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

• Sponsor: Diurnal Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02716818
• Collaborator: (none)
• Enrollment: 122
• Location: 1
• Arms: 2
• Actual Duration (Months): 29.1
• Patients Per Site Per Month: 4.2

Study Details

Study Description

Brief Summary

This study is a parallel arm, randomised, open-label study, including dose titration and admissions for four overnight stays for 24-hour endocrine profiles. It will compare the efficacy, safety and tolerability of Chronocort® with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia (CAH) over a treatment period of 6 months. Dose titration decisions in both treatment groups will be made by a central independent physician, blinded to the treatment arm, using information generated from the 24-hour endocrine profiles. Each treatment arm will be subject to the same titration rules throughout the study, ensuring that opportunities for optimisation and control of androgens are the same in both groups.

Condition or Disease	Intervention/Treatment	Phase
Congenital Adrenal Hyperplasia	Drug: Chronocort®; Drug: standard glucocorticoid therapy	Phase 3

Detailed Description

At baseline, subjects will be admitted overnight for a 24-hour endocrine profile whilst on their standard therapy. Subjects will attend the study site in the morning and have 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) levels assessed at 15:00, 17:00, 19:00, 21:00, 23:00, 01:00, 03:00, 05:00, 07:00, 09:00, 11:00, 13:00 and 15:00. Safety laboratory tests, a DEXA scan for body composition, and height, weight and waist circumference will be recorded. Subjects will then be randomised to Chronocort® or to continue on their standard care. Randomisation will be stratified by baseline treatment:

1. hydrocortisone only or

2. prednisone or prednisolone, alone or in combination with hydrocortisone

3. dexamethasone only or in combination with any other glucorticoid

The initial dose setting at the start of the Chronocort® treatment will be based on hydrocortisone dose equivalent of baseline therapy in accordance with standard clinical practice. Further dose refinement/titration will be conducted in both treatment groups as necessary after 4 weeks and 12 weeks using a standardised titration algorithm after the subject has been re-admitted for further 24-hour endocrine profiles. Safety endpoints will also be measured at the 07:00 morning sample of each 24-hour profile assessment day. The decision to change doses in both treatment groups will be made by a central independent blinded physician, with the actual change in dose then being made by the local investigator looking after the subject. At 6 months, all the baseline tests will be repeated (including the 24-hour profile). All subjects may then continue on Chronocort®, whatever their randomised treatment, as part of an open-label extension study (to be conducted under a separate protocol). Stress doses of hydrocortisone will be given throughout the study for intercurrent illnesses as medically indicated according to "sick day rules".

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Study of Efficacy, Safety and Tolerability of Chronocort® Compared With Standard Glucocorticoid Replacement Therapy in the Treatment of Congenital Adrenal Hyperplasia
• Actual Study Start Date: Feb 22, 2016
• Actual Primary Completion Date: Jul 28, 2018
• Actual Study Completion Date: Jul 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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 subjects previous glucocorticoid therapy dose and then dose titrated to effect.	Drug: 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.; Other Names: Hydrocortisone
Active Comparator: standard glucocorticoid therapy Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect.	Drug: standard glucocorticoid therapy; Subjects in this arm will continue on their standard hydrocortisone therapy; Other Names: hydrocortisone prednisone prednisolone dexamethasone

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP [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 (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).

Secondary Outcome Measures

1. Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 [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).

2. 17-OHP and A4 by Individual Baseline Treatment Strata. [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).

3. Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit [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.

4. Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) [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.

5. Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. [Baseline and 24 weeks]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood with documented (at any time) elevated 17-OHP and/or A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum of 6 months.

2. Provision of signed written informed consent.

3. Non-pregnant, non-lactating females who are post menopausal, naturally or surgically sterile, or of childbearing potential with a negative urinary pregnancy test and using a medically acceptable method of contraception.

4. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.

5. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.

Exclusion Criteria:

1. Co-morbid condition requiring daily administration of a medication (or consumption of any material) that interferes with the metabolism of glucocorticoids.

2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or elevated liver function tests (ALT or AST >2 times the ULN).

3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.

4. Subjects with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial.

5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study).

6. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study.

7. Subjects with a history of bilateral adrenalectomy.

8. Subjects having previously been exposed to Chronocort®.

9. Subjects unable to comply with the requirements of the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892-1932

Sponsors and Collaborators

• Diurnal Limited

Investigators

• Principal Investigator: Debbie Merke, MD, National Institutes of Health (NIH)

Study Documents (Full-Text)

• Study Protocol - Aug 23, 2017
• Statistical Analysis Plan - Sep 13, 2018

More Information

Publications

None provided.

• Responsible Party: Diurnal Limited
• ClinicalTrials.gov Identifier: NCT02716818
• Other Study ID Numbers: DIUR-005
• First Posted: Mar 23, 2016
• Last Update Posted: May 26, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Diurnal Limited: Glucocorticoid therapy
• Additional relevant MeSH terms: Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Adrenocortical Hyperfunction; Hyperplasia; Dexamethasone; Prednisone; Prednisolone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Glucocorticoids

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Chronocort®	Standard Glucocorticoid Therapy
Arm/Group Description	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.	Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: Hydrocortisone only Prednisone or prednisolone, alone or in combination with hydrocortisone Dexamethasone, alone or in combination with any other glucocorticoid
Period Title: Overall Study
STARTED	61	61
COMPLETED	58	59
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Chronocort®	Standard Glucocorticoid Therapy	Total
Arm/Group Description	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.	Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: Hydrocortisone only Prednisone or prednisolone, alone or in combination with hydrocortisone Dexamethasone, alone or in combination with any other glucocorticoid	Total of all reporting groups
Overall Participants	61	61	122
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	61 100%	59 96.7%	120 98.4%
>=65 years	0 0%	2 3.3%	2 1.6%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	35.2	37.5	36.3
Sex: Female, Male (Count of Participants)
Female	42 68.9%	36 59%	78 63.9%
Male	19 31.1%	25 41%	44 36.1%
Race/Ethnicity, Customized (Count of Participants)
White	60 98.4%	60 98.4%	120 98.4%
Asian	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	0 0%
Other	1 1.6%	1 1.6%	2 1.6%
Region of Enrollment (participants) [Number]
United States	4 6.6%	4 6.6%	8 6.6%
Europe	57 93.4%	57 93.4%	114 93.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP
Description	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).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Chronocort®	Standard Glucocorticoid Therapy
Arm/Group Description	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.	Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: Hydrocortisone only Prednisone or prednisolone, alone or in combination with hydrocortisone Dexamethasone, alone or in combination with any other glucocorticoid
Measure Participants	53	52
Mean (Standard Deviation) [Z-score]	-0.403 (0.8499)	-0.172 (0.7776)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Standard Glucocorticoid Therapy
	Comments	The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS profile for the natural logarithm of 17-OHP. The SDS profile was calculated as the SDS of log transformed 17-OHP concentration unsigned. 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.5521
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.069
	Confidence Interval	(2-Sided) 95%; -0.299 to 0.161
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4
Description	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).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Chronocort®	Standard Glucocorticoid Therapy
Arm/Group Description	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.	Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: Hydrocortisone only Prednisone or prednisolone, alone or in combination with hydrocortisone Dexamethasone, alone or in combination with any other glucocorticoid
Measure Participants	53	52
Mean (Standard Deviation) [Z-score]	0.113 (0.9221)	-0.041 (0.7731)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Standard Glucocorticoid Therapy
	Comments	Change from Baseline to 24 Weeks in A4 Using an ANCOVA Model - The analysis conducted for the primary endpoint variable analysis of 17-OHP was repeated for A4.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.7405
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95%; -0.234 to 0.329
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	17-OHP and A4 by Individual Baseline Treatment Strata.
