0.000195% CI: [-133.98, 89.999]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 553.8 nanomoles per liter | Standard Deviation 170.8 |
| Hydrocortisone Tablet TID - Part A | Maximal Concentration (Cmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 446.9 nanomoles per liter | Standard Deviation 129.3 |
p-value: 0.035795% CI: [16.755, 204.078]Fisher's non-parametric permutation test
Secondary
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).
Time frame: Up to Month 6 follow-up
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Participant Compliance- Part B | 102.3 percentage use | Standard Deviation 12.8 |
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 10.1 percentage of AUC | Standard Deviation 7.9 |
| Hydrocortisone Tablet TID - Part A | Percentage (%) of Area Under the Concentration Time Curve (AUC) Extrapolation of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 9.26 percentage of AUC | Standard Deviation 12.74 |
p-value: <0.000195% CI: [2.94, 12.646]ANOVA
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A | 429.7 percentage of fluctuation | Standard Deviation 117.3 |
| Hydrocortisone Tablet TID - Part A | Percentage (%) of Fluctuation in Concentrations of S-cortisol at Steady State in Plasma After Single and Multiple Dosing During Part A | 396.2 percentage of fluctuation | Standard Deviation 99 |
p-value: 0.039695% CI: [1.734, 65.329]Fisher's non-parametric permutation test
Secondary
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.
Time frame: Baseline (week 0), month 6
Population: Part B ITT population with participants evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | Improvement (Patient) | 10.7 percentage of participants |
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | Improvement (Investigator) | 14.0 percentage of participants |
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | No change (Patient) | 73.2 percentage of participants |
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | No change (Investigator) | 70.0 percentage of participants |
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | Worsening (Patient) | 16.1 percentage of participants |
| Hydrocortisone MR Tablet OD - Part A | Percentage (%) of Participants With Change From Baseline in Patient Tolerability Questionnaire at Month 6, Assessed by Patient and Investigator - Part B | Worsening (Investigator) | 16.0 percentage of participants |
Comparison: Patientp-value: 0.6072Sign test
Comparison: Investigatorp-value: 1Sign test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 2.26 (hour per nanomole)*10^6 | Standard Deviation 1.69 |
| Hydrocortisone Tablet TID - Part A | Time to First Detectable Concentration Adjusted by Dose (Tfirst/Dose) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 2.32 (hour per nanomole)*10^6 | Standard Deviation 1.43 |
p-value: 0.782795% CI: [-0.444, 0.334]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.229 hours |
| Hydrocortisone Tablet TID - Part A | Time to First Detectable Concentration (Tfirst) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.208 hours |
p-value: 0.668795% CI: [-0.038, 0.024]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 1.00 hours |
| Hydrocortisone Tablet TID - Part A | Time to Peak Plasma Concentration (Tmax1) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.750 hours |
p-value: 0.021495% CI: [0.028, 0.512]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 5.00 hours |
| Hydrocortisone Tablet TID - Part A | Time to Peak Plasma Concentration (Tmax2) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 6.00 hours |
p-value: 0.071495% CI: [-2.098, 0.015]Fisher's non-parametric permutation test
Secondary
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.
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
Population: Part A ITT population with participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydrocortisone MR Tablet OD - Part A | Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.250 hours |
| Hydrocortisone Tablet TID - Part A | Time to Reach a Concentration of 200 Nanometers (nM) (T200) of S-cortisol in Plasma After Single and Multiple Dosing During Part A | 0.167 hours |
p-value: 0.02895% CI: [0.006, 0.093]Fisher's non-parametric permutation test