Clinical Trial Results:
A Randomized, Double-Blind, Active-Controlled, Phase 3 Study of Chronocort Compared With Immediate-Release Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia
Summary
|
|
EudraCT number |
2021-003668-29 |
Trial protocol |
FR |
Global end of trial date |
02 Feb 2024
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
17 Aug 2024
|
First version publication date |
17 Aug 2024
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
DIUR-014
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT05063994 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
Diurnal Limited
|
||
Sponsor organisation address |
Cardiff Medicentre, Heath Park, Cardiff, United Kingdom, CF14 4UJ
|
||
Public contact |
Clinical Trials Information, Diurnal Limited, +44 0 292 068 2069, info@diurnal.co.uk
|
||
Scientific contact |
Clinical Trials Information, Diurnal Limited, +44 0 292 068 2069, info@diurnal.co.uk
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
25 Apr 2024
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
02 Feb 2024
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
02 Feb 2024
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
This study is a randomized, double-blind, active-controlled, phase III study of Chronocort® compared with immediate-release hydrocortisone replacement therapy in participants aged 16 years and over with Congenital Adrenal Hyperplasia.
|
||
Protection of trial subjects |
The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, in accordance with ICH GCP requirements, and in accordance with the United States of America (USA) Code of Federal Regulations on Protection of Human Rights (21 CFR 50) (for USA sites only).
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 May 2022
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
France: 21
|
||
Country: Number of subjects enrolled |
Japan: 9
|
||
Country: Number of subjects enrolled |
United States: 23
|
||
Worldwide total number of subjects |
53
|
||
EEA total number of subjects |
21
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
7
|
||
Adults (18-64 years) |
46
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
|||||||||||||||||||||||||
Recruitment
|
|||||||||||||||||||||||||
Recruitment details |
- | ||||||||||||||||||||||||
Pre-assignment
|
|||||||||||||||||||||||||
Screening details |
Participants received IRHC (Cortef) during the run-in therapy for 4 weeks prior to randomization. Once eligibility for the study was confirmed at the Baseline visit, participants were randomized on a 1:1 basis (Chronocort:Cortef). 55 participants entered the run-in period and 53 were randomized to treatment. | ||||||||||||||||||||||||
Pre-assignment period milestones
|
|||||||||||||||||||||||||
Number of subjects started |
55 [1] | ||||||||||||||||||||||||
Number of subjects completed |
53 | ||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
|
|||||||||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 1 | ||||||||||||||||||||||||
Reason: Number of subjects |
Did not meet the inclusion/exclusion criteria: 1 | ||||||||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Two participants discontinued prior to randomization. |
|||||||||||||||||||||||||
Period 1
|
|||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||
Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||
Arms
|
|||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||
Arm title
|
Chronocort | ||||||||||||||||||||||||
Arm description |
Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Chronocort
|
||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||
Other name |
Hydrocortisone modified-release
|
||||||||||||||||||||||||
Pharmaceutical forms |
Modified-release capsule, hard
|
||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||
Dosage and administration details |
Participants received dosage and administration as specified in the arm description.
|
||||||||||||||||||||||||
Arm title
|
Cortef | ||||||||||||||||||||||||
Arm description |
Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Cortef
|
||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||
Other name |
Immediate-release hydrocortisone, IRHC
|
||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||
Dosage and administration details |
Participants received dosage and administration as specified in the arm description.
|
||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Chronocort
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cortef
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Chronocort
|
||
Reporting group description |
Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | ||
Reporting group title |
Cortef
|
||
Reporting group description |
Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. |
|
|||||||||||||
End point title |
Percentage of participants who were biochemical responders at Week 28 | ||||||||||||
End point description |
Biochemical response was defined as a participant who a) was in biochemical control at the 08:00 assessment and b) was receiving a total daily dose of hydrocortisone of not more than 25 mg if the participant was in biochemical control at baseline or not more than 30 mg if the participant was not in biochemical control at baseline. Biochemical control was defined as both a 17-OHP concentration equal to or below the upper limit for optimal control (1200 ng/dL [36.4 nmol/L]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL [5.2 nmol/L] for men and 200 ng/dL [7.0 nmol/L] for women).