Description	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).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Pre-Baseline - Hydrocortisone - 17-OHP	Pre-Baseline - Prednisone/Prednisolone - 17-OHP	Pre-Baseline - Dexamethasone - 17-OHP	Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP	Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP	Pre-Baseline - Hydrocortisone - A4	Pre-Baseline - Prednisone/Prednisolone - A4	Pre-Baseline - Dexamethasone - A4	Pre-Baseline - Chronocort vs. Hydrocortisone - A4	Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4	Pre-Baseline - Chronocort vs. Dexamethasone - A4
Arm/Group Description	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).	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).	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).	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).	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).	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).	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)	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)	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)	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)	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)	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)
Measure Participants	27	21	4	31	18	4	27	21	4	31	18	4
Mean (Standard Deviation) [Z-score]	-0.248 (0.7661)	-0.061 (0.8051)	-0.245 (0.8522)	-0.431 (0.8727)	-0.320 (0.7627)	-0.565 (1.2343)	-0.211 (0.7426)	0.100 (0.8339)	0.368 (0.3521)	0.015 (1.0128)	0.328 (0.7256)	-0.092 (1.0310)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.8186
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.037
	Confidence Interval	(2-Sided) 95%; -0.354 to 0.281
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard Glucocorticoid Therapy, Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.4655
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.135
	Confidence Interval	(2-Sided) 95%; -0.508 to 0.237
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pre-Baseline - Dexamethasone - 17-OHP, Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9081
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.065
	Confidence Interval	(2-Sided) 95%; -1.32 to 1.451
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pre-Baseline - Hydrocortisone - A4, Pre-Baseline - Chronocort vs. Hydrocortisone - A4
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.6729
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; -0.343 to 0.527
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pre-Baseline - Prednisone/Prednisolone - A4, Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.5322
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.116
	Confidence Interval	(2-Sided) 95%; -0.257 to 0.489
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pre-Baseline - Dexamethasone - A4, Pre-Baseline - Chronocort vs. Dexamethasone - A4
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.2885
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.568
	Confidence Interval	(2-Sided) 95%; -1.799 to 0.662
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit
Description	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.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Chronocort - 09:00h Response - 17-OHP	Chronocort - 09:00h Response - A4	Standard Glucocorticoid Therapy - 09:00h Response - 17-OHP	Standard Glucocorticoid Therapy - 09:00h Response - A4
Arm/Group Description	Number of participants in the Chronocort arm (from the efficacy evaluable analysis set) achieving 17-OHP levels within the optimal range expected at 09:00h at the week 24 visit.	Number of participants in the Chronocort arm (from the efficacy evaluable analysis set) achieving A4 levels within the optimal range expected at 09:00h at the week 24 visit.	Number of participants in the standard glucocorticoid arm (from the efficacy evaluable analysis set) achieving 17-OHP levels within the optimal range expected at 09:00h at the week 24 visit.	Number of participants in the standard glucocorticoid arm (from the efficacy evaluable analysis set) achieving A4 levels within the optimal range expected at 09:00h at the week 24 visit.
Measure Participants	53	53	52	52
Count of Participants [Participants]	30 49.2%	25 41%	30 24.6%	30 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Pre-Baseline - Dexamethasone - 17-OHP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.9877
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.45 to 2.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Standard Glucocorticoid Therapy, Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.8498
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.43 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass)
Description	Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

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. German subjects were excluded from this analysis subset.

Arm/Group Title	Chronocort - DEXA - Fat Mass	Standard Glucocorticoid Therapy - DEXA - Fat Mass	Chronocort - DEXA - Lean Mass	Standard Glucocorticoid Therapy - DEXA - Lean Mass
Arm/Group Description	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.
Measure Participants	43	39	43	39
Mean (Standard Deviation) [kilograms]	-0.575 (3.2744)	0.445 (2.4660)	0.640 (2.3304)	0.234 (1.3689)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Standard Glucocorticoid Therapy
	Comments	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.156
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.96
	Confidence Interval	(2-Sided) 95%; -2.294 to 0.374
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pre-Baseline - Dexamethasone - 17-OHP, Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP
	Comments	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.3392
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.425
	Confidence Interval	(2-Sided) 95%; -0.455 to 1.305
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany.
Description	Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

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. German subjects were excluded from this analysis subset.

Arm/Group Title	Chronocort - DEXA - Bone Mineral Density	Standard Glucocorticoid Therapy - DEXA - Bone Mineral Density
Arm/Group Description	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.	German subjects have been excluded from this analysis group as DEXA scans are not performed at German sites.
Measure Participants	35	36
Mean (Standard Deviation) [g/cm^2]	-0.001 (0.0250)	-0.008 (0.0399)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronocort®, Standard Glucocorticoid Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.2614
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.025
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event information was collected from the point of enrolment to completion of the study (6 months).
Adverse Event Reporting Description	Adverse event information was collected at each visit by the investigator and reported accordingly.
Arm/Group Title	Chronocort®		Standard Glucocorticoid Therapy
Arm/Group Description	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.		Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of: Hydrocortisone only Prednisone or prednisolone, alone or in combination with hydrocortisone Dexamethasone, alone or in combination with any other glucocorticoid
All Cause Mortality
	Chronocort®		Standard Glucocorticoid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		0/61 (0%)
Serious Adverse Events
	Chronocort®		Standard Glucocorticoid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/61 (11.5%)		5/61 (8.2%)
Endocrine disorders
Adrenocortical Insufficiency (acute)	0/61 (0%)	0	3/61 (4.9%)	3
Adrenal Insufficiency	1/61 (1.6%)	1	0/61 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/61 (1.6%)	1	0/61 (0%)	0
Vomiting	0/61 (0%)	0	1/61 (1.6%)	1
General disorders
Oedema Peripheral	0/61 (0%)	0	1/61 (1.6%)	2
Pyrexia	1/61 (1.6%)	1	0/61 (0%)	0
Infections and infestations
Gastroenteritis	2/61 (3.3%)	2	1/61 (1.6%)	1
Gastroenteritis Viral	0/61 (0%)	0	1/61 (1.6%)	1
Appendicitis	1/61 (1.6%)	1	0/61 (0%)	0
Salpingitis	1/61 (1.6%)	1	0/61 (0%)	0
Tonsilitis	1/61 (1.6%)	1	0/61 (0%)	0
Diverticulitis	0/61 (0%)	0	1/61 (1.6%)	1
Herpes Zoster	0/61 (0%)	0	1/61 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/61 (0%)	0	1/61 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Chronocort®		Standard Glucocorticoid Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/61 (96.7%)		48/61 (78.7%)
Blood and lymphatic system disorders
Anaemia	4/61 (6.6%)	4	3/61 (4.9%)	3
Iron Deficiency Anaemia	1/61 (1.6%)	1	0/61 (0%)	0
Cardiac disorders
Palpitations	1/61 (1.6%)	1	3/61 (4.9%)	3
Tachycardia	1/61 (1.6%)	1	0/61 (0%)	0
Sinus Tachycardia	0/61 (0%)	0	1/61 (1.6%)	1
Ear and labyrinth disorders
Ear Pain	1/61 (1.6%)	1	0/61 (0%)	0
Tinnitus	1/61 (1.6%)	1	0/61 (0%)	0
Vertigo	1/61 (1.6%)	1	0/61 (0%)	0
Ear Deformity Acquired	0/61 (0%)	0	1/61 (1.6%)	2
Tympanic Membrane Perforation	0/61 (0%)	0	1/61 (1.6%)	1
Vertigo Positional	0/61 (0%)	0	1/61 (1.6%)	1
Endocrine disorders
Mineralocorticoid Deficiency	1/61 (1.6%)	1	0/61 (0%)	0
Eye disorders
Chalazion	0/61 (0%)	0	1/61 (1.6%)	1
Vision Blurred	3/61 (4.9%)	3	1/61 (1.6%)	1
Foreign Body Sensation in Eyes	1/61 (1.6%)	1	0/61 (0%)	0
Lacrimation Increased	1/61 (1.6%)	1	0/61 (0%)	0
Gastrointestinal disorders
Abdominal Pain	2/61 (3.3%)	2	2/61 (3.3%)	3
Abdominal Pain Upper	4/61 (6.6%)	7	0/61 (0%)	0
Constipation	1/61 (1.6%)	1	0/61 (0%)	0
Dental Caries	1/61 (1.6%)	1	0/61 (0%)	0
Epigastric Discomfort	1/61 (1.6%)	2	0/61 (0%)	0
Inguinal Hernia	1/61 (1.6%)	1	0/61 (0%)	0
Nausea	8/61 (13.1%)	9	4/61 (6.6%)	5
Vomiting	4/61 (6.6%)	4	3/61 (4.9%)	4
Abdominal Pain Lower	0/61 (0%)	0	1/61 (1.6%)	1
Diverticulum Intestinal	0/61 (0%)	0	1/61 (1.6%)	1
Dyspepsia	0/61 (0%)	0	1/61 (1.6%)	1
Faeces Soft	0/61 (0%)	0	1/61 (1.6%)	1
Food Poisoning	0/61 (0%)	0	1/61 (1.6%)	1
Gastrooesophageal Reflux Disease	0/61 (0%)	0	1/61 (1.6%)	1
Diarrhoea	4/61 (6.6%)	6	3/61 (4.9%)	3
General disorders
Asthenia	4/61 (6.6%)	6	3/61 (4.9%)	3
Chest Pain	1/61 (1.6%)	1	0/61 (0%)	0
Fat Tissue Increased	1/61 (1.6%)	2	0/61 (0%)	0
Fatigue	9/61 (14.8%)	13	10/61 (16.4%)	20
Inflammation	1/61 (1.6%)	1	0/61 (0%)	0
Influenza-like Illness	2/61 (3.3%)	3	4/61 (6.6%)	4
Malaise	5/61 (8.2%)	5	2/61 (3.3%)	2
Pyrexia	9/61 (14.8%)	9	4/61 (6.6%)	4
Therapeutic Response Unexpected	10/61 (16.4%)	15	1/61 (1.6%)	1
Thirst	1/61 (1.6%)	1	0/61 (0%)	0
Oedema Peripheral	0/61 (0%)	0	1/61 (1.6%)	3
Peripheral Swelling	0/61 (0%)	0	1/61 (1.6%)	1
Sensation of Foreign Body	0/61 (0%)	0	1/61 (1.6%)	1
Infections and infestations
Acute Sinusitis	1/61 (1.6%)	1	0/61 (0%)	0
Bronchitis	1/61 (1.6%)	1	0/61 (0%)	0
Conjunctivitis viral	1/61 (1.6%)	1	0/61 (0%)	0
Cystitis	1/61 (1.6%)	1	0/61 (0%)	0
Ear infection fungal	1/61 (1.6%)	1	0/61 (0%)	0
Gastroenteritis	1/61 (1.6%)	1	4/61 (6.6%)	4
Gastroenteritis viral	1/61 (1.6%)	1	1/61 (1.6%)	1
Influenza	2/61 (3.3%)	2	1/61 (1.6%)	1
Lower Respiratory Tract Infection	1/61 (1.6%)	2	0/61 (0%)	0
Nasopharyngitis	1/61 (1.6%)	1	0/61 (0%)	0
Otitis media	1/61 (1.6%)	1	0/61 (0%)	0
Paronychia	1/61 (1.6%)	1	0/61 (0%)	0
Pharyngitis	2/61 (3.3%)	2	0/61 (0%)	0
Sinusitis	2/61 (3.3%)	2	1/61 (1.6%)	1
Tonsilitis	2/61 (3.3%)	2	0/61 (0%)	0
Upper Respiratory Tract Infection	1/61 (1.6%)	1	3/61 (4.9%)	3
Urinary Tract Infection	4/61 (6.6%)	4	2/61 (3.3%)	2
Viral Infection	1/61 (1.6%)	1	0/61 (0%)	0
Viral Upper Respiratory Tract Infection	12/61 (19.7%)	16	13/61 (21.3%)	15
Diarrhoea Infectious	0/61 (0%)	0	1/61 (1.6%)	1
Oral Candidiasis	0/61 (0%)	0	1/61 (1.6%)	1
Otitis Media Acute	0/61 (0%)	0	1/61 (1.6%)	1
Tooth Infection	0/61 (0%)	0	1/61 (1.6%)	1
Viral Rash	0/61 (0%)	0	1/61 (1.6%)	1
Salpingitis	1/61 (1.6%)	2	0/61 (0%)	0
Herpes zoster	0/61 (0%)	0	1/61 (1.6%)	1
Injury, poisoning and procedural complications
Contusion	1/61 (1.6%)	1	0/61 (0%)	0
Head Fracture	1/61 (1.6%)	1	0/61 (0%)	0
Limb Injury	1/61 (1.6%)	1	0/61 (0%)	0
Procedural Pain	1/61 (1.6%)	1	0/61 (0%)	0
Auricular Haematoma	0/61 (0%)	0	1/61 (1.6%)	1
Ear Injury	0/61 (0%)	0	1/61 (1.6%)	1
Ligament Sprain	0/61 (0%)	0	1/61 (1.6%)	1
Procedural Complication	0/61 (0%)	0	1/61 (1.6%)	1
Sunburn	0/61 (0%)	0	1/61 (1.6%)	1
Toxicity to Various Agents	0/61 (0%)	0	1/61 (1.6%)	1
Wound	0/61 (0%)	0	1/61 (1.6%)	1
Investigations
Alanine Aminotransferase Increased	1/61 (1.6%)	1	0/61 (0%)	0
Blood Sodium Decreased	1/61 (1.6%)	1	0/61 (0%)	0
Body Temperature Increased	2/61 (3.3%)	2	0/61 (0%)	0
Osteocalcin Decreased	1/61 (1.6%)	1	0/61 (0%)	0
Renin Increased	3/61 (4.9%)	3	7/61 (11.5%)	7
Urine Output Decreased	1/61 (1.6%)	1	0/61 (0%)	0
Aspartate Aminotransferase Increased	0/61 (0%)	0	1/61 (1.6%)	1
Blood Creatine Phosphokinase Increased	0/61 (0%)	0	1/61 (1.6%)	1
Blood Glucose Increased	0/61 (0%)	0	1/61 (1.6%)	1
C-Telopeptide Increased	0/61 (0%)	0	1/61 (1.6%)	1
Haematocrit Decreased	0/61 (0%)	0	1/61 (1.6%)	1
Haemoglobin Decreased	0/61 (0%)	0	1/61 (1.6%)	1
Liver Function Test Abnormal	0/61 (0%)	0	1/61 (1.6%)	1
Weight Increased	0/61 (0%)	0	1/61 (1.6%)	1
White Blood Cell Count Increased	0/61 (0%)	0	1/61 (1.6%)	1
Metabolism and nutrition disorders
Abnormal Loss of Weight	1/61 (1.6%)	1	0/61 (0%)	0
Abnormal Weight Gain	3/61 (4.9%)	3	2/61 (3.3%)	2
Decreased Appetite	2/61 (3.3%)	2	0/61 (0%)	0
Fluid Retention	1/61 (1.6%)	1	2/61 (3.3%)	2
Gluten Sensitivity	1/61 (1.6%)	1	0/61 (0%)	0
Hyperglycaemia	1/61 (1.6%)	1	0/61 (0%)	0
Hyperinsulinaemia	3/61 (4.9%)	3	1/61 (1.6%)	1
Impaired Fasting Glucose	3/61 (4.9%)	3	1/61 (1.6%)	1
Increased Appetite	5/61 (8.2%)	5	2/61 (3.3%)	2
Weight Fluctuation	1/61 (1.6%)	1	0/61 (0%)	0
Alcohol Intolerance	0/61 (0%)	0	1/61 (1.6%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/61 (3.3%)	3	2/61 (3.3%)	2
Back Pain	4/61 (6.6%)	4	3/61 (4.9%)	3
Joint Stiffness	1/61 (1.6%)	1	0/61 (0%)	0
Muscle Fatigue	1/61 (1.6%)	1	0/61 (0%)	0
Muscle Spasms	1/61 (1.6%)	1	0/61 (0%)	0
Muscle Tightness	1/61 (1.6%)	1	1/61 (1.6%)	1
Muscular Weakness	2/61 (3.3%)	2	0/61 (0%)	0
Musculoskeletal Pain	2/61 (3.3%)	2	1/61 (1.6%)	1
Myalgia	1/61 (1.6%)	1	1/61 (1.6%)	1
Neck Pain	1/61 (1.6%)	1	0/61 (0%)	0
Osteoarthritis	1/61 (1.6%)	1	0/61 (0%)	0
Pain in Extremity	1/61 (1.6%)	2	1/61 (1.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	0/61 (0%)	0	1/61 (1.6%)	1
Nervous system disorders
Carpal Tunnel Syndrome	2/61 (3.3%)	2	0/61 (0%)	0
Circardian Rhythm Sleep Disorder	1/61 (1.6%)	1	0/61 (0%)	0
Dizziness	7/61 (11.5%)	13	4/61 (6.6%)	5
Dizziness Postural	1/61 (1.6%)	1	0/61 (0%)	0
Headache	15/61 (24.6%)	19	15/61 (24.6%)	22
Memory Impairment	1/61 (1.6%)	1	0/61 (0%)	0
Migraine	1/61 (1.6%)	2	1/61 (1.6%)	1
Paraesthesia	2/61 (3.3%)	2	1/61 (1.6%)	1
Peripheral Nerve Lesion	1/61 (1.6%)	1	0/61 (0%)	0
Poor Quality Sleep	1/61 (1.6%)	1	0/61 (0%)	0
Sensory Loss	1/61 (1.6%)	1	0/61 (0%)	0
Somnolence	1/61 (1.6%)	1	1/61 (1.6%)	1
Lethargy	0/61 (0%)	0	1/61 (1.6%)	2
Psychomotor Hyperactivity	0/61 (0%)	0	1/61 (1.6%)	1
Syncope	0/61 (0%)	0	1/61 (1.6%)	1
Tension Headache	0/61 (0%)	0	2/61 (3.3%)	2
Tremor	0/61 (0%)	0	1/61 (1.6%)	1
Psychiatric disorders
Affect Lability	1/61 (1.6%)	1	0/61 (0%)	0
Anxiety	1/61 (1.6%)	2	0/61 (0%)	0
Burnout Syndrome	1/61 (1.6%)	1	0/61 (0%)	0
Depressed Mood	2/61 (3.3%)	2	1/61 (1.6%)	1
Depression	2/61 (3.3%)	3	2/61 (3.3%)	2
Insomnia	5/61 (8.2%)	6	4/61 (6.6%)	4
Irritability	1/61 (1.6%)	1	0/61 (0%)	0
Libido Decreased	1/61 (1.6%)	1	1/61 (1.6%)	1
Stress	1/61 (1.6%)	1	3/61 (4.9%)	3
Agitation	0/61 (0%)	0	2/61 (3.3%)	3
Emotional Distress	0/61 (0%)	0	1/61 (1.6%)	1
Sleep Disorder	0/61 (0%)	0	2/61 (3.3%)	2
Reproductive system and breast disorders
Menstruation Irregular	1/61 (1.6%)	1	0/61 (0%)	0
Erectile Dysfunction	0/61 (0%)	0	1/61 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/61 (1.6%)	1	0/61 (0%)	0
Cough	3/61 (4.9%)	4	0/61 (0%)	0
Oropharyngeal Pain	1/61 (1.6%)	1	1/61 (1.6%)	1
Rhinorrhoea	1/61 (1.6%)	1	1/61 (1.6%)	1
Nasal Congestion	0/61 (0%)	0	1/61 (1.6%)	1
Dyspnoea	1/61 (1.6%)	1	1/61 (1.6%)	1
Skin and subcutaneous tissue disorders
Acne	2/61 (3.3%)	2	0/61 (0%)	0
Alopecia	1/61 (1.6%)	1	0/61 (0%)	0
Cold Sweat	1/61 (1.6%)	1	0/61 (0%)	0
Eczema	1/61 (1.6%)	1	1/61 (1.6%)	1
Erythema	1/61 (1.6%)	1	0/61 (0%)	0
Hair Growth Abnormal	1/61 (1.6%)	1	0/61 (0%)	0
Hyperhidrosis	2/61 (3.3%)	2	1/61 (1.6%)	1
Psoriasis	1/61 (1.6%)	1	0/61 (0%)	0
Rash	3/61 (4.9%)	3	0/61 (0%)	0
Urticaria	1/61 (1.6%)	1	0/61 (0%)	0
Blister	0/61 (0%)	0	1/61 (1.6%)	1
Chloasma	0/61 (0%)	0	1/61 (1.6%)	1
Vascular disorders
Haematoma	1/61 (1.6%)	1	0/61 (0%)	0
Hypotension	1/61 (1.6%)	1	0/61 (0%)	0
Hypertension	0/61 (0%)	0	1/61 (1.6%)	1
Pallor	0/61 (0%)	0	1/61 (1.6%)	1

Limitations/Caveats

A limitation of the pre-defined primary endpoint was that it included an unsigned SDS score over a 24-hour period.

More Information

Certain Agreements

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

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."