Trial Outcomes & Findings for Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia (NCT NCT02716818)

Last Updated: 2021-05-26

Results Overview

Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP (17-Hydroxyprogesterone). The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP when compared to baseline (0).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

122 participants

Primary outcome timeframe

24 weeks

Results posted on

2021-05-26

Participant Flow

This study was conducted at 11 study sites in 7 countries: Denmark 1, France 2, Germany 1,Netherlands 1, Sweden 1, UK 4, and USA 1.

Following written informed consent and screening tests (Visit 0), eligible participants were called back for the baseline visit. As part of the baseline assessment, participants were admitted overnight for a 24- hour endocrine profile whilst remaining on their standard therapy. Participants were then randomised to Chronocort or standard therapy.

Participant milestones

Participant milestones
Measure	Chronocort® Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subject's previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid
Overall Study STARTED	61	61
Overall Study COMPLETED	58	59
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Chronocort® n=61 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=61 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Total n=122 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	61 Participants n=5 Participants	59 Participants n=7 Participants	120 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Age, Continuous	35.2 years n=5 Participants	37.5 years n=7 Participants	36.3 years n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	36 Participants n=7 Participants	78 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	25 Participants n=7 Participants	44 Participants n=5 Participants
Race/Ethnicity, Customized White	60 Participants n=5 Participants	60 Participants n=7 Participants	120 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Europe	57 participants n=5 Participants	57 participants n=7 Participants	114 participants n=5 Participants

PRIMARY outcome

Timeframe: 24 weeks

Population: The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105.

Outcome measures

Outcome measures
Measure	Chronocort® n=53 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=52 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP	-0.403 Z-score Standard Deviation 0.8499	-0.172 Z-score Standard Deviation 0.7776	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 24 weeks

Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for A4 (androstenedione). This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of A4 when compared to baseline (0).

Outcome measures

Outcome measures
Measure	Chronocort® n=53 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=52 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4	0.113 Z-score Standard Deviation 0.9221	-0.041 Z-score Standard Deviation 0.7731	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 24 weeks

17-OHP and A4 by individual baseline treatment strata presented in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks). Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP and A4. This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP and A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP and A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP and A4 when compared to baseline (0).

Outcome measures

Outcome measures
Measure	Chronocort® n=27 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=21 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP n=4 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP n=31 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP n=18 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP n=4 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 n=27 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 n=21 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 n=4 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 n=31 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 n=18 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 n=4 Participants Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
17-OHP and A4 by Individual Baseline Treatment Strata.	-0.248 Z-score Standard Deviation 0.7661	-0.061 Z-score Standard Deviation 0.8051	-0.245 Z-score Standard Deviation 0.8522	-0.431 Z-score Standard Deviation 0.8727	-0.320 Z-score Standard Deviation 0.7627	-0.565 Z-score Standard Deviation 1.2343	-0.211 Z-score Standard Deviation 0.7426	0.100 Z-score Standard Deviation 0.8339	0.368 Z-score Standard Deviation 0.3521	0.015 Z-score Standard Deviation 1.0128	0.328 Z-score Standard Deviation 0.7256	-0.092 Z-score Standard Deviation 1.0310

SECONDARY outcome

Timeframe: 24 weeks

17-OHP and A4 levels at 09:00 at the week 24 visit, as a responder analysis (i.e. the number of participants achieving results in the optimal range). Optimal range for 17-OHP (male) = 1.2\* - 6.7 nmol/L (female) = 1.2\* - 8.6 Optimal range for A4 (male) = 1.4 - 5.2 nmol/L (female) = 1.0 - 7.0 nmol/L \* = There is no lower reference range available for 17-OHP, hence the lower limit of the optimal range was used in the derivation of the average Standard Deviation Score. This enabled calculation of an 'unsigned' SDS score which was used to assess potential over-treatment as well as under-treatment.

Outcome measures

Outcome measures
Measure	Chronocort® n=53 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=53 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP n=52 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP n=52 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit	30 Participants	25 Participants	30 Participants	30 Participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.

Outcome measures

Outcome measures
Measure	Chronocort® n=43 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=39 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP n=43 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP n=39 Participants Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass)	-0.575 kilograms Standard Deviation 3.2744	0.445 kilograms Standard Deviation 2.4660	0.640 kilograms Standard Deviation 2.3304	0.234 kilograms Standard Deviation 1.3689	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany.

Outcome measures

Outcome measures
Measure	Chronocort® n=35 Participants Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=36 Participants Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid	Pre-Baseline - Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).	Pre-Baseline - Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)	Pre-Baseline - Chronocort vs. Dexamethasone - A4 Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)
Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany.	-0.001 g/cm^2 Standard Deviation 0.0250	-0.008 g/cm^2 Standard Deviation 0.0399	—	—	—	—	—	—	—	—	—	—

Adverse Events

Chronocort®

Serious events: 7 serious events

Other events: 59 other events

Deaths: 0 deaths

Standard Glucocorticoid Therapy

Serious events: 5 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Chronocort® n=61 participants at risk Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. Chronocort®: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.	Standard Glucocorticoid Therapy n=61 participants at risk Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: 1. Hydrocortisone only 2. Prednisone or prednisolone, alone or in combination with hydrocortisone 3. Dexamethasone, alone or in combination with any other glucocorticoid
Infections and infestations Gastroenteritis	3.3% 2/61 • Number of events 2 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Gastroenteritis Viral	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Appendicitis	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Salpingitis	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Tonsilitis	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Diverticulitis	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Infections and infestations Herpes Zoster	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Endocrine disorders Adrenocortical Insufficiency (acute)	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	4.9% 3/61 • Number of events 3 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Endocrine disorders Adrenal Insufficiency	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
General disorders Oedema Peripheral	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 2 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
General disorders Pyrexia	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Gastrointestinal disorders Diarrhoea	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Gastrointestinal disorders Vomiting	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/61 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.	1.6% 1/61 • Number of events 1 • Adverse event information was collected from the point of enrolment to completion of the study (6 months). Adverse event information was collected at each visit by the investigator and reported accordingly.

Other adverse events

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Specified in the contractual agreements between the Sponsor and investigators: "Neither the CRO, nor the Heath Board, nor the Investigator shall register the Clinical Trial, or the results, on any publicly accessible clinical trial registry."
Publication restrictions are in place

Restriction type: OTHER