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Week 28
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of Biochemical Responders | ||||||||||||
Comparison groups |
Chronocort v Cortef
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.0003 [2] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
25.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.5 | ||||||||||||
upper limit |
48.9 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
11.82
|
||||||||||||
Notes [1] - Non-inferiority of Chronocort to Cortef was declared if the 95% CI for the difference in biochemical response rates between the 2 treatment arms (Chronocort minus Cortef) was wholly above minus 15 percentage points. [2] - One-sided non-inferiority. The Ge et al (2011) method was used to calculate the estimate, standard error, confidence interval and P-value for the treatment difference from the results of a logistic regression analysis. |
|
|||||||||||||
End point title |
Percentage of participants who were dose responders at Week 28 | ||||||||||||
End point description |
Dose response was defined as a participant who a) was receiving a total daily dose of hydrocortisone of not more than 25 mg and b) was in biochemical control at the 08:00 assessment.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 28
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of Dose Responders | ||||||||||||
Comparison groups |
Chronocort v Cortef
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.012 [4] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
25.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
3.3 | ||||||||||||
upper limit |
47.3 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
11.24
|
||||||||||||
Notes [3] - Superiority of Chronocort to Cortef with respect to the dose response after 28 weeks of randomized treatment was declared if the two-sided 95% CI for the difference in response rates between the 2 treatment arms (Chronocort minus Cortef) was wholly above zero, provided that non-inferiority of Chronocort to Cortef with respect to the biochemical response had been declared under the primary efficacy objective. [4] - One-sided superiority. The Ge et al (2011) method was used to calculate the estimate, standard error, confidence interval and P-value for the treatment difference from the results of a logistic regression analysis. |
|
|||||||||||||
End point title |
Total daily dose of hydrocortisone at Week 28 | ||||||||||||
End point description |
Least squares (LS) mean was assessed using mixed model repeated measures (MMRM).
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 28
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of Total Daily Dose of Hydrocortisone | ||||||||||||
Comparison groups |
Chronocort v Cortef
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.0005 [6] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-5.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.2 | ||||||||||||
upper limit |
-2.5 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.66
|
||||||||||||
Notes [5] - Superiority of Chronocort to Cortef was declared if the two-sided 95% CI for difference in means between the 2 treatment arms (Chronocort minus Cortef) was wholly below zero, provided that non-inferiority of Chronocort to Cortef in terms of biochemical response had been declared under the primary efficacy objective, and superiority of Chronocort to Cortef in terms of dose response has been declared. [6] - One sided-superiority. |
|
|||||||||||||||||||
End point title |
Percentage of participants in biochemical control | ||||||||||||||||||
End point description |
Biochemical control was defined as both a 17-OHP concentration (assessed at 08:00) equal to or below the upper limit for optimal control (1200 ng/dL [36.4 nmol/L]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL [5.2 nmol/L] for men and 200 ng/dL [7.0 nmol/L] for women).
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline and Week 28
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [7] - Baseline: n=27 Week 28: n=25 |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in mean of 08:00 and 13:00 17-OHP levels at Week 28 | ||||||||||||
End point description |
LS mean was assessed using analysis of covariance (ANCOVA).
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in mean of 08:00 and 13:00 A4 levels at Week 28 | ||||||||||||
End point description |
LS mean was assessed using ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Percentage of participants with menstrual regularity (females of childbearing potential only) | ||||||||||||||||||||||||
End point description |
Data are presented for the number of participants with more than monthly menstrual cycles, monthly menstrual cycles, and number of participants with oligomenorrhoea and amenorrhoea. Oligomenorrhoea was defined as fewer than 9 menstrual cycles per year or cycle length >35 days and amenorrhoea as absent menses for ≥ 3 months.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants of childbearing potential with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Week 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in luteinizing hormone levels (males only) at Week 28 | ||||||||||||
End point description |
LS mean was assessed using ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only male participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percent Change From Baseline in size of testicular adrenal rest tumors (males Only) at Week 28 | ||||||||||||
End point description |
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only male participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in hirsutism at Week 28 using the Ferriman-Gallwey score (females only) at Week 28 | ||||||||||||
End point description |
Ferriman-Gallwey score is a method used to assess and quantify hirsutism in women. A total score < 8 is considered normal whereas a score of 8 to 15 indicates mild hirsutism. A score >15 indicates moderate or severe hirsutism. The Ferriman-Gallwey score ranged from 0 to 36. Higher score indicated more hirsutism. Change from baseline is reported (negative change from baseline indicated improvement).
LS mean was assessed using ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in acne using the Global Evaluation Acne (GEA) scale (females only) at Week 28 | ||||||||||||
End point description |
Acne severity was assessed according to GEA scale, which ranged from 0 (Clear. No lesions) to 5 (Very severe). Higher score indicated higher severity of acne. Change from baseline is reported (negative change from baseline indicated improvement).
LS mean was assessed using ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in glycated hemoglobin (HbA1c) percent levels at Week 28 | ||||||||||||
End point description |
LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in waist circumference at Week 28 | ||||||||||||
End point description |
LS mean was assessed using ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in body weight at Week 28 | ||||||||||||
End point description |
LS mean was assessed by ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Change from baseline quality of life using the self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36) total score for the physical and mental components and the sub-domain of vitality at Week 28 | |||||||||||||||||||||
End point description |
SF-36 evaluates aspects of functional health and well-being. Physical component has 4 sub-scales: physical function, role limitations due to physical problems, pain, and general health perception; and mental component has 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Total scores for the physical and mental component are presented as well as the sub-scale score for vitality. Scores were summarized and transformed into a range from 0 to 100; 0=worst, and 100=best outcome. Higher scores indicated better outcome. Change from baseline is reported (positive change from baseline indicated improvement.
LS mean was assessed by ANCOVA.
Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation.
FAS: All participants with CAH who were randomized into the study and received at least 1 dose of study drug. Participants with evaluable data were analyzed.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 28
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 30 days after last study dose (maximum treatment duration of approximately 53 weeks; median exposure = 255.0 days for Chronocort and 230.5 days for Cortef)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Cortef and Chronocort reporting groups were assessed using the safety analysis set that included all participants who were randomized and received at least 1 dose of study drug in the treatment period.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cortef
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Chronocort
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received Chronocort at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
04 May 2021 |
• Amended blinding procedure to avoid inadvertent unblinding
• Allowed access to commercial Chronocort, depending on the territory |
||
27 Jan 2022 |
• Added additional exclusion criteria
• Changed maximum blood volume to be drawn during the study
• Clarified concomitant therapy
• Added section for interactions with other medicinal product
• Expended on Dose Modification reasons
• Added section for COVID-19 Procedures
• New section added on remote monitoring visits |
||
04 Mar 2022 |
• Revised schedule of assessment
• Clarified exclusion criteria
• Clarified rescue medication
• Clarified participant discontinuation
• Clarified dosing schedule
• Amended serious adverse event reporting procedure
• Clarified fasting requirements
• Revised Clinical Laboratory Tests |
||
23 Mar 2022 |
• Correction made to schedule of assessments
• Clarified study assessments and procedures
• Clarified adverse event definition |
||
09 Feb 2023 |
• Duration of the fixed-dose period has been reduced from 36 weeks to 12 weeks and the number of patients reduced from approximately 150 to approximately 50 (or an enrolment cut-off date of 30 April 2023, whichever is reached first) |
||
30 Oct 2023 |
• Revised non-inferiority margin
• Clarified when last dose of study medication will be taken
• Clarified EOS visit sample analysis
• Clarified procedure for recording of physical examination findings |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |