Clinical trial NCT05063994
Conditions: Congenital Adrenal Hyperplasia
Sponsor: Neurocrine UK Limited
Start date: 2022-05-24; Completion date: 2024-02-02
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
The study will compare the efficacy, safety and tolerability of twice daily Chronocort with twice daily immediate release hydrocortisone replacement therapy (IRHC) (Cortef®) in participants aged 16 years and over with known classic Congenital Adrenal Hyperplasia (CAH) due to 21 hydroxylase deficiency.

Arms: arm 1: 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 2: 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.
Interventions: intervention 1: Chronocort intervention 2: Cortef intervention 3: Placebo
Intervention descriptions: intervention 1: Over-encapsulated hydrocortisone modified-release capsule for oral administration. intervention 2: Over-encapsulated hydrocortisone immediate-release tablet for oral administration. intervention 3: Matching placebo

Protocol documents:
Prot_000.pdf: 
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Title Page 
Protocol Title: 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 
Study Name: CONnECT 
Protocol Number: DIUR-014 
Compound: Chronocort® 
Study Phase: 3  
Short Title: Double-blind comparison of Chronocort versus standard hydrocortisone 
replacement therapy in participants aged 16 years and over with congenital adrenal 
hyperplasia 
Sponsor Name: Diurnal Ltd 
Legal Registered Address: 
Cardiff Medicentre 
Heath Park 
Cardiff, CF14 4UJ 
United Kingdom  
Regulatory Agency Identifier Numbers: IND number: 76485 
         EudraCT number: 2021-003668-29 
Approval Date: Version 7.0 – 30 October 2023 
This protocol is based on the TransCelerate protocol template: 
https://www.transceleratebiopharmainc.com/assets/clinical-content-reuse-solutions/ 
NCT #: NCT05063994


 
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Sponsor Signatory: 
 
  
 
 
 
Date 
 
The Investigator agreement pages are provided as stand-alone documents. 
 
The medical monitor’s name and contact information will be provided separately. 
 
 
03-Nov-2023 | 10:27 GMT


 
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Protocol Amendment Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
30-Oct-2023 
Amendment 5 
09-Feb-2023 
Amendment 4 
23-Mar-2022 
Amendment 3 
04-Mar-2022 
Amendment 2 
27-Jan-2022 
Amendment 1 
04-May-2021 
Original Protocol 
16-Apr-2021 
Amendment 6 (30-Oct-2023) 
Overall Rationale for the Amendment: 
After finalization of amendment 5, it was noted that in some places the non-inferiority margin 
still stated 10% instead of the updated 15%, so this was corrected. In addition, a few small 
clarifications were made to reflect the study procedures. All the changes are marked in the 
tracked changes version of the protocol, with the key changes summarized below: 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents 
Protocol Amendment Summary of Changes .......................................................................... 3 
1. 
Protocol Summary ..................................................................................................... 8 
1.1. 
Synopsis ....................................................................................................................... 8 
1.2. 
Schema ....................................................................................................................... 19 
1.3. 
Schedule of Activities ................................................................................................ 20 
2. 
Introduction .............................................................................................................. 23 
2.1. 
Study Rationale .......................................................................................................... 23 
2.2. 
Background ................................................................................................................ 24 
2.3. 
Benefit/Risk Assessment ........................................................................................... 26 
3. 
Objectives, Outcome Variables, and Analyses ...................................................... 28 
4. 
Study Design ............................................................................................................. 34 
4.1. 
Overall Design ........................................................................................................... 34 
4.2. 
Titration Rules ........................................................................................................... 36 
4.3. 
Stress Dosing Rules ................................................................................................... 37 
4.4. 
Scientific Rationale for Study Design ....................................................................... 37 
4.5. 
Justification for Dose ................................................................................................. 42 
4.6. 
End of Study Definition ............................................................................................. 43 
5. 
Study Population ...................................................................................................... 44 
5.1. 
Inclusion Criteria ....................................................................................................... 44 
5.2. 
Exclusion Criteria ...................................................................................................... 45 
5.3. 
Lifestyle Considerations ............................................................................................ 46 
5.4. 
Screen Failures ........................................................................................................... 46 
6. 
Study Treatment ...................................................................................................... 47 
6.1. 
Study Treatments Administered ................................................................................ 47 
6.1.1. 
Rescue Medication ..................................................................................................... 48 
6.2. 
Preparation/Handling/Storage/Accountability ........................................................... 49 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ....................................... 49 
6.4. 
Study Treatment Compliance .................................................................................... 51 
6.5. 
Concomitant Therapy ................................................................................................ 51 
6.5.1. 
Interactions With Other Medicinal Products and Other Forms of Interaction........... 52 
6.6. 
Dose Modification ..................................................................................................... 52 
6.7. 
Treatment after the End of the Study ......................................................................... 53 
7. 
Discontinuation of Study Treatment and Participant Discontinuation/ 
Withdrawal ............................................................................................................... 54 
7.1. 
Discontinuation of Study Treatment .......................................................................... 54 
7.2. 
Participant Discontinuation/Withdrawal from the Study ........................................... 54 
7.3. 
Lost to Follow-up....................................................................................................... 55 
8. 
Study Assessments and Procedures........................................................................ 56 
8.1. 
Study Visits ................................................................................................................ 57 
8.1.1. 
Visit 1 (Screening Visit - Week -4) ........................................................................... 57 
8.1.2. 
Visit 2 (Baseline Visit - Day 1: 4 Weeks After the Screening Visit) ........................ 58 
8.1.3. 
Visit 3 (Titration Visit - Week 4 + 1 Week) .............................................................. 60 
8.1.4. 
Telephone Call T3.1 (Visit 3 + 2 to 5 Weeks) ........................................................... 61 


 
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8.1.5. 
Visit 4 (Titration Visit - Week 10 ± 1 Week) ............................................................ 61 
8.1.6. 
Telephone Call T4.1 (Visit 4 + 2 to 5 Weeks) ........................................................... 63 
8.1.7. 
Visit 5 (Titration Visit - Week 16 ± 1 Week) ............................................................ 63 
8.1.8. 
Telephone Call T5.1 (Visit 5 + 2 to 5 Weeks) ........................................................... 65 
8.1.9. 
Telephone Call T5.2 (Week 22 ± 2 Weeks) .............................................................. 65 
8.1.10. Visit 6 (End of Study/Early Withdrawal Visit - 28 Weeks + 1 Week From 
Randomization or at Point of Discontinuing Treatment or Withdrawing From the 
Study) ......................................................................................................................... 65 
8.1.11. Telephone Call T6.1 (Visit 6 + 30 Days ± 1 Week) .................................................. 67 
8.1.12. Unscheduled Visits or Telephone Calls ..................................................................... 67 
8.1.13. COVID-19 Procedures ............................................................................................... 67 
8.2. 
Efficacy Assessments ................................................................................................ 67 
8.2.1. 
Efficacy Blood Samples ............................................................................................. 67 
8.2.2. 
Adrenal Insufficiency Checklist ................................................................................ 68 
8.2.3. 
Saliva Samples ........................................................................................................... 68 
8.2.4. 
Body Weight .............................................................................................................. 68 
8.2.5. 
Waist Circumference ................................................................................................. 68 
8.2.6. 
Fertility ....................................................................................................................... 69 
8.2.7. 
Quality of Life Questionnaires................................................................................... 69 
8.2.8. 
Hirsutism .................................................................................................................... 70 
8.2.9. 
Acne ........................................................................................................................... 70 
8.2.10. Alertness .................................................................................................................... 70 
8.2.11. Preference for Treatment ........................................................................................... 71 
8.3. 
Safety Assessments .................................................................................................... 71 
8.3.1. 
Physical Examinations ............................................................................................... 71 
8.3.2. 
Vital Signs .................................................................................................................. 72 
8.3.3. 
Electrocardiograms .................................................................................................... 72 
8.3.4. 
Clinical Safety Laboratory Assessments ................................................................... 72 
8.3.5. 
Stress Dosing Rules ................................................................................................... 73 
8.4. 
Adverse Events and Serious Adverse Events ............................................................ 73 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information ...................... 73 
8.4.2. 
Method of Detecting AEs and SAEs ......................................................................... 74 
8.4.3. 
Follow-up of AEs and SAEs ...................................................................................... 74 
8.4.4. 
Regulatory Reporting Requirements for SAEs .......................................................... 74 
8.4.5. 
Pregnancy ................................................................................................................... 74 
8.4.6. 
Cardiovascular and Death Events .............................................................................. 75 
8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs .......................................................................................................................... 75 
8.4.8. 
Adverse Events of Special Interest ............................................................................ 75 
8.5. 
Treatment of Overdose .............................................................................................. 76 
8.6. 
Pharmacokinetics ....................................................................................................... 76 
8.7. 
Pharmacodynamics .................................................................................................... 76 
8.8. 
Genetics ..................................................................................................................... 76 
8.9. 
Biomarkers ................................................................................................................. 77 
8.10. 
Immunogenicity Assessments.................................................................................... 77 
8.11. 
Health Economics ...................................................................................................... 77 
9. 
Statistical Considerations ........................................................................................ 78 


 
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9.1. 
Statistical Hypotheses ................................................................................................ 78 
9.1.1. 
Primary Analysis ........................................................................................................ 78 
9.1.2. 
First Key Secondary Analysis .................................................................................... 78 
9.1.3. 
Second Key Secondary Analysis ............................................................................... 79 
9.2. 
Sample Size Determination ....................................................................................... 79 
9.3. 
Populations for Analyses ........................................................................................... 80 
9.4. 
Statistical Analyses .................................................................................................... 80 
9.4.1. 
General Considerations .............................................................................................. 80 
9.4.2. 
Efficacy Analyses ...................................................................................................... 80 
9.5. 
Interim Analyses ........................................................................................................ 87 
9.6. 
Data Safety Management Board ................................................................................ 87 
10. 
Supporting Documentation and Operational Considerations ............................. 88 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................................... 88 
Appendix 2: Clinical Laboratory Tests ..................................................................................... 93 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ................................................................................................. 94 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information .................... 99 
Appendix 5: Adrenal Insufficiency Checklist......................................................................... 103 
Appendix 6: Stress Dosing Rules ........................................................................................... 104 
Appendix 7: Abbreviations ..................................................................................................... 106 
Appendix 8: Protocol Amendment History ............................................................................ 108 
11. 
References ............................................................................................................... 118 
 


 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: 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 
Study Name: CONnECT 
Short Title: Double-blind comparison of Chronocort versus standard hydrocortisone 
replacement therapy in participants aged 16 years and over with congenital adrenal 
hyperplasia 
Rationale: Congenital adrenal hyperplasia (CAH) is most commonly caused by 
21-hydroxylase deficiency that results in cortisol deficiency and androgen excess, with or 
without aldosterone deficiency. Patients are currently treated with glucocorticoid replacement 
therapy, but immediate-release formulations fail to replicate the natural cortisol circadian 
rhythm, and patients often struggle to take an afternoon dose, resulting in patients being 
poorly controlled. Chronocort is a newly developed modified release oral formulation of 
hydrocortisone, and it is designed to closely replicate the normal serum levels of the 
endogenous cortisol circadian rhythm, offering the prospect of an improved treatment 
outcome and a novel treatment paradigm. The proposed study will evaluate whether a twice 
daily dosing regimen of Chronocort, with two-thirds of the total daily dose given at night and 
one-third in the morning (the ‘toothbrush regimen’), which can more closely replicate 
circadian cortisol levels, will improve control of adrenal androgen production (as measured 
by 17-hydroxyprogesterone [17-OHP] and androstenedione [A4] concentrations) compared to 
a similarly titrated regimen of twice daily immediate-release hydrocortisone replacement 
therapy (IRHC) in conditions broadly resembling routine clinical practice. 
Objectives, Outcome Variables, and Analyses 
 
Objectives 
Outcome Variable and  
Analyses Supporting the Objectives 
Primary Efficacy 
 
• To compare Chronocort to IRHC in 
terms of biochemical responder rate 
after 28 weeks of randomized treatment. 
 
 
• The primary efficacy outcome variable is whether 
or not the participant is a biochemical responder 
after 28 weeks of randomized treatment.  
A biochemical responder is a participant who: 
i) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 
upper limit of the reference range), and 
ii) is receiving after 28 weeks of randomized 
treatment a total daily dose of hydrocortisone 
of not more than 25 mg (if the participant was 


 
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in biochemical control at baseline) or not more 
than 30 mg (if the participant was not in 
biochemical control at baseline). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are biochemical responders 
28 weeks after randomization will be estimated in 
the full analysis set (FAS). Participants who die or 
withdraw from treatment before 28 weeks will be 
classified as not a biochemical responder. 
Participants receiving rescue medication under the 
‘stress dosing rules’ within 5 days before the 
scheduled visit at 28 weeks after randomization 
will have their visit delayed appropriately1. 
Biochemical non-inferiority of Chronocort to 
IRHC will be declared if the 95% confidence 
interval (CI) for the difference in proportions lies 
wholly above minus 15 percentage points.   
Key Secondary Efficacy 
 
• 1) To compare Chronocort to IRHC in 
terms of dose responder rate after 
28 weeks of randomized treatment. 
 
 
• The first key secondary efficacy outcome variable 
is whether or not the participant is a dose 
responder after 28 weeks of randomized 
treatment.  
A dose responder is a participant who: 
i) is receiving after 28 weeks of randomized 
treatment a total daily dose of hydrocortisone 
of not more than 25 mg, and 
ii) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 
upper limit of the reference range). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are dose responders 28 weeks 
after randomization will be estimated in the FAS. 
Participants who die or withdraw from treatment 
before 28 weeks will be classified as not a dose 
responder. Participants receiving rescue 
medication under the ‘stress dosing rules’ within 
5 days before the scheduled visit at 28 weeks after 
randomization will have their visit delayed 
appropriately1. 
Dose superiority of Chronocort to IRHC will be 
declared if the 95% CI for the difference in 
proportions lies wholly above zero, provided that 
biochemical non-inferiority of Chronocort to 
IRHC has been declared under the primary 
efficacy objective. 


 
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• 2) To compare Chronocort to IRHC in 
terms of total daily dose after 28 weeks 
of randomized treatment. 
• The second key secondary efficacy outcome 
variable is the total daily dose (mg) after 
28 weeks of randomized treatment.  
The difference (Chronocort minus IRHC) 
between the mean total daily dose after 28 weeks 
of randomized treatment in each treatment arm 
will be estimated in the FAS. Superiority of 
Chronocort to IRHC with respect to total daily 
dose after 28 weeks of randomized treatment will 
be declared if the 95% CI for the difference in 
means lies wholly below zero, provided that dose 
superiority of Chronocort to IRHC has been 
declared under the first key secondary efficacy 
objective. 
Other Secondary Efficacy 
 
• To compare Chronocort to IRHC in 
terms of biochemical responders at 4, 
10, and 16 weeks after randomization. 
 
• The outcome variables whether or not the 
participant is a biochemical responder at 08:00 
hours at 4, 10, and 16 after randomization are 
compared between treatment arms by calculating 
the difference in proportion of participants 
responding. These outcome variables are to be 
analyzed in the same manner as the primary 
efficacy outcome variable. 
• To compare Chronocort to IRHC in 
terms of dose responders at 10 and 16 
weeks after randomization. 
• The outcome variables whether or not the 
participant is a dose responder at 08:00 hours at 
10 and 16 weeks after randomization are 
compared between treatment arms by calculating 
the difference in proportion of participants 
responding. These outcome variables are to be 
analyzed in the same manner as the first key 
secondary outcome variable. 
• To compare Chronocort to IRHC in 
terms of total daily dose at 10 and 16 
weeks after randomization. 
 
 
• The outcome variables total daily dose at 10 and 
16 weeks after randomization are compared 
between treatment arms by calculating the 
difference in mean total daily dose. These 
outcome variables are to be analyzed in the same 
manner as the second key secondary outcome 
variable. 
• To compare Chronocort to IRHC in 
terms of biochemical control at 4, 10, 
16, and 28 weeks after randomization. 
 
 
• The outcome variables whether or not the 
participant is in biochemical control (provided 
total daily dose is not more than 30 mg) at 08:00 
hours at 4, 10, 16, and 28 weeks after 
randomization are compared between treatment 
arms by calculating the difference in proportion 
of participants in control. 


 
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• To compare Chronocort to IRHC in 
terms of the impact on 17-OHP range. 
• The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of 17-OHP levels at 4, 10, 16, and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on A4 range. 
• The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of A4 levels at 4, 10, 16, and 28 
weeks after randomization and their changes from 
baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on mean 17-OHP 
and A4. 
• The mean of the 08:00 and 13:00 measurements 
of 17-OHP levels and A4 levels at 4, 10, 16, and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on glucocorticoid 
dose. 
• The total daily glucocorticoid dose at 4, 10, 16, 
and 28 weeks after randomization will be 
summarized and compared between treatment 
arms. 
• The relationship between daily glucocorticoid 
dose and biochemical control at 28 weeks after 
randomization will be explored. 
• To compare Chronocort to IRHC in 
terms of changes in menstrual 
regularity. 
 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in menstrual 
regularity (only in pre-menopausal women 
without hysterectomy and not using hormonal 
contraception) will be summarized and compared 
between treatment arms.  
• To compare Chronocort to IRHC in 
terms of the impact on luteinizing 
hormone (LH) levels. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in LH levels (men 
only) will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on testicular adrenal 
rest tumor (TART) size. 
• The change from baseline to 28 weeks of 
randomized treatment in size of TART (men 
only) will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on sperm count. 
• The change from baseline to 28 weeks of 
randomized treatment in sperm count (men only) 
will be summarized and compared between 
treatment arms. 
• 
To compare Chronocort to IRHC in 
terms of the impact on subjective 
hirsutism in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in subjective 
hirsutism using a visual analog scale (VAS) 
(women only) will be summarized and compared 
between treatment arms. 


 
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• To compare Chronocort to IRHC in 
terms of the impact on objective 
hirsutism in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective 
hirsutism using the Ferriman-Gallwey score 
(women only) will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on subjective acne 
in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in subjective acne 
using a VAS (women only) will be summarized 
and compared between treatment arms. 
• 
To compare Chronocort to IRHC in 
terms of the impact on objective acne in 
female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective acne 
using the Global Evaluation Acne (GEA) scale 
(women only) will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on glycated 
hemoglobin (HbA1c) levels. 
• The change from screening to 4, 10, 16, and 28 
weeks of randomized treatment in HbA1c levels 
will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on waist 
circumference. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in waist 
circumference will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on body weight. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in body weight 
will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on quality of life 
(QoL) using the self-completed Medical 
Outcome Study 36-Item Short Form 
Health Survey (SF-36®) total score and 
the sub-domain of vitality. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
self-completed SF-36® total score and the 
sub-domain of vitality will be summarized and 
compared between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on QoL using the 
Multidimensional Assessment of 
Fatigue (MAF). 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
MAF will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on QoL using the 
5-level Standardized Health 
Questionnaire (EQ-5D-5L™). 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
EQ-5D-5L™ will be summarized and compared 
between treatment arms. 
Compliance 
 
• To assess compliance over the study 
period. 
• The percentage treatment compliance between 
visits and overall will be summarized. 
Exploratory Efficacy 
  
• 
 
 
  
 
 
 
 
 
 
 
 


 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
• To assess the safety and tolerability of 
Chronocort relative to IRHC. 
• The incidence, nature, severity, relatedness, 
duration, outcome, seriousness and expectedness 
of treatment-emergent adverse events (TEAEs) 
will be tabulated by treatment arm. Adverse 
events (AEs) of special interest will additionally 
be tabulated separately, with particular note of 
adrenal crises. 
• To assess the need for use of additional 
glucocorticoid doses (stress dosing 
rules). 
• The use of medication from the stress dosing 
packs or use of any additional glucocorticoid 
treatment during the study will be tabulated by 
treatment arm. 
• To evaluate the safety of Chronocort 
compared to IRHC by assessment of 
routine safety laboratory assessments, 
physical examination, vital signs, and 
electrocardiogram (ECG). 
• Safety hematology, biochemistry, urinalysis, and 
vital signs conducted at each post-randomization 
visit and the physical examination and ECG 
assessments conducted after 28 weeks of 
randomized treatment, and their changes from 
baseline, will be summarized by treatment arm. 
1 This description aligns with the International Council for Harmonization (ICH) E9 requirement for the 
definition of an Estimand.  
Outcome variables are underlined. 
Note: The reference range for A4 is up to 150 ng/dL (5.2 nmol/L) for men and up to 200 ng/dL (7.0 nmol/L) for 
women (based on the luteal phase) (based on data from The Mayo Clinic). 
The optimal range for 17-OHP in adults (post-pubertal males or females aged >16 years) is up to 1200 ng/dL 
(36.4 nmol/L). 
Overall Design: This study is a randomized, double-blind, active-controlled, titrated, parallel 
arm, multicenter study. It will compare the efficacy, safety and tolerability of twice daily 
Chronocort with twice daily IRHC (Cortef®) over a randomized treatment period of up to 
28 weeks in participants aged 16 years and over with known classic CAH due to 
21-hydroxylase deficiency. The primary efficacy assessment of biochemical responder rate 
and the key secondary assessments of dose responder rate and mean total daily dose will be 
assessed after 28 weeks of randomized treatment.  
Participants will attend a screening visit 4 weeks prior to the baseline visit. Participants will 
be asked to take their usual medication at the usual times up until the screening visit, with 
details of the dosing regimen and the timing of doses of CAH medication recorded 
throughout the screening visit and for the previous 24 hours. At this screening visit, informed 
consent/assent will be obtained and then the screening assessments will be conducted. 
Participants will then be switched to 20 mg IRHC in the morning on waking (typically 
between 06:00 and 08:00 hours) and 10 mg in the afternoon (between 15:00 and 17:00 hours) 
for the next 4 weeks as run-in therapy. This total daily dose is based on the guidelines for 
adrenal replacement, where the recommended dose is between 15 and 25 mg, plus an 


 
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acknowledgement that patients with CAH may need a higher dose [Speiser et al. 2018]. This 
total daily dose was safely used in the Chronocort Phase 2 and 3 studies and equates to the 
dose used in large cohort studies [Arlt et al, 2010; Finkielstain et al, 2012]. 
After 4 weeks on this run-in therapy, participants will attend a baseline visit for all the 
baseline assessments. If at the end of the 4-week run-in period there are persistent signs of 
adrenal insufficiency, or the participant does not tolerate treatment, then they should be 
withdrawn from the study before randomization. Assessment of baseline androgen levels 
(17-OHP and A4) will be made at 08:00 hours before the morning dose of IRHC and at 
13:00 hours, with a window of ±30 minutes allowed around each sampling timepoint. These 
baseline adrenal androgens will be analyzed by the central laboratory and participants with 
17-OHP equal to or below the upper limit for optimal control at 08:00 hours and A4 equal to 
or below the upper limit of the reference range at 08:00 hours will be subsequently classified 
as ‘in biochemical control’ during the analysis. If the measurements are outside these criteria 
the participant will be classified as ‘not in biochemical control’ during the analysis. Once 
eligibility for the study is confirmed, the Investigator will then randomize the participants on 
a 1:1 basis (Chronocort:IRHC) using an interactive response technology (IRT) system, with 
randomization being stratified within each treatment arm based on fludrocortisone 
replacement status (requires fludrocortisone or does not require fludrocortisone). Note: the 
results of the baseline androgen tests are NOT needed prior to the participant being 
randomized to the study. The IRT will also be programmed with blind-breaking instructions. 
Participants randomized to Chronocort will change to a dosing regimen of 10 mg in the 
morning on waking (typically between 06:00 and 08:00 hours) and 20 mg at night just prior 
to going to bed (typically between 22:00 hours and midnight). Participants randomized to 
IRHC will continue the same dosing regimen as they were receiving during the run-in period 
(20 mg in the morning on waking [typically between 06:00 and 08:00 hours] and 10 mg in 
the afternoon [between 15:00 and 17:00 hours]). To ensure blinding of the study, both study 
treatments will be over-encapsulated and placebo capsules will also be used, so participants 
will take a combination of capsules (active and placebo) in the morning on waking, in the 
afternoon, and in the evening before going to bed (i.e., three times daily). The time of the first 
dose of randomized medication on Day 1 will be recorded in an electronic participant diary.  
Participants will return to the study site for titration visits at 4, 10, and 16 weeks after 
randomization, with androgen levels assessed at each of these visits at 08:00 hours (before 
the morning dose of study medication) and 13:00 hours (±30 minutes). After each of these 
3 visits, dose reductions (in 5 mg steps at each visit) can be conducted if required, based on 
androgen results (17-OHP <300 ng/dL and A4 <150 ng/dL [males] and <200 ng/dL 
[females]) and adrenal insufficiency symptoms collected using the adrenal insufficiency 
checklist. The decision to change doses in both treatment groups will be made by an 
independent blinded physician and the appropriate investigational medicinal product (IMP) 
packs will be sent to the participant, either to collect from their local study site or sent 
directly to the participant’s home. The treatment packs for each participant will always 
contain the same number of capsules as the previous supplies (with placebo capsules masking 
any changes) to maintain the blinding and to ensure the participant is not aware of any dose 
changes. 
Once the titration visit at 16 weeks is complete and the dose subsequently adjusted, if 
necessary, the dose of study medication will then be fixed and should remain unchanged until 


 
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the end of study (EOS) visit (up to 12 weeks of fixed dose treatment) if possible. The last 
dose of study medication will be taken in the morning of the last dosing day. 
The analysis of all 17-OHP and A4 levels will be conducted by a central laboratory and the 
results will be sent to an independent blinded physician, with the independent blinded 
physician being unaware of the participant’s treatment allocation. The Investigator will also 
complete an adrenal insufficiency checklist at each visit which will be made available to the 
independent blinded physician. At the titration visits at 4, 10, and 16 weeks, if the 
independent blinded physician considers a dose reduction is necessary, the dose should be 
reduced by a total of 5 mg at each titration visit, as detailed in the dose titration rules in 
Section 4.2. Each treatment arm will be subject to the same titration rules throughout the 
study, ensuring that opportunities for optimization and control of androgens are the same in 
both arms and thus minimizing bias in the management of participants. Note that only dose 
reductions are permitted at the titration visits at 4, 10, and 16 weeks (unless the dose has 
previously been reduced, in which case it can be reverted back to the previous higher dose if 
needed without having to wait until the next titration point). Dose increases can only be made 
in an urgent situation where the Investigator believes the participant is exhibiting signs of 
adrenal insufficiency, and in all cases, this should be discussed with the medical monitor 
before a dose increase is initiated (see Section 4.2 for further details).  
The EOS visit will be conducted 28 weeks after randomization or at early withdrawal from 
the study. The total study duration is up to 40 weeks (screening period up to 4 weeks prior to 
the screening visit, 4 weeks run-in period on IRHC up to the baseline visit, 16 weeks dose 
titration on randomized treatment, 12 weeks fixed dose period on randomized treatment, and 
follow-up phone call 4 weeks/30 days after the EOS visit). In some cases (e.g., if the 
participant lives a long way from the study site, or if pandemic guidelines dictate) Visits 3 
and 4 may be performed as domiciliary visits and IMP shipments can be made directly to the 
participant’s home. However, the following visits must be performed at the study site: 
Screening (Visit 1), Baseline (Visit 2), Week 16 (Visit 5), and end of treatment/early 
withdrawal visit (Visit 6). If necessary in some cases, IMP at Visit 5 can also be delivered to 
the participant's home. If a domiciliary visit is conducted the safety and endocrine blood 
samples must be sent to the central laboratory for analysis and the Investigator must complete 
the adrenal insufficiency checklist. The assessment of hirsutism and acne can be conducted 
via a video call (within ±2 days of the domiciliary visit). If androgen samples are analyzed 
locally for safety reasons the participant must be withdrawn from treatment. 
At the end of the study, participants who have completed the study will be offered the option 
of continuing in a long-term safety study (DIUR-015) where all participants will receive 
open-label Chronocort treatment or they will be offered commercial supplies of Chronocort 
(the options will be dependent on territory), or the participant can return to the standard 
treatment they were receiving before entry into this study. For participants who agree to enter 
the long-term safety study DIUR-015, the EOS visit (Visit 6) will be their last assessment in 
this study. Participants who decide not to enter the long-term safety study or who withdrew 
from the study early will receive a telephone call 30 days after the last study visit to ask about 
any AEs that were ongoing and any new serious adverse events (SAEs) that could be related 
to the study medication. This telephone call will be considered the last assessment for these 
participants, although ongoing SAEs will be followed until resolution or stabilization, the 
event is otherwise explained, or the participant is lost to follow-up.  


 
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Disclosure Statement: This is a double-blind parallel group treatment study with 2 arms. 
Number of Participants: Sufficient participants will be screened to achieve approximately 
50 participants randomly assigned to either Chronocort or IRHC (25 participants per 
treatment arm, regardless of baseline strata), or until a cut-off date of 30 April 2023, 
whichever is reached first. Individual study sites should not randomize more than 8 
participants without first consulting the Sponsor. A sample size of 25 participants per 
treatment arm will provide at least 80% power to demonstrate non-inferiority of Chronocort 
to IRHC when the biochemical response rate in the IRHC arm is 40%, the non-inferiority 
margin is 15% and the biochemical response rate in the Chronocort arm is 68% using a 
1-sided continuity corrected z-test with unpooled variance and a 1-sided alpha of 2.5%. 
Inclusion/Exclusion Criteria: Participants are eligible to be included in the study only if 
they meet all the following inclusion criteria and none of the exclusion criteria 
(note: re-screening is permitted if the Investigator considers that the circumstances leading to 
screening failure will not be relevant when the participant is re-screened at a later time): 
 
Inclusion Criteria 
Exclusion Criteria 
Male or female participants must be aged 16 
years or older at the time of signing the 
informed consent/assent. 
Clinical or biochemical evidence of hepatic or 
renal disease e.g., creatinine >2 times the upper 
limit of normal (ULN) or elevated liver function 
tests (alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST] >2 times the 
ULN). 
In participants aged <18 years, height velocity 
must be less than 2 cm/year in the last year and 
puberty must be completed (Tanner stage V). 
History of bilateral adrenalectomy. 
 
Participants with known classic CAH due to 
21-hydroxylase deficiency diagnosed in 
childhood with documented (at any time) 
elevated 17-OHP and with or without elevated 
A4 and currently treated with hydrocortisone, 
prednisone, prednisolone or dexamethasone (or 
a combination of the aforementioned 
glucocorticoids) and on stable glucocorticoid 
therapy for a minimum of 3 months. 
History of malignancy (other than basal cell 
carcinoma successfully treated >26 weeks prior 
to entry into the study). 
 
Participants who are receiving fludrocortisone 
must be on a documented stable dose for a 
minimum of 3 months prior to enrollment and 
must have stable renin levels at screening. 
Participants who have type 1 diabetes, receive 
regular insulin, have uncontrolled diabetes, or 
have a screening HbA1c greater than 8%. 
 
Female participants of childbearing potential 
and all male participants must agree to the use 
of an accepted method of contraception during 
the study. 
Persistent signs of adrenal insufficiency or the 
participant does not tolerate treatment at the end 
of the 4-week run-in period. 


 
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Inclusion Criteria 
Exclusion Criteria 
A female participant is eligible to participate if 
she is not pregnant, not breastfeeding, and she 
is either not a woman of childbearing potential 
(WOCBP) or has a negative pregnancy test at 
entry into the study. Note: females presenting 
with oligomenorrhea or amenorrhea who are 
aged ≤55 years should be considered 
potentially fertile and therefore should undergo 
pregnancy testing like all other female 
participants. 
Participants with any other significant medical or 
psychiatric conditions that in the opinion of the 
Investigator would preclude participation in the 
study. 
Capable of giving signed informed 
consent/assent which includes compliance with 
requirements and restrictions listed in the 
informed consent form (ICF) and in this 
protocol. 
Participants on regular daily inhaled, topical, 
nasal or oral steroids for any indication other than 
CAH. 
 
Co-morbid condition requiring daily 
administration of a medication or consumption of 
any material that interferes with the metabolism 
of glucocorticoids. 
 
Participants who are receiving <10 mg 
hydrocortisone dose at screening or the 
hydrocortisone dose equivalent. 
Participants anticipating regular prophylactic use 
of additional steroids e.g., for strenuous exercise. 
Participation in another clinical study of an 
investigational or licensed drug or device within 
the 12 weeks prior to screening. 
Inclusion in any natural history or translational 
research study that would require evaluation of 
androgen levels during the study period outside 
of this protocol’s assessments. 
Participants who have previously been exposed to 
Chronocort in any Diurnal study. 
Participants who routinely work night shifts and 
so do not sleep during the usual night-time hours.  
Participants, who in the opinion of the 
Investigator, will be unable to comply with the 
requirements of the protocol. 
Participants with a known hypersensitivity to any 
of the components of the Chronocort capsules, 
the Cortef tablets, or the placebo capsules. 
Participants with congenital galactosemia, 
malabsorption of glucose and galactose, or who 
are lactase deficient. 
Participants with a body weight of 45 kg or less. 


 
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Treatment Groups and Duration: Treatment will continue for a total of 32 weeks (4-week 
run-in with IRHC, 16-week dose titration to randomized treatment, and 12 weeks fixed 
dosing period to randomized treatment) or until early withdrawal from the study. Participants 
will attend the study sites for a total of 6 visits during the study: screening, baseline, Week 4 
(titration visit), Week 10 (titration visit), Week 16 (titration visit), and Week 28 (EOS visit). 
If a participant who was enrolled under an earlier version of the protocol (where the study 
was up to 52 weeks in duration) had attended Visit 5 at Week 16 and is ongoing treatment, 
they must continue taking the study medication and must return at 28 weeks for the EOS 
(Visit 6) assessments. If they have already had more than 28 weeks of treatment then they 
must return as soon as possible (but not within 4 weeks of previous blood sampling) for the 
EOS (Visit 6) assessments according to this amendment. After completion of the study, 
participants may join a long-term safety study (Protocol DIUR-015) or they will be offered 
commercial supplies of Chronocort (the options will be dependent on territory), or they can 
return to standard glucocorticoid replacement regimen (as determined by the Investigator). 
The test IMP for this study is Chronocort (hydrocortisone modified release capsule). In this 
study Chronocort will be supplied in 2 dose strengths of 5 mg and 10 mg per capsule for oral 
administration. The capsules will be over-encapsulated to maintain blinding. The comparator 
IMP for this study is IRHC (Cortef). IRHC will be supplied as 5 mg and 10 mg tablets for 
oral administration. The tablets will be over-encapsulated to maintain blinding. 
In addition, stress dosing packs (Section 6.1.1) will be provided for use in the case of incurrent 
illness. 
Data Safety Management Board: Yes 
1.2. 
Schema 
 
EOS = end of study; IRHC = immediate-release hydrocortisone; IRT = interactive response technology 
Note: timelines not to scale 


 
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1.3. Schedule of Activities 
 
 
 
 
 
 
Description
Screening Visit
Baseline 
 Titration Visit
Telephone call
Titration Visit
Telephone call
Titration Visit and 
Start of Fixed Dose 
Period
Visit Number
V1
V2
V315
Call T3.1
V415
Call T4.1
V5
Week
Week -4
Day 1
Week 4 + 1 week
V3 + 2-5 weeks Week 10 ± 1 week V4 + 2-5 weeks
Week 16 ± 1 week
Consent1
X
Medical history2
X
Concomitant medications3
X
X
X
X
X
X
X
Demographic data
X
Inclusion/exclusion criteria
X
X13
Physical examination
X
X
Abbreviated physical examination (if indicated by AEs)
X
X
X
Vital signs (blood pressure, heart rate, respiratory rate, 
temperature)
X
X
X
X
X
17-OHP and A4 (at 08:00 and 13:00 ± 30 minutes)4
X
X
X
X
X
Safety laboratory tests (hematology, biochemistry, urinalysis)
X
X
X
X
X
Pregnancy test (females)
X
X
X
X
X
Plasma renin5
X
 
 
 
 
 
HbA1c
X
X
X
X
FSH and osteocalcin 
X
X
X
X
ECG
X
QoL (SF-36®, MAF, EQ-5D-5L™)
X
X
X
X
Adrenal insufficiency checklist
X
X
X
X
X
Height, waist circumference, weight
X
X
X
X
X
Assessment of menstrual cycle pattern in females6 and LH levels 
in males
X
X
X
X
Hirsutism assessment in female participants using VAS and  
Ferriman-Gallwey score7
X
X
X
X
Acne assessment  in female participants7
X
X
X
X
TART measurement  in male participants by ultrasound8
X
Sperm count  in male participants 9 
X
Treatment preference assessment using VAS7
Alertness assessment using VAS10
X
X
X
X
Serum 11-ketotestosterone and DHEA
X
Serum testosterone
X
4 weeks run-in IRHC medication
X
Randomization
X
Salivary samples for exploratory analysis 11
X
X
X
X
Dose titration, if required12
X
X
X
Recording details of  glucocorticoid doses for previous 24 hours 
and throughout visit
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
Compliance
X
X
X
X


 
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Description
Telephone call
Telephone Call
End of Study/Early Withrawal 
Visit
Telephone call
Visit Number
Call T5.1
Call T5.2
V6
Call T6.1
Week
V5 + 2-5 weeks Week 22 ± 2 weeks 
Week 28 + 1 week from 
randomization or early 
termination visit14
30 days after V6 ± 
1 week
Consent1
Medical history2
Concomitant medications3
X
X
X
Demographic data
Inclusion/exclusion criteria
Physical examination
X
Abbreviated physical examination (if indicated by AEs)
Vital signs (blood pressure, heart rate, respiratory rate, 
temperature)
X
17-OHP and A4 (at 08:00 and 13:00 ± 30 minutes)4
X
Safety laboratory tests (hematology, biochemistry, urinalysis)
X
Pregnancy test (females)
X
Plasma renin5
X
HbA1c
X
FSH and osteocalcin 
X
ECG
X
QoL (SF-36®, MAF, EQ-5D-5L™)
X
Adrenal insufficiency checklist
X
Height, waist circumference, weight
X
Assessment of menstrual cycle pattern in females6 and LH levels 
in males
X
Hirsutism assessment in female participants using VAS and  
Ferriman-Gallwey score7
X
Acne assessment  in female participants7
X
TART measurement  in male participants by ultrasound8
X
Sperm count  in male participants 9 
X
Treatment preference assessment using VAS7
X
Alertness assessment using VAS10
X
Serum 11-ketotestosterone and DHEA
X
Serum testosterone
X
4 weeks run-in IRHC medication
Randomization
Salivary samples for exploratory analysis 11
X
Dose titration, if required12
Recording details of  glucocorticoid doses for previous 24 hours 
and throughout visit
X
Adverse events
X
X
X
X
Compliance
X


 
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17-OHP = 17-hydroxyprogesterone; A4 = androstenedione; AE = adverse event; DHEA = 
dehydroepiandrosterone; ECG = electrocardiogram; EQ-5D-5L™ = 5-level Standardized Health Questionnaire; 
FSH = follicle stimulating hormone; HbA1c = glycated hemoglobin; IMP = investigational medicinal product; 
IRHC = immediate-release hydrocortisone; LH = luteinizing hormone; MAF = Multidimensional Assessment of 
Fatigue; QoL = quality of life; SF-36® = Medical Outcome Study 36-Item Short Form Health Survey; TART = 
testicular adrenal rest tumors; VAS = visual analog scale. 
Notes:  
 
The screening visit can be split over 2 days, if necessary, to help facilitate consent and the conduct of the 
screening study procedures. 
If visits have to be moved (e.g., due to use of ‘stress dosing rules’) this should be noted in the electronic case 
report form (eCRF). However, the participant should return to their usual visit schedule as soon as possible (i.e., 
all subsequent visits should not be moved out as well). 
1  Consent forms will be sent to the participant at least 24 hours prior to the visit so they can review the 
document and ask any questions. The consent form must be signed at or before the screening visit (Visit 1) 
prior to any study related procedures. 
2  Including menstrual history, menopausal status and oral contraceptive use for female participants. 
3  Previous treatments for CAH (last 26 weeks) and any other previous treatments (last 4 weeks) will be 
recorded at the screening visit (Visit 1). At each visit details of the study medication use at each visit and for 
the 24 hours preceding each visit will be recorded plus any changes in other concomitant medications. CAH 
medication will be recorded separately from other concomitant medications. 
4  If the participant has been receiving their usual medication for the previous 5 days (i.e. ‘stress dosing rules’ 
have not been applied in the 5 days preceding the visit date) they will be admitted to the clinic for androgen 
testing (17-OHP and A4). If ‘stress dosing rules’ have been applied in the previous 5 days, then the visit 
should be postponed until the participant has been receiving their usual medication for 5 days. Samples for 
androgen testing to be taken at 08:00 (before the morning dose of study medication) and 13:00 hours 
(±30 minutes). Exact times of sampling to be recorded in eCRF.  
5  Plasma renin concentration or activity will be assessed at screening and at the end of study according to local 
practice (preferably after the participant has been supine for 30 minutes). Participants who are receiving 
fludrocortisone must be on a documented stable dose for a minimum of 3 months prior to enrollment and 
must have stable renin levels at screening. 
6  Electronic participant diary used to record menstrual cycle details in all pre-menopausal women. 
7  Assessed using a 10 cm VAS at each visit (hirsutism also assessed by the Investigator using Ferriman-
Gallwey score and acne also assessed by the Investigator using Global Evaluation [GEA] scale). 
8  TARTs measured by ultrasound and results read by central laboratory. 
9  Sperm count measured at home using a testing kit supplied to the male participants (only in participants who 
agree to this assessment). 
10  Alertness assessed weekly before the morning dose of study medication, and results recorded in the electronic 
participant diary. 
11  Saliva samples collected for exploratory analysis at 8.00 and 13.00 hours (optional). 
12  Dose titrations based on the adrenal insufficiency checklist and the endocrine profiles at 08:00 and 13:00 
hours (±30 minutes) from the central laboratory and dose adjustments made by an independent blinded 
physician in accordance with the dose titration rules. 
13  Limited check of inclusion/exclusion criteria  
14 The last dose of study medication should be taken in the morning of the last dosing day. If the participant 
discontinues early from study treatment or from the whole study then androgen measurements and as many 
other assessments as possible should be completed within 48 hours of the last dose of the study medication. If 
the participant only discontinues study treatment, they should remain in the study where possible and be 
followed for safety assessments until the scheduled end of the study. 
15   In some cases (e.g., if the participant lives a long way from the study site or pandemic guidelines are in 
place) Visits 3 and 4 may be performed as domiciliary visits and IMP shipments can be made directly to the 
participant’s home. However, the following visits must be performed at the study site: Screening (Visit 1), 
Baseline (Visit 2), Week 16 (Visit 5), and end of study/early withdrawal visit (Visit 6). If necessary in some 
cases, IMP at Visit 5 can also be delivered to the participant's home. If a domiciliary visit is conducted the 
safety and endocrine blood samples must be sent to the central laboratory for analysis and the Investigator 
must complete the adrenal insufficiency checklist. The assessment of hirsutism and acne can be conducted 
via a video call (within ±2 days of the domiciliary visit). If androgen samples are analyzed locally for safety 
reasons the participant must be withdrawn from treatment.


 
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2. 
Introduction 
Chronocort® is a newly developed modified-release oral formulation of hydrocortisone. It is 
designed to replicate the normal serum levels of the endogenous cortisol circadian rhythm 
with the aim of improving control in patients with congenital adrenal hyperplasia (CAH) who 
are receiving glucocorticoid replacement therapy. 
2.1. 
Study Rationale 
CAH, generally due to 21-hydroxylase deficiency, is a disease of the adrenal cortex 
characterized by cortisol deficiency and androgen excess, with or without aldosterone 
deficiency. The severe or classic form occurs in 1 in 15,000 births worldwide [Pang et al, 
1993; Therrell, 2001; Merke and Bornstein, 2005]. The discovery of glucocorticoid therapy 
as a treatment for CAH occurred in the 1950s resulting in patients with classic CAH 
surviving. However, existing glucocorticoid treatment remains suboptimal and many 
unresolved clinical problems exist [Han et al, 2014].  
There is currently no standard treatment for this condition, with glucocorticoid therapies 
varying by country and by treating site. Current treatments also often fail to normalize the 
patient’s condition, with abnormal growth and development in children, and iatrogenic 
Cushing’s syndrome, hyperandrogenism, infertility or the development of metabolic 
syndrome in adults [Arlt et al, 2010]. Chronocort, a newly developed modified-release oral 
formulation of hydrocortisone, is designed to replicate the normal serum levels of the 
endogenous cortisol circadian rhythm, offering the prospect of an improved treatment 
outcome and a novel treatment paradigm. The proposed study aims to build on the results of 
the Phase 2 study (DIUR-003) and the completed Phase 3 study (DIUR-005), as well as the 
ongoing Phase 3 extension study (DIUR-006). It is designed to further evaluate whether a 
twice daily dosing regimen of Chronocort with two-thirds of the total daily dose given at 
night and one-third in the morning (the ‘toothbrush regimen’), which can more closely 
replicate circadian cortisol levels and also avoids the afternoon dose which can be difficult 
for some patients, can provide improved long-term control of CAH (using 
17-hydroxyprogesterone [17-OHP] and androstenedione [A4] concentrations as markers) 
compared to the same total daily dose of twice daily (morning and afternoon) 
immediate-release hydrocortisone (IRHC) replacement therapy in conditions broadly 
resembling routine clinical practice. Adults and adolescents aged 16 or older who have 
completed their growth are included in this study, with the adolescent age group being 
included following feedback from pediatric endocrinologists that this group is particularly 
challenging to manage with standard care IRHCs, yet improved control at this age may be 
particularly relevant for future health. 
This study should help delineate the benefits derived from a more physiological delivery of 
cortisol by the modified release Chronocort preparation from benefits due to the potential for 
reduced daily dose requirements with a more physiological preparation. 
 


 
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2.2. 
Background 
Cortisol is an essential steroid hormone secreted by the adrenal gland, with severe deficiency 
ultimately resulting in death through an adrenal crisis. Endogenous cortisol is secreted in a 
circadian rhythm, with levels building up overnight to peak first thing in the morning then 
falling over the day with a nadir at midnight. Patients with adrenal failure that is either 
primary (Addison’s disease and CAH) or secondary (hypothalamic-pituitary dysfunction) are 
deficient in cortisol and have to take life-long glucocorticoid replacement (such as 
hydrocortisone, the synthetic form of cortisol). 
Hydrocortisone was first isolated from adrenal glands in 1937 [Reichstein and Steiger, 1937] 
and is now a well characterized therapeutic molecule widely used in clinical practice to treat 
adrenal insufficiency [Speiser et al, 2018]. The majority of existing marketed oral 
formulations of hydrocortisone are provided at doses of 5 mg, 10 mg and 20 mg and are 
designed to deliver “immediate-release” of the active ingredient. In order to achieve 
efficacious plasma levels of hydrocortisone, multiple daily dosing is required (typically 2 or 
3 times daily [Speiser et al, 2018]), which results in high peak-to-trough fluctuations in 
plasma concentrations [Maguire et al, 2007]. Furthermore, this results in low early morning 
cortisol levels and high adrenocorticotropic hormone (ACTH) levels, causing fatigue in 
patients with Addison’s disease and high adrenal androgen levels in patients with CAH. It is 
therefore not possible to replicate physiological cortisol release using this therapeutic 
regimen. Thrice daily regimens can also be difficult to manage for busy adults, meaning that 
many will use twice daily dosing. Treatment is also complicated by the fact that excessive 
steroid replacement with hydrocortisone or other glucocorticoids causes complications in its 
own right, by reducing growth in the child and causing osteoporosis and skin atrophy in the 
adult, so a balance needs to be maintained between under-treatment leading to excessive 
androgens and ultimately an adrenal crisis but avoiding the side effects of over-treatment. 
Diurnal has developed a novel modified-release formulation of hydrocortisone (Chronocort) 
which closely replicates the physiological circadian profile for cortisol and therefore has the 
potential to provide optimal control of all forms of adrenal insufficiency. To date, 3 studies 
evaluating Chronocort in healthy volunteers (DIUR-002, DIUR-004 and DIUR-008) and 
2 studies evaluating Chronocort in patients with CAH (DIUR-003 and DIUR-005) have been 
completed. An extension study allowing participants enrolled into the 2 CAH studies to 
receive long-term Chronocort treatment is ongoing (DIUR-006). In total, 71 healthy 
volunteers (65 who received Chronocort) and 138 patients with CAH (120 who received 
Chronocort) have been evaluated to date.  
The results from the studies to date show that the pharmacokinetic (PK) profile of Chronocort 
after 20 mg at 23:00 hours and 10 mg at 07:00 hours both in healthy subjects and in subjects 
with CAH is characterized by an overnight rise in cortisol levels, reaching a maximal 
concentration approximately 8 hours post-dosing, which is consistent with the physiological 
endogenous profile of cortisol reported in normal individuals. Physiological replacement of 
cortisol with Chronocort, replicating the cortisol circadian rhythm, improved the control of 
disease-related biomarker androgens in subjects with CAH when compared to subjects on 
baseline standard therapy, particularly in the early morning period when androgens typically 
peak in conventionally-treated patients, with this being achieved with a similar or lower dose 
of glucocorticoid. PK data indicated that food slightly delayed and reduced the rate of 
absorption of Chronocort. However, overall exposure was similar in fed and fasted subjects, 


 
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so this effect was not considered clinically relevant. In a relative bioequivalence study, 
Chronocort was bioequivalent to IRHC (Cortef®) with respect to the area under the plasma 
concentration versus time curve (AUC). 
Results of the Phase 3 studies in patients with CAH showed improved control of adrenal 
androgen precursors (17-OHP and A4) in the critical morning and early afternoon periods 
following Chronocort treatment, with a similar or lower dose of Chronocort being used to 
attain better morning and similar evening androgen control compared to standard 
glucocorticoid therapy. Post-hoc analyses demonstrated reduced variability of disease 
biomarkers and a reduced AUC for 17-OHP and A4 with Chronocort therapy compared to 
standard therapy. In CAH, elevated 17-OHP is diagnostic and widely used in monitoring 
therapy, and it plays a central role in driving excess adrenal androgens. 17-OHP in CAH 
displays a marked diurnal rhythm that is not seen in the normal population. In CAH patients, 
elevated 17-OHP drives the production of excess adrenal androgens through the 3 adrenal 
androgen pathways: The Classic, The Alternative and The 11-Oxygenated [Storbeck et al, 
2019]. In the pathophysiology of CAH, the Classic pathway, via dehydroepiandrosterone 
(DHEA) to A4 is down regulated, as evidenced by normal or low DHEA levels in poorly 
controlled CAH patients, and it is the raised 17-OHP that directly drives A4 production 
[Debono et al, 2015]. When 17-OHP is controlled into the optimal range (<1200 ng/dL) 
throughout 24 hours, as shown in the Diurnal DIUR-005 and DIUR-006 studies, this direct 
route from 17-OHP to A4 is switched off, meaning that A4 levels are either normal or low as 
it is neither generated from 17-OHP nor DHEA (Chronocort DIUR-005 Clinical Study 
Report [CSR]). A4 may be low in well-controlled CAH, even when using adrenal 
replacement doses of hydrocortisone, i.e., lower than those typically used in CAH, as shown 
in the DIUR-006 efficacy and safety extension study (DIUR-006 CSR) where a number of 
patients were treated for extended periods on 10 mg daily Chronocort with low A4. To reduce 
the glucocorticoid dose below these doses in this situation would put patients at risk of 
adrenal insufficiency and crisis. Thus, as 17-OHP plays the central role for A4 generation, 
17-OHP is the better biomarker for control of androgens in CAH. Interest has been expressed 
by endocrinologists in using 11-keto androgens as biomarkers for monitoring disease, and 
there are published [Jones et al, 2017] and unpublished data suggesting that Chronocort can 
control these markers more effectively than standard therapies, however, there is as yet no 
universally recognised and validated 11-keto-steroid biomarker and so Diurnal has chosen to 
include one of these biomarkers (11-ketotestosterone) as an exploratory endpoint rather than 
as the primary endpoint. 
In studies DIUR-005 and DIUR-006 there was a reduced incidence of potentially 
life-threatening adrenal crises, and a reduction in the need for supplementary steroid stress 
dosing, with an increased incidence of therapeutic benefits (fatigue reduction, improvement 
of hirsutes, menstrual benefits) being reported. No safety concerns have been raised in any of 
the studies and the adverse event (AE) profile resembles that of other hydrocortisone 
products used at comparable dose levels for glucocorticoid replacement therapy in CAH 
patients.  
Further details on the use of Chronocort in humans is provided in Section 6 of the 
Investigator’s Brochure. Details on the comparator product are provided in the Cortef 
prescribing information.  


 
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2.3. 
Benefit/Risk Assessment 
The participants planned to be included in this study all have classic CAH and, as such, they 
have an absolute requirement for life-long glucocorticoid replacement therapy. The currently 
used glucocorticoid replacement therapies do not accurately replicate physiological cortisol 
profiles. Chronocort is a novel modified-release formulation of hydrocortisone that has been 
shown to closely replicate the physiological circadian profile of cortisol. Hydrocortisone is an 
established therapy for CAH that has been used for over 60 years. The safety profile when 
used in a low dose adrenal replacement regimen is well understood and the development 
program for Chronocort has shown no differences in safety profile to established IRHC 
preparations. Results of completed clinical studies using Chronocort have demonstrated that 
cortisol levels on Chronocort approximated physiological cortisol rhythm over 24 hours, and 
improved control of androgens (17-OHP and A4) in participants with CAH when compared 
to their disease control on conventional glucocorticoid therapy. Thus, it is proposed that the 
formulation of hydrocortisone being evaluated in this study (Chronocort) has characteristics 
that may improve the outcome in these participants. This hypothesis applies to adults and 
adolescents who have completed their growth and may benefit from improved control, 
particularly considering potential positive impacts on fertility and metabolic parameters. 
There are no formulation-specific concerns regarding the use of this modified-release 
presentation of hydrocortisone in this age group. 
The risks associated with this study include those associated with blood sampling and general 
involvement with clinical studies. The Investigators in this study are all highly experienced 
both in clinical studies and in the management of patients with CAH, and so these risks are 
considered negligible. In addition, to minimize the risk of anemia associated with the 
withdrawal of multiple blood samples for laboratory testing (as seen in a previous study), the 
planned blood volume to be drawn during this study has been limited to a maximum of 
approximately 200 mL.  
Other risks relate to the potential under- or over-treatment of participants with 
glucocorticoids as seen in day-to-day clinical practice. These risks apply to both conventional 
treatment and Chronocort. All participants included in this study will be informed of the 
potential for under-treatment (as occurs when there is an intercurrent illness), and the routine 
teaching on how to manage this with supplemental steroids (emergency pack for ‘stress 
dosing rules’) and to seek medical assistance will be reinforced. 
 
 
 
 
 
 
 
 
 
 
 
 
Both under- and over-treatment with hydrocortisone are common as physicians try to balance 
androgens and clinical symptoms. Regular assessment of the participants (both biochemically 


 
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and clinically) and review of these results will identify under- and over-treatment, which will 
be corrected by the recommendations from an independent blinded physician through a 
modification in the dose. Thus, the potential risks are minimized and mitigated by the 
Investigator’s oversight, dose modification by the independent blinded physician, use of 
‘stress dosing rules’ by the individual participants when needed, and specific study activities 
(e.g. identification of AEs).  
 
 
 
 
 
 
All participants will be given the relevant information about the risks and potential benefits of 
the study and all participants have to sign a consent form prior to inclusion in the study that 
meets all the requirements of Good Clinical Practice (GCP) and national regulations. Thus, 
the risks of Chronocort are expected to be no greater than the risks of an equivalent dose of 
hydrocortisone and similar to the risks associated with current glucocorticoid therapy the 
participant will have received prior to entry into the study. However, the delivery of 
hydrocortisone with Chronocort has been demonstrated to produce a cortisol profile more 
similar to the endogenous cortisol profile than current IRHC formulations 
 
 
 
 
 
 
 
  
 
  


 
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3. 
Objectives, Outcome Variables, and Analyses 
Objectives 
Outcome Variable and  
Analyses Supporting the Objectives 
Primary Efficacy 
 
• To compare Chronocort to IRHC in 
terms of biochemical responder rate 
after 28 weeks of randomized treatment. 
 
 
 
 
 
 
 
• The primary efficacy outcome variable is whether 
or not the participant is a biochemical responder 
after 28 weeks of randomized treatment.  
A biochemical responder is a participant who: 
i) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 
upper limit of the reference range), and 
ii) is receiving after 28 weeks of randomized 
treatment 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). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are biochemical responders 
28 weeks after randomization will be estimated in 
the full analysis set (FAS). Participants who die or 
withdraw from treatment before 28 weeks will be 
classified as not a biochemical responder. 
Participants receiving rescue medication under the 
‘stress dosing rules’ within 5 days before the 
scheduled visit at 28 weeks after randomization 
will have their visit delayed appropriately1. 
Biochemical non-inferiority of Chronocort to 
IRHC will be declared if the 95% confidence 
interval (CI) for the difference in proportions lies 
wholly above minus 15 percentage points.   
Key Secondary Efficacy 
 
• 1) To compare Chronocort to IRHC in 
terms of dose responder rate after 
28 weeks of randomized treatment. 
 
• The first key secondary efficacy outcome variable 
is whether or not the participant is a dose 
responder after 28 weeks of randomized 
treatment.  
A dose responder is a participant who: 
i) is receiving after 28 weeks of randomized 
treatment a total daily dose of hydrocortisone 
of not more than 25 mg, and 
ii) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 


 
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upper limit of the reference range). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are dose responders 28 weeks 
after randomization will be estimated in the FAS. 
Participants who die or withdraw from treatment 
before 28 weeks will be classified as not a dose 
responder. Participants receiving rescue 
medication under the ‘stress dosing rules’ within 
5 days before the scheduled visit at 28 weeks after 
randomization will have their visit delayed 
appropriately1. 
Dose superiority of Chronocort to IRHC will be 
declared if the 95% CI for the difference in 
proportions lies wholly above zero, provided that 
biochemical non-inferiority of Chronocort to 
IRHC has been declared under the primary 
efficacy objective. 
• 2) To compare Chronocort to IRHC in 
terms of total daily dose after 28 weeks 
of randomized treatment. 
• The second key secondary efficacy outcome 
variable is the total daily dose (mg) after 
28 weeks of randomized treatment.  
The difference (Chronocort minus IRHC) 
between the mean total daily dose after 28 weeks 
of randomized treatment in each treatment arm 
will be estimated in the FAS. Superiority of 
Chronocort to IRHC with respect to total daily 
dose after 28 weeks of randomized treatment will 
be declared if the 95% CI for the difference in 
means lies wholly below zero, provided that dose 
superiority of Chronocort to IRHC has been 
declared under the first key secondary efficacy 
objective. 
Other Secondary Efficacy 
 
• To compare Chronocort to IRHC in 
terms of biochemical responders at 4, 
10, and 16 weeks after randomization. 
 
 
• The outcome variables whether or not the 
participant is a biochemical responder at 08:00 
hours at 4, 10, and 16 weeks after randomization 
are compared between treatment arms by 
calculating the difference in proportion of 
participants responding. These outcome variables 
are to be analyzed in the same manner as the 
primary efficacy outcome variable. 
• To compare Chronocort to IRHC in 
terms of dose responders at 10 and 16 
weeks after randomization. 
 
 
• The outcome variables whether or not the 
participant is a dose responder at 08:00 hours at 
10 and 16 weeks after randomization are 
compared between treatment arms by calculating 
the difference in proportion of participants 
responding. These outcome variables are to be 
analyzed in the same manner as the key 
secondary outcome variable. 


 
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• To compare Chronocort to IRHC in 
terms of total daily dose at 10 and 16 
weeks after randomization. 
 
 
• The outcome variables total daily dose at 10 and 
16 weeks after randomization are compared 
between treatment arms by calculating the 
difference in mean total daily dose. These 
outcome variables are to be analyzed in the same 
manner as the second key secondary outcome 
variable. 
• To compare Chronocort to IRHC in 
terms of biochemical control at 4, 10, 
16, and 28 weeks after randomization. 
 
 
• The outcome variables whether or not the 
participant is in biochemical control (provided 
total daily dose is not more than 30 mg) at 08:00 
hours at 4, 10, 16, and 28 weeks after 
randomization are compared between treatment 
arms by calculating the difference in proportion 
of participants in control. 
• To compare Chronocort to IRHC in 
terms of the impact on 17-OHP range. 
• The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of 17-OHP levels at 4, 10, 16,  and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on A4 range. 
• The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of A4 levels at 4, 10, 16, and 28 
weeks after randomization and their changes from 
baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on mean 17-OHP 
and A4. 
• The mean of the 08:00 and 13:00 measurements 
of 17-OHP levels and A4 levels at 4, 10, 16,  and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on glucocorticoid 
dose. 
• The total daily glucocorticoid dose at 4, 10, 16,  
and 28 weeks after randomization will be 
summarized and compared between treatment 
arms. 
• The relationship between daily glucocorticoid 
dose and biochemical control at 28 weeks after 
randomization will be explored. 
• To compare Chronocort to IRHC in 
terms of changes in menstrual 
regularity. 
 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in menstrual 
regularity (only in pre-menopausal women 
without hysterectomy and not using hormonal 
contraception) will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on luteinizing 
hormone (LH) levels. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in LH levels (men 
only) will be summarized and compared between 
treatment arms. 


 
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• To compare Chronocort to IRHC in 
terms of the impact on testicular adrenal 
rest tumors (TART) size. 
• The change from baseline to 28 weeks of 
randomized treatment in size of TART (men 
only) will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on sperm count. 
• The change from baseline to 28 weeks of 
randomized treatment in sperm count (men only) 
will be summarized and compared between 
treatment arms. 
• 
To compare Chronocort to IRHC in 
terms of the impact on subjective 
hirsutism in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in subjective 
hirsutism using a visual analog scale (VAS) 
(women only) will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on objective 
hirsutism in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective 
hirsutism using the Ferriman-Gallwey score 
(women only) will be summarized and compared 
between treatment arms. 
• 
To compare Chronocort to IRHC in 
terms of the impact on subjective acne 
in female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in subjective acne 
using a VAS (women only) will be summarized 
and compared between treatment arms. 
• 
To compare Chronocort to IRHC in 
terms of the impact on objective acne in 
female participants. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective acne 
using the Global Evaluation Acne (GEA) scale 
(women only) will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on glycated 
hemoglobin (HbA1c) levels. 
• The change from screening to 4, 10, 16, and 28 
weeks of randomized treatment in HbA1c levels 
will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on waist 
circumference. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in waist 
circumference will be summarized and compared 
between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on body weight. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in body weight 
will be summarized and compared between 
treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on quality of life 
(QoL) using the self-completed Medical 
Outcome Study 36-Item Short Form 
Health Survey (SF-36®) total score and 
the sub-domain of vitality. 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
self-completed SF-36® total score and the 
sub-domain of vitality will be summarized and 
compared between treatment arms. 
• To compare Chronocort to IRHC in 
terms of the impact on QoL using the 
Multidimensional Assessment of 
Fatigue (MAF). 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
MAF will be summarized and compared between 
treatment arms. 


 
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• To compare Chronocort to IRHC in 
terms of the impact on QoL using the 
5-level Standardized Health 
Questionnaire (EQ-5D-5L™). 
• The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using the 
EQ-5D-5L™ will be summarized and compared 
between treatment arms. 
Compliance 
 
• To assess compliance over the study 
period. 
• The percentage treatment compliance between 
visits and overall will be summarized. 
Exploratory Efficacy 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Safety 
 
• To assess the safety and tolerability of 
Chronocort relative to IRHC. 
• The incidence, nature, severity, relatedness, 
duration, outcome, seriousness and expectedness 
of treatment-emergent adverse events (TEAEs) 
will be tabulated by treatment arm. AEs of special 
interest will additionally be tabulated separately, 
with particular note of adrenal crises. 
• To assess the need for use of additional 
glucocorticoid doses (stress dosing 
rules). 
• The use of medication from the stress dosing 
packs or use of any additional glucocorticoid 
treatment during the study will be tabulated by 
treatment arm. 
• To evaluate the safety of Chronocort 
compared to IRHC by assessment of 
routine safety laboratory assessments, 
physical examination, vital signs, and 
electrocardiogram (ECG). 
• Safety hematology, biochemistry, urinalysis, and 
vital signs conducted at each post-randomization 
visit and the physical examination and ECG 
assessments conducted after 28 weeks of 
randomized treatment, and their changes from 
baseline, will be summarized by treatment arm. 
1 This description aligns with the International Council for Harmonization (ICH) E9 requirement for the 
definition of an Estimand. 
Outcome variables are underlined 
Note: The reference range for A4 is up to 150 ng/dL (5.2 nmol/L) for men and up to 200 ng/dL (7.0 nmol/L) for 
women (based on the luteal phase) (based on data from The Mayo Clinic). 
The optimal range for 17-OHP in adults (post-pubertal males or females aged >16 years) is up to 1200 ng/dL 
(36.4 nmol/L). 


 
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4. 
Study Design 
4.1. 
Overall Design 
This study is a randomized, double-blind, active-controlled, titrated, parallel arm, multicenter 
study. It will compare the efficacy, safety and tolerability of twice daily Chronocort with 
twice daily IRHC over a randomized treatment period of up to 28 weeks in participants aged 
16 years and over with known classic CAH due to 21-hydroxylase deficiency. The primary 
efficacy assessment of biochemical responder rate and the key secondary assessments of dose 
responder rate and mean total daily dose will be assessed after 28 weeks of randomized 
treatment. 
Participants will attend a screening visit 4 weeks prior to the baseline visit. Participants will 
be asked to take their usual medication at the usual times up until the screening visit, with 
details of the dosing regimen and the timing of doses of CAH medication recorded 
throughout the screening visit and for the previous 24 hours. At this screening visit, informed 
consent/assent will be obtained and then the screening assessments will be conducted. 
Participants will then be switched to 20 mg IRHC in the morning on waking (typically 
between 06:00 and 08:00 hours) and 10 mg in the afternoon (between 15:00 and 17:00 hours) 
for the next 4 weeks as run-in therapy. This total daily dose is based on the guidelines for 
adrenal replacement, where the recommended dose is between 15 and 25 mg, plus an 
acknowledgement that patients with CAH may need a higher dose [Speiser et al. 2018]. This 
total daily dose was safely used in the Chronocort Phase 2 and 3 studies and equates to the 
dose used in large cohort studies [Arlt et al, 2010; Finkielstain et al, 2012]. 
After 4 weeks on this run-in therapy, participants will attend a baseline visit for all the 
baseline assessments. If at the end of the 4-week run-in period there are persistent signs of 
adrenal insufficiency, or the participant does not tolerate treatment, then they should be 
withdrawn from the study before randomization. Assessment of baseline androgen levels 
(17-OHP and A4) will be made at 08:00 hours before the morning dose of IRHC and at 
13:00 hours, with a window of ±30 minutes allowed around each sampling timepoint. These 
baseline adrenal androgens will be analyzed by the central laboratory and participants with 
17-OHP equal to or below the upper limit for optimal control at 08:00 hours and A4 equal to 
or below the upper limit of the reference range at 08:00 hours will be classified as ‘in 
biochemical control’. If the measurements are outside these criteria the participant will be 
classified as ‘not in biochemical control’. Once eligibility for the study is confirmed, the 
Investigator will randomize the participants on a 1:1 basis (Chronocort:IRHC) using an 
interactive response technology (IRT) system, with randomization being stratified within 
each treatment arm based on fludrocortisone replacement status (requires fludrocortisone or 
does not require fludrocortisone). Note: the results of the baseline androgen tests are NOT 
needed prior to the participant being randomized to the study.  
Participants randomized to Chronocort will change to a dosing regimen of 10 mg in the 
morning on waking (typically between 06:00 and 08:00 hours) and 20 mg at night just prior 
to going to bed (typically between 22:00 hours and midnight). Participants randomized to 
IRHC will continue the same dosing regimen as they were receiving during the run-in period 
(20 mg in the morning on waking [typically between 06:00 and 08:00 hours] and 10 mg in 
the afternoon [between 15:00 and 17:00 hours]). The time of the first dose of randomized 
medication on Day 1 will be recorded in an electronic participant diary. 


 
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Participants will return to the study site for titration visits at 4, 10 and 16 weeks after 
randomization, with androgen levels assessed at each of these visits at 08:00 hours (before 
the morning dose of study medication) and 13:00 hours (±30 minutes). At each of these 
3 visits dose reductions (in 5 mg steps at each visit) can be conducted if required, based on 
androgen results and adrenal insufficiency symptoms collected using the adrenal 
insufficiency checklist. The decision to change doses in both treatment groups will be made 
by an independent blinded physician and the appropriate investigational medicinal product 
(IMP) packs will be sent to the participant, either to collect from their local study site or sent 
directly to the participant’s home. The treatment packs for each participant will always 
contain the same number of capsules as the previous supplies (with placebo capsules masking 
any changes) to maintain the blinding and to ensure the participant is not aware of any dose 
changes. 
Once the titration visit at 16 weeks is complete and the dose adjusted, if necessary, the dose 
of study medication will then be fixed and should remain unchanged until the end of study 
(EOS) visit (up to 12 weeks of fixed dose treatment) if possible. The last dose of study 
medication will be taken in the morning of the last dosing day. 
The analysis of all 17-OHP and A4 levels will be conducted by a central laboratory and the 
results will be sent to an independent blinded physician, with the independent blinded 
physician being unaware of the participant’s treatment allocation. The Investigator will also 
complete an adrenal insufficiency checklist at each visit which will be made available to the 
independent blinded physician. If at the titration visits at Weeks 4, 10, and 16 the independent 
blinded physician considers a dose reduction is necessary, the dose should be reduced by a 
total of 5 mg at each titration visit. Each treatment arm will be subject to the same titration 
rules throughout the study, ensuring that opportunities for optimization and control of 
androgens are the same in both arms and thus minimizing bias in the management of 
participants. At the titration visits at Weeks 4, 10, and 16, only dose reductions are permitted, 
unless the dose has previously been reduced, in which case it can be reverted back to the 
previous higher dose if needed without having to wait until the next titration point. Dose 
increases can only be made in an urgent situation where the Investigator believes the 
participant is exhibiting signs of adrenal insufficiency, and in all cases, this should be 
discussed with the medical monitor before a dose increase is initiated (see Section 4.2 for 
further details). 
The EOS visit will be conducted 28 weeks after randomization or at early withdrawal from 
the study. The total study duration is up to 40 weeks (screening period up to 4 weeks prior to 
screening visit, 4 weeks run-in period on IRHC up to the baseline visit, 16 weeks dose 
titration on randomized treatment, 12 weeks fixed dose period on randomized treatment, and 
follow-up phone call 4 weeks/30 days after the EOS visit). In some cases (e.g. if the 
participant lives a long way from the study site, or if pandemic guidelines dictate) study visits 
3 and 4 may be performed as domiciliary visits and IMP shipments can be made directly to 
the participant’s home. However, the following visits must be performed at the study site: 
Screening (Visit 1), Baseline (Visit 2), Week 16 (Visit 5), and EOS/early withdrawal visit 
(Visit 6). If necessary in some cases, IMP at Visit 5 can also be delivered to the participant's 
home. If a domiciliary visit is conducted the safety and endocrine blood samples must be sent 
to the central laboratory for analysis and the Investigator must complete the adrenal 
insufficiency checklist. The assessment of hirsutism and acne can be conducted via a video 


 
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call (within ±2 days of the domiciliary visit). If androgen samples are analyzed locally for 
safety reasons the participant must be withdrawn from treatment. 
At the end of the study, participants who have completed the study will be offered the option 
of continuing in a long-term safety study (DIUR-015) where all participants will receive 
Chronocort treatment or they will be offered commercial supplies of Chronocort (the options 
will be dependent on territory), or the participant can return to the standard treatment they 
were receiving before entry into this study (see Section 6.7). For participants who agree to 
enter the long-term safety study DIUR-015, the EOS visit (Visit 6) will be their last 
assessment in this study. Participants who decide not to enter the long-term safety study or 
who withdrew from the study early will receive a telephone call 30 days after the last study 
visit to ask about any AEs that were ongoing and any new serious adverse events (SAEs) that 
could be related to the study medication. This telephone call will be considered the last 
assessment for these participants, although ongoing SAEs will be followed until resolution or 
stabilization, the event is otherwise explained, or the participant is lost to follow-up.  
An independent DSMB will meet on a regular basis during the study to review the safety data 
and will operate in accordance with a pre-defined charter (see Section 9.6). 
4.2. 
Titration Rules 
The aim of titration is to establish participants on the lowest dose of glucocorticoid which 
will provide adequate adrenal replacement and control androgens. At each titration visit 
during the titration period, adrenal insufficiency symptoms will be collected using the adrenal 
insufficiency checklist (Appendix 5) and androgen results will be assessed at 08:00 and 13:00 
hours. The adrenal insufficiency checklist should only be used to determine if symptoms of 
under- or over-replacement of glucocorticoids have occurred since the last visit and this 
questionnaire should not be used to record AEs due to other causes. The analysis of all 
17-OHP and A4 levels will be conducted by a central laboratory and the results will be sent 
to an independent blinded physician, with the independent blinded physician being unaware 
of the participant’s treatment allocation. The independent blinded physician will decide if the 
dose should be maintained or if a dose reduction is needed and the appropriate packs will be 
sent to the participant, either to collect from their local study site or sent directly to the 
participant’s home. The treatment packs for each participant will always contain the same 
number of capsules as the previous supplies (with placebo capsules masking any changes), 
thus ensuring the participant is not aware of any dose changes.  
If the independent blinded physician considers a dose reduction is necessary, a maximum 
dose reduction of 5 mg is allowed at each titration visit at Weeks 4, 10, and 16. The 
independent blinded physician will inform the IRT system of the recommended dose changes 
or that the dose does not need to be changed, which will then inform the pharmacist which 
IMP packs to dispense based on previous titrations according to the titration rules. The total 
daily dose must not exceed 30 mg and the afternoon IRHC dose must not exceed 10 mg at 
any point. 
For all dose reductions, the results from the 08:00 hours androgen sample will be used to 
guide adjustment of the Chronocort night-time dose and IRHC morning dose, and the 
13:00 hours androgen sample will be used to guide adjustment of the Chronocort morning 
dose and the IRHC afternoon dose. If 17-OHP is <300 ng/dL (the upper limit of the reference 
range) and A4 is <150 ng/dL for males and <200 ng/dL for females (sex-specific upper limit 


 
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of the reference range), then the dose will be adjusted down by a total of 5 mg. If one or both 
androgen results are above these limits, then no titration will be undertaken. Clinical 
symptoms of adrenal insufficiency on the adrenal insufficiency checklist should take 
precedence over androgen results and would inhibit titration. Only 1 of the 2 doses a 
participant receives (i.e. morning or afternoon/evening) should be titrated at each titration 
point but no dose should be reduced below 5 mg. If the androgen results indicate that both 
doses should be reduced, then precedence should be given to reducing the morning dose of 
Chronocort and the afternoon dose of IRHC. If the same situation then recurs at the next 
titration timepoint then the dose reduced should be alternated to avoid a mismatch of dosing. 
Each treatment arm will be subject to the same titration rules throughout the study, ensuring 
that opportunities for optimization and control of androgens are the same in both arms and 
thus minimizing bias in the management of participants. These androgen precursor limits 
have been defined based on data from previous studies in the clinical development program. 
If a participant shows persistent signs of under-replacement on the randomized starting dose 
of 30 mg Chronocort or IRHC they will be monitored and if symptoms do not resolve the 
participant should be withdrawn from treatment and given alternative therapy at the 
Investigator’s discretion. If a participant shows persistent signs of under-replacement during 
the titration period and the participant has received at least 1 down titration of 5 mg, a 
reversion to the previous dose is permitted (i.e. an increase of 5 mg) after discussion with the 
medical monitor. If symptoms persist, no further dose increases can be made, and the 
participant should be withdrawn from study treatment (such cases should be discussed with 
the medical monitor). If the Investigator thinks that the dose needs to be adjusted between 
visits, they should contact the medical monitor to discuss the case. For emergency situations, 
the emergency treatment pack can be used, and the medical monitor should be contacted as 
soon as possible. 
Any dose titrations should be made within 2 to 3 weeks of the visit (dependent on the 
laboratory turnaround time of androgen samples, the time needed by the independent blinded 
physician to evaluate the data, and for new supplies to be provided to the participant). At each 
delivery of new supplies to the participant, all the old supplies will be collected to ensure that 
the participant cannot take the wrong medication. All participants will receive a telephone 
call 1 week after they have received the new treatment packs to enquire as to whether there 
have been any AEs and reinforce any other protocol requirements. 
4.3. 
Stress Dosing Rules 
All participants will be supplied with ‘stress dosing rules’ and an emergency treatment pack 
for use during intercurrent illness, as medically indicated. Participants should attend each 
visit only if they have been taking the study medication alone for the previous 5 days 
(i.e. ’stress dosing rules’ have not been applied in the 5 days preceding the visit date). If 
‘stress dosing rules’ have been applied in the previous 5 days, then the study visit should be 
delayed until the participant has a 5-day period of normal dosing. 
4.4. 
Scientific Rationale for Study Design 
Study Design 
A previous Phase 2 study (a 2-part, single cohort, open-label, multiple dose protocol 
[DIUR-003]) demonstrated that Chronocort, when given as a twice daily regimen to 


 
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participants with CAH, enabled physiological replacement of cortisol that resulted in 
improved control of androgen precursors (17-OHP and A4) without increasing glucocorticoid 
exposure [Mallappa et al, 2015]. Chronocort, in contrast to IRHC, provided the physiological 
cortisol rise overnight thus improving the morning androgen control in CAH using an adrenal 
replacement dose of hydrocortisone. The designs used in study DIUR-005 (a Phase 3 study of 
efficacy, safety and tolerability of Chronocort compared with standard glucocorticoid 
replacement therapy in the treatment of CAH) and in study DIUR-006 (a Phase 3 open-label 
extension study for participants who were enrolled in studies DIUR-003 and DIUR-005), 
have also been taken into consideration in the design of this new study. The Sponsor has 
undertaken a prolonged period of consultation with the Food and Drug Administration (FDA) 
to obtain advice and this advice has also been incorporated into this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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Twice daily Chronocort will be compared to twice daily IRHC since hydrocortisone is the 
first line recommended glucocorticoid replacement for patients with adrenal insufficiency and 
CAH. Dosing times used in studies DIUR-003, DIUR-005 and DIUR-006 are continued for 
this present study. A double-blind technique has been used to minimize bias that may be 
present using an open-label design and over-encapsulation of both IMPs will be used to 
maintain the blinding. 
Randomization to either Chronocort or IRHC will be stratified within each treatment arm 
based on fludrocortisone replacement status (requires fludrocortisone or does not require 
fludrocortisone).  
Dose adjustment will be allowed at 3 titration visits to optimize control of CAH based on the 
participant symptoms (as documented by the Investigator in the adrenal insufficiency 
checklist) as well as by measurement of androgens as is currently recommended for clinical 
practice, with one subsequent visit to allow correction in any participant who may have been 
excessively down-titrated or for safety reasons. The decision whether to adjust the dose will 
be made by an independent blinded physician who will remain blinded to the participant’s 
treatment assignment. 
Androgens 
The challenge in managing CAH is controlling the overnight and early morning rise in 
adrenal androgens using replacement doses of hydrocortisone [Han et al, 2014]. Daytime 
dosing controls adrenal androgens in CAH during the day, especially in the afternoon, but 
excess androgens are generated before waking. This morning peak often necessitates a higher 
dose of steroid to achieve control by the mid to late morning and dosing of immediate-release 
glucocorticoids at night when cortisol levels in healthy individuals are low. The expected 
benefit of Chronocort is in preventing the overnight rise in adrenal androgens before morning 
dosing, leading to a normalized level and profile of the androgen precursors 17-OHP and A4 
which are relatively constant throughout the 24 hours with little circadian variability in 
individuals without CAH. The earliest practical sampling in the clinic is at 08:00 hours and 
therefore sampling will be undertaken at 08:00 hours before the morning dosing of 
Chronocort or IRHC. Timed sampling is recommended in the Endocrine Society guidelines, 
and although the timing of samples is not universal amongst endocrinologists, a pre-dose 
early morning sample is a recognized and established practice. Diurnal anticipates that this 
sampling practice might then inform the Chronocort label and become an established 
universal monitoring practice. 


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Although there is no consensus on when to measure androgen levels, it is recommended to 
measure levels both before and after treatment [Merke and Bornstein, 2005; Merke, 2008], 
with the optimal time to measure adrenal androgens on treatment considered to be in the early 
morning and during the afternoon [Debono et al, 2015]. Androgens were measured using 
24-hour profiling in a tightly controlled inpatient environment in studies DIUR-003 and
DIUR-005, but this study is designed to broadly reflect real-life clinical practice and so blood
samples for androgen assessment will be taken at more practical times of 08:00 and
13:00 hours, as has been done in the ongoing study DIUR-006. The timing of these samples
was considered to reflect the expected time of effect of administered doses of glucocorticoid
and would provide a good overview of daily control of adrenal androgens. The analysis of all
scheduled 17-OHP and A4 levels will be conducted by a central laboratory to ensure
consistency in the results.
The decision to use both 17-OHP and A4 in the primary endpoint of biochemical responder 
rates is based on the fact that in CAH patients, elevated 17-OHP and A4 are considered 
diagnostic, are widely used in monitoring therapy, and play a central role in driving excess 
adrenal androgens. Only the upper limit of the optimal range for 17-OHP has been included 
in the study for assessing biochemical control, rather than the reference range. With current 
standard of care for CAH, dosing glucocorticoid therapy with the goal of controlling 17-OHP 
reference range risks excess glucocorticoid therapy [Speiser et al, 2018], and clinicians who 
manage these patients use an "optimal range" for 17-OHP to define disease control [Arlt et al, 
2010; Finkielstain et al, 2012]. The upper limit for the optimal range for 17-OHP in adults 
(post-pubertal males or females aged >16 years) is <1200 ng/dL (36.4 nmol/L). 17-OHP 
levels vary little in healthy individuals during 24 hours [Ghizzoni et al, 1994], and many 
laboratories (e.g. The Mayo Clinic) do not quote a lower bound of the reference range. The 
challenge in CAH with current therapy is keeping the 17-OHP below the upper limit of the 
optimal range before morning dosing on an adrenal replacement dose of hydrocortisone since 
current therapies, even when given in reverse circadian pattern, fail to control the early 
morning ACTH-driven surge in adrenal androgens. In the DIUR-006 study of Chronocort, 
80% of patients had a morning 17-OHP less than the upper limit of the optimal range on a 
median hydrocortisone dose of 20 mg and therefore the dose would not be reduced as this 
would risk giving inadequate adrenal replacement therapy. 
Interest has been expressed by endocrinologists in using 11-keto androgens as biomarkers for 
monitoring disease, and there are both published [Jones et al, 2017] and unpublished data 
suggesting that Chronocort can control these markers more effectively than standard 
therapies. However, there is as yet no universally recognized and validated 11-keto-steroid 
biomarker and so one of these biomarkers (11-ketotestosterone) is included as an exploratory 
endpoint. 
Endpoints 
The goal of therapy in CAH is to reduce excessive androgen secretion by replacing the 
deficient glucocorticoid hormones [Speiser et al, 2010]. This study will achieve this goal by 
close monitoring of adrenal androgens (17-OHP and A4) and modifying the glucocorticoid 
dose in the light of biochemical control and clinical signs and symptoms of the adequacy of 
glucocorticoid replacement.  
A participant is a dose responder if their dose after 28 weeks of randomized treatment is less 
than the starting dose of 30 mg/day, provided they are in biochemical control at that time. All 


 
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dose responders are biochemical responders: additionally, participants who were out of 
biochemical control at baseline but are in biochemical control after 28 weeks of randomized 
treatment are also biochemical responders, provided their dose at that time is not higher than 
the starting dose of 30 mg/day.  
The primary efficacy analysis will be to compare Chronocort to IRHC in terms of 
biochemical responder rate after 28 weeks of randomized treatment. The first key secondary 
efficacy analysis will be to compare Chronocort to IRHC in terms of dose responder rate after 
28 weeks of randomized treatment. The second key secondary efficacy analysis will be to 
compare Chronocort to IRHC in terms of total daily dose after 28 weeks of randomized 
treatment.   
In addition, clinical endpoints will be assessed over the course of the study to evaluate the 
impact on participants’ QoL and other clinical consequences of CAH.  
 
 
 
 
 
 
 
 
 
 
 
Subject reported outcomes were used in studies DIUR-003, DIUR-005 and DIUR-006, and 
these have also been included in this study.  
4.5. 
Justification for Dose 
The recommended hydrocortisone dose in adults for adrenal insufficiency is 15 to 25 mg 
given twice daily in the morning on waking and early afternoon [Bornstein et al, 2016]. 
Although this is the guideline dose range for adrenal insufficiency, it is recognized that many 
patients with CAH require a higher dose [Speiser et al, 2018]. In the Phase 3 study 
DIUR-005, participants were titrated in a blinded manner to a final dose on both Chronocort 
and standard treatment of approximately 30 mg a day (15.8 and 17.0 mg/m2/day, 
respectively) and this is a similar dose to that reported in published studies in patients with 
CAH of 15 to 18 mg/m2/day [Chakhtoura et al, 2008; Arlt et al, 2010; Schnaider-Rezek et al, 
2011; Finkielstain et al, 2012]. This dose then reflects real world patient care and additionally 
provides a dose where patients are not at risk of adrenal crisis. In addition, in the Phase 2 
study DIUR-003, Chronocort patients were safely transferred from standard therapy to a dose 
of 30 mg hydrocortisone and then down-titrated with no ill effects [Mallappa et al, 2015].  
Participants in this study will receive IRHC 30 mg a day for 4 weeks during the run-in period 
and will then be randomized to either stay on this therapy or switch to Chronocort 30 mg a 
day. If a participant shows persistent signs of under-replacement during the run-in period they 
must be withdrawn from the study. After 4 weeks of randomized treatment, a maximum of 
3 down titrations of 5 mg will be allowed, so potentially reaching a minimum final dose of 


 
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15 mg a day, consistent with the lower range boundary of the recommended adrenal 
insufficiency dose. If a participant shows persistent signs of under-replacement during the 
titration period and has received at least 1 down titration of 5 mg, a reversion to the previous 
dose is permitted (i.e. an increase of 5 mg). If symptoms persist at a dose of 30 mg, no further 
dose increases can be made, and the participant should be withdrawn from study treatment 
(but will remain in the study and followed for safety assessments). 
4.6. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all study 
visits up to the EOS visit (Visit 6). If the participant enters the long-term safety study 
DIUR-015, no further data are collected in this study. If the participant does not enter the 
long-term safety study (DIUR-015), a final telephone call will be made 30 days after Visit 6 
to ask about any AEs that were ongoing at Visit 6 and any new SAEs that could be related to 
the study medication.  
The end of the whole study is defined as the date of the last study visit or telephone call of the 
last participant (i.e. last participant last visit [LPLV]).  


 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply 
(note: if a participant fails to meet an inclusion criterion, re-screening is permitted if the 
Investigator considers that the circumstances leading to screening failure will not be relevant 
when the participant is re-screened at a later time): 
Age 
1. Participant must be aged 16 years or older at the time of signing the informed 
consent/assent. 
2. In participants aged <18 years, height velocity must be less than 2 cm/year in the last 
year and puberty must be completed (Tanner stage V). 
Type of Participant and Disease Characteristics 
3. Participants with known classic CAH due to 21-hydroxylase deficiency diagnosed in 
childhood with documented (at any time) elevated 17-OHP and with or without 
elevated A4 and currently treated with hydrocortisone, prednisone, prednisolone or 
dexamethasone (or a combination of the aforementioned glucocorticoids) and on 
stable glucocorticoid therapy for a minimum of 3 months. 
4. Participants who are receiving fludrocortisone must be on a documented stable dose 
for a minimum of 3 months prior to enrollment and must have stable renin levels at 
screening. 
Sex 
5. Male and female participants. 
Female participants of childbearing potential and all male participants must agree to 
the use of an accepted method of contraception during the study. 
A female participant is eligible to participate if she is not pregnant 
(Appendix 4), not breastfeeding, and at least one of the following conditions 
applies: 
 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. 
OR 
A WOCBP with a negative pregnancy test at entry into the study.  
 
Note: females presenting with oligomenorrhea or amenorrhea who are aged 
≤55 years should be considered potentially fertile and therefore should 
undergo pregnancy testing like all other female participants. 


 
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Informed Consent/Assent 
6. Capable of giving signed informed consent/assent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply (note: if a 
participant meets an exclusion criterion, re-screening is permitted if the Investigator considers 
that the circumstances leading to screening failure will not be relevant when the participant is 
re-screened at a later time): 
Medical Conditions 
1. Clinical or biochemical evidence of hepatic or renal disease e.g., creatinine >2 times 
the upper limit of normal (ULN) or elevated liver function tests (alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] >2 times the ULN). 
2. History of bilateral adrenalectomy. 
3. History of malignancy (other than basal cell carcinoma successfully treated 
>26 weeks prior to entry into the study). 
4. Participants who have type 1 diabetes, receive regular insulin, have uncontrolled 
diabetes, or have a screening HbA1c greater than 8%. 
5. Persistent signs of adrenal insufficiency or the participant does not tolerate treatment 
at the end of the 4-week run-in period. 
6. Participants with any other significant medical or psychiatric conditions that in the 
opinion of the Investigator would preclude participation in the study. 
Prior/Concomitant Therapy 
7. Participants on regular daily inhaled, topical, nasal or oral steroids for any indication 
other than CAH.  
8. Co-morbid condition requiring daily administration of a medication or consumption 
of any material that interferes with the metabolism of glucocorticoids (examples 
provided at http://medicine.iupui.edu/clinpharm/ddis/clinical-table/). 
9. Participants who are receiving <10 mg hydrocortisone dose at screening or the 
hydrocortisone dose equivalent. 
10. Participants anticipating regular prophylactic use of additional steroids e.g. for 
strenuous exercise. 
Prior/Concurrent Clinical Study Experience 
11. Participation in another clinical study of an investigational or licensed drug or device 
within the 12 weeks prior to screening. 
12. Inclusion in any natural history or translational research study that would require 
evaluation of androgen levels during the study period outside of this protocol’s 
assessments. 
13. Participants who have previously been exposed to Chronocort in any Diurnal study. 


 
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Other Exclusions 
14. Participants who routinely work night shifts and so do not sleep during the usual 
night-time hours.  
15. Participants, who in the opinion of the Investigator, will be unable to comply with the 
requirements of the protocol. 
16. Participants with a known hypersensitivity to any of the components of the 
Chronocort capsules, the Cortef tablets, or the placebo capsules (see Section 6.1). 
17. Participants with congenital galactosemia, malabsorption of glucose and galactose, or 
who are lactase deficient. 
18. Participants with a body weight of 45 kg or less. 
5.3. 
Lifestyle Considerations 
• All participants will take study medication (or matching placebo) 3 times a day 
(morning, afternoon, and evening). The study medication should be taken in the 
morning on waking (typically between 06:00 and 08:00 hours), in the afternoon 
(between 15:00 and 17:00 hours), and just prior to going to bed (typically between 
22:00 hours and midnight).  
• When attending a clinic visit, participants should not eat any food prior to the 
08:00 hour blood sampling timepoint.  
• Male participants should not take multivitamins or dietary supplements containing 
biotin or vitamin B7 for 12 hours prior to each visit (to avoid interference with LH 
test results).  
• Male participants should not ejaculate for 3 days prior to Visits 2 and 6 when sperm 
counts will be assessed (note: sperm count conducted at home only in participants 
who agree to this assessment). 
• Participants should not take regular additional prophylactic steroids e.g. for strenuous 
exercise. 
• Participants should not have their androgen levels assessed outside of the study visits 
during this study (including the use of home assessment kits). 
• Participants are requested not to reveal details of the study on social media. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered into the IRHC run-in period. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs. 
If a participant fails to meet the screening criteria, re-screening of any inclusion/exclusion 
criteria is permitted if the Investigator considers that the circumstances leading to failure will 
not be relevant when the participant is re-screened at a later time. Re-screened participants 
should be assigned the same participant number as they were assigned during their initial 
screening visit. 
 


 
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6. 
Study Treatment 
Study treatment is defined as any investigational intervention, marketed product, placebo, or 
medical device intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Treatments Administered 
The IMPs for this study are Chronocort and IRHC (Cortef). All participants will receive 
4 weeks run-in with 30 mg IRHC (20 mg in the morning on waking [typically between 06:00 
and 08:00 hours] and 10 mg in the afternoon [between 15:00 and 17:00 hours]). At the end of 
the 4-week run-in period, participants will be randomized to either Chronocort or to continue 
with IRHC treatment. The last dose of study medication will be taken in the morning of the 
last dosing day. 
Arm name: 
Chronocort 
IRHC 
Placebo 
Treatment name: 
Chronocort 
Cortef 
Placebo 
Type: 
Drug 
Drug 
Placebo 
Dosage formulation: 
Hydrocortisone modified-
release capsule 
Hydrocortisone 
immediate-release tablet 
Placebo capsule 
Unit dose strengths: 
5 mg and 10 mg.  
5 mg presented in white 
opaque body/blue opaque 
cap size 1 hard gelatin 
capsules, printed with 
‘CHC 5 mg’ on the 
capsule body.  
10 mg presented in white 
opaque body/green 
opaque cap size 1 hard 
gelatin capsules, printed 
with ‘CHC 10 mg’ on the 
capsule body. 
5 mg and 10 mg. 
5 mg presented as white 
tablet with CORTEF 5 
printed on one side. 
10 mg presented as white 
tablet with CORTEF 10 
printed on one side.  
Swedish Orange capsule 
shells filled with inert 
excipient. 
Dosage levels: 
Starting dose of 30 mg 
with 3 possible 5 mg dose 
reductions to a minimum 
dose of 15 mg 
Starting dose of 30 mg 
with 3 possible 5 mg dose 
reductions to a minimum 
dose of 15 mg 
Adapted to match dose of 
IMP dosing 
Route of 
Administration:  
Oral 
Oral 
Oral 
Use: 
Experimental 
Active comparator 
Placebo 
IMP:  
IMP 
Comparator 
Placebo 
Dosing instructions: 
 
10 mg in the morning on 
waking (typically 
between 06:00 and 08:00 
hours) and 20 mg at night 
just prior to bed (typically 
between 22:00 hours and 
midnight) then titrated as 
per protocol. All doses 
taken with a small drink 
of water.  
20 mg in the morning on 
waking (typically 
between 06:00 and 08:00 
hours) and 10 mg in the 
afternoon (between 15:00 
hours and 17:00 hours) 
then titrated as per 
protocol. All doses taken 
with a small drink of 
water. 
Adapted to match dose of 
Chronocort and Cortef. 
All doses taken with a 
small drink of water.  
Sourcing: 
Provided centrally by the 
Sponsor  
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor  
Manufacturer: 
Diurnal 
Pfizer 
Diurnal 


 
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Packaging and 
Labelling: 
 
Both dose strengths 
over-encapsulated with 
Swedish Orange capsule 
shells. All supplies will 
be labelled in accordance 
with local requirements. 
Both dose strengths 
over-encapsulated with 
Swedish Orange capsule 
shells and back-filled 
with inert excipient. All 
supplies will be labelled 
in accordance with local 
requirements. 
Placebo provided as 
Swedish Orange capsule 
shells filled with inert 
excipient. All supplies 
will be labelled in 
accordance with local 
requirements 
IMP=investigational medical product 
The active ingredients and excipients are shown below: 
 
Chronocort 
Placebo  
Cortef 
Active ingredient 
Active ingredient: hydrocortisone  
Active ingredient: none 
Active ingredient: hydrocortisone 
Excipients 
Microcrystalline cellulose 
Povidone 
Methacrylic acid-methyl 
methacrylate copolymer (1:2) 
Methacrylic acid-methyl 
methacrylate copolymer (1:1) 
Talc 
Dibutyl sebacate 
Microcrystalline cellulose  
Calcium stearate 
Corn starch 
Lactose 
Mineral oil 
Sorbic acid 
Sucrose 
Capsule 
Capsule 
Tablet Coating 
Gelatin 
5 mg: 
Titanium dioxide (E171) 
Indigotine (E132) 
10 mg: 
Titanium dioxide (E171) 
Indigotine (E132) 
Yellow iron oxide (E172)  
Printing ink:  
Shellac 
Black iron oxide (E172) 
Propylene glycol 
Potassium hydroxide 
Gelatin 
5 mg: 
Titanium dioxide (E171) 
Indigotine (E132) 
10 mg: 
Titanium dioxide (E171) 
Indigotine (E132) 
Yellow iron oxide (E172)  
Printing ink:  
Shellac 
Black iron oxide (E172) 
Propylene glycol 
Potassium hydroxide 
None 
Over-encapsulating Swedish Orange capsule shells 
Red Iron Oxide (E172) 
Red Iron Oxide (E172) 
Red Iron Oxide (E172) 
Titanium Dioxide (E171) 
Titanium Dioxide (E171) 
Titanium Dioxide (E171) 
Gelatin (Bovine) 
Gelatin (Bovine) 
Gelatin (Bovine) 
 
6.1.1. 
Rescue Medication 
Medication to be used when the ‘stress dosing rules’ are implemented will be supplied by the 
study site as part of an emergency treatment pack. The contents will typically include 
(according to local practice): 
• 
A one-week supply of 10 mg oral hydrocortisone tablets (to allow rescue medication 
doses of up to 60 mg daily on top of the dose of IMP)  
• 
Hydrocortisone for injection plus syringes and needles (to be given on top of the dose 
of IMP) 


 
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• 
The standard information guidance regarding ‘stress dosing rules’. 
Diurnal will provide appropriate labels for the emergency treatment pack that can be used to 
label the drugs dispensed to participants (see Appendix 6). The participant number must be 
written on the emergency treatment pack label.  
Participants will continue to take their usual study medication when taking emergency 
treatment pack medications. Any additional doses of hydrocortisone needed should only be 
taken from the emergency treatment pack and should not be taken from the study medication 
pack or any other supplies the participant may have at home. Use of the emergency treatment 
pack medications does not require authorization but should be recorded in the electronic 
participant diary that is provided to each participant. 
6.2. 
Preparation/Handling/Storage/Accountability 
The pharmacist or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported 
and resolved before use of the study treatments. Only participants enrolled in the study may 
receive study treatment and only authorized staff may supply or administer study treatment. 
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled storage conditions with access 
limited to the pharmacy staff. The pharmacist is responsible for study treatment 
accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation, and final 
disposition records) of supplies. 
At each visit, the independent blinded physician will decide if a dose adjustment is needed 
and the appropriate IMP packs will be sent to the participant, either to collect from their local 
study site or sent directly to the participant’s home (note: the changes will also include the 
relevant changes to the placebo capsules to maintain the blinding). At the same time, the 
participant’s current supplies will be collected for accountability purposes and to ensure that 
the participant cannot take the wrong medication. The returns pharmacy will count the 
number of returned capsules and enter the information in the IRT, so compliance can be 
calculated. Following Sponsor’s approval, all returned active and placebo capsules will either 
be returned to the supplier or destroyed on site. 
At each visit to the study site, the participants must return the stress dosing pack and 
accountability must be performed at each study visit. If the emergency treatment pack has 
been used this must be documented and reconciled with the reported AEs for that period. If 
the contents of the emergency treatment pack have not been used and the products remain 
with sufficient expiry date then it is acceptable for it to be returned to the participant (i.e. a 
new emergency treatment pack does not need to be issued). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blinded study with 2 treatment arms. The blinded treatment to be taken by a 
participant will be assigned using an IRT on a 1:1 basis (Chronocort:IRHC). Before the study 
is initiated, the login information and instructions for use of the IRT will be provided to each 
site. The randomization list will be generated by the study statistician using a computer-
generated central randomization list using balanced blocks. Randomization will be balanced 


 
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within site and stratified by the participant’s fludrocortisone replacement status (requires 
fludrocortisone or does not require fludrocortisone).  
Participants will be allocated an identifying number sequentially per site at the screening visit 
(Visit 1) in the following format: Study No.-Site No.-Screening No. (e.g. 
, 
etc. for site 1; 
 etc. for site 2). When the participant is 
randomized at the baseline visit (Visit 2), a separate randomization number will be allocated, 
which will be used internally for the purposes of treatment allocation and stratum 
identification. The screening number will still be used for participant identification purposes, 
so there may be gaps in participant ID numbers for screen failures. Randomization numbers 
will be assigned sequentially within each stratum as soon as participants fully satisfy all of 
the inclusion and none of the exclusion criteria. Screening and randomization numbers once 
assigned to a participant must not be re-assigned to another participant. Re-screened 
participants should be assigned the same participant number as they were assigned during 
their initial screening visit. 
Potential bias in this study will be reduced by the following steps:  
• Records will be kept of any participants screened, whether or not they enter the study. 
This will enable an assessment of the representative nature of the participants 
randomized. 
• Both study treatments will be over-encapsulated so that they look the same, so both 
the participant and the Investigator will not know which treatment group the 
participant has been randomized to. 
• The titration of each participant’s dose of study treatment will be the same in both 
arms and will be based on the adrenal insufficiency checklist and androgen sampling 
thus ensuring that opportunities for optimization and control of androgens are the 
same in both arms. 
• The dose titration decisions will be made by an independent blinded physician who 
will be unaware of the treatment allocation to each participant. 
• The treatment packs for each participant will be pre-packed and packs issued by the 
IRT to ensure that each participant receives the correct number of active and placebo 
capsules. After each visit, new supplies will be provided to the participant that contain 
the same number of capsules as the previous supplies (with placebo capsules masking 
any changes), regardless of whether the dose was titrated or not, thus ensuring the 
participant is not aware of any dose changes. 
• The primary endpoint is an objective biochemical measure that is not subject to bias. 
• Efforts will be made to ensure that all participants remain in the study and are 
evaluable.  
• There will be rigorous monitoring of sites to ensure compliance with all study 
procedures. 
• The statistical analysis plan (SAP) will be completed before screening of the first 
participant to the study. 
• Treatment will be allocated using block randomization. The block size will be 
determined by the statistician and will not be communicated to the study team. 
• To minimize bias whilst the study is ongoing, the study team will remain blinded to 
aggregated and individual data prior to database lock and any data reviews will use a 
dummy randomization list with generic labels. 


 
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• Participants and Investigators will be requested not to reveal details of the study on 
social media. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the medical monitor prior to unblinding a 
participant’s intervention assignment unless this could delay emergency treatment for the 
participant. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours of this occurrence. The date and reason for the unblinding must be 
recorded. 
6.4. 
Study Treatment Compliance 
At each delivery of new supplies to a participant, their current supplies will be collected for 
accountability purposes and to ensure that the participant cannot take the wrong medication. 
The research team will count the number of returned capsules and enter the information in the 
IRT, so compliance can be calculated.  
6.5. 
Concomitant Therapy 
Previous treatments for CAH (last 26 weeks) and any other previous treatments (last 4 weeks) 
will be recorded at the screening visit (Visit 1) in the eCRF. Any medication or vaccine 
(including over-the-counter or prescription medicines, vitamins, herbal supplements etc.) that 
the participant is receiving at the time of enrollment or receives during the study must be 
recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency. 
 
In particular, use of multivitamins or dietary supplements containing biotin or vitamin B7 in 
male participants should be recorded since their use is prohibited for 12 hours prior to each 
visit (to avoid interference with LH test results).  
If a participant has received the COVID-19 vaccine then the next visit must be scheduled at 
least 5 days post vaccine. If the participant experiences any side effects from the COVID-19 
vaccine then they should take additional stress doses in line with the “stress dosing rules” 
(see Appendix 6). If a stress dose is taken within 5 days of a visit (scheduled clinic visit or 
home assessment timepoint), then the visit should be delayed until the participant has had a 
5-day period without use of any stress dose. 
Participants will be instructed that no additional medication will be allowed without the prior 
consent of the Investigator. Any medication considered necessary for the participant’s safety 
and well-being may be given at the discretion of the Investigator but must be recorded in the 
eCRF. The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. Participants must not take part in another clinical study of an 
investigational or licensed drug or device within the 12 weeks prior to screening or during the 
course of this study. 


 
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Fludrocortisone treatment and dose adjustment will be allowed if medically indicated and 
will be based on blood pressure (BP) measurements and laboratory data (goal supine plasma 
renin activity [PRA] or plasma renin concentration [PRC] above the lower limit and <2 times 
ULN except in participants with known hypertension or who have a raised PRA or PRC for 
other reasons). 
Participants receiving insulin or who are on regular daily inhaled, topical, nasal or oral 
steroids for any indication other than CAH at entry to the study are excluded (Section 5.2). 
A participant should not be given any steroids (even on an irregular basis) within 5 days of a 
study visit. If there is a medical need for steroid treatment within this time-frame then the 
visit should be postponed until a 5-day interval has elapsed. 
6.5.1. 
Interactions With Other Medicinal Products and Other Forms of Interaction 
Hydrocortisone is metabolized by cytochrome P450 3A4 (CYP3A4). Concomitant 
administration of medicinal products that are inhibitors or inducers of CYP3A4 may therefore 
lead to unwanted alterations in serum concentrations of hydrocortisone with the risk of 
adverse reactions, particularly adrenal crisis. The need for dose adjustment when such 
medicinal products are used can be anticipated and should be considered at time of inclusion 
of a participant in the study. Participants should be closely monitored, although it should be 
noted that any dose changes should be conducted in line with the titration schedule and due to 
the blinded nature of the study, Investigators will not be able to individually adjust 
participant’s doses during the study. 
Medicinal products inducing CYP3A4, requiring a potential increase in Chronocort dosing, 
include but are not limited to: 
• Anticonvulsants: phenytoin, carbamazepine and oxcarbazepine 
• Antibiotics: rifampicin and rifabutin 
• Barbiturates including phenobarbital and primidone 
• Antiretroviral medicinal products: efavirenz and nevirapine 
• Herbal medicinal products such as St. John’s Wort 
Medicinal products/substances inhibiting CYP3A4, requiring a potential decrease in 
hydrocortisone dosing, include but are not limited to: 
• Anti-fungals: itraconazole, posaconazole, voriconazole 
• Antibiotics: erythromycin and clarithromycin 
• Antiretroviral medicinal products: ritonavir 
• Grapefruit juice 
• Liquorice 
The desired actions of hypoglycaemic medicinal products including insulin are antagonised 
by corticosteroids. 
6.6. 
Dose Modification 
Monitoring of the clinical response is necessary, and participants should be observed closely 
for signs that might require dose adjustment, including changes in clinical status resulting 
from remissions or exacerbations of the disease, changes in electrolytes particularly 
hypokalemia, individual responsiveness to the medicinal product, and the effect of stress (e.g. 


 
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surgery, infection, trauma). Concerns with an individual participant should be raised with the 
medical monitor as due to the blinded nature of the study, Investigators are not permitted to 
routinely adjust the dose during the study. As the treatment has a modified-release profile, 
blood tests are used to monitor clinical response by the independent blinded physician, with 
dose titrations being made after Visits 3, 4, and 5. Both treatment arms are subject to similar 
titration rules at each visit (see Section 4.2). The only dose titration permitted at the titration 
visits at Visits 3, 4, and 5 are a 5 mg decrease in dose, except if a participant shows persistent 
signs of under-replacement during the titration period and the participant has received at least 
1 down titration of 5 mg, in which case a reversion to the previous dose is permitted (i.e. an 
increase of 5 mg). If symptoms persist, no further dose increases can be made, and the 
participant should be withdrawn from study treatment (such cases should be discussed with 
the medical monitor). If the Investigator thinks that the dose needs to be adjusted between 
visits, they should contact the medical monitor to discuss the case. Any other dose increases 
can only be made in an urgent situation where the Investigator believes the participant is 
exhibiting signs of adrenal insufficiency, and in all cases, this should be discussed with the 
medical monitor before a dose increase is initiated. For emergency situations, the emergency 
treatment pack can be used, and the medical monitor should be contacted as soon as possible. 
6.7. 
Treatment after the End of the Study 
All participants who have completed the study will be offered commercial supplies of 
Chronocort or the option to enter an open-label extension study (to be conducted under a 
separate protocol DIUR-015). This will be dependent on territory. Participants discontinuing 
from the study will not be offered the option to enter the open-label extension study. 


 
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7. 
Discontinuation of Study Treatment and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Treatment 
Events that will result in discontinuation of study treatment include:  
• Inability to tolerate either study treatment secondary to perceived or observed side 
effects. 
• Pregnancy (not due to safety reasons but because pregnancy may interfere with the 
primary endpoint) 
• Any other changes to clinical signs or changes in laboratory values, physical status or 
AEs that could compromise the participant’s status if they were to continue with the 
study treatment or if the Investigator feels that it is not in the best interests of the 
participant. 
If a participant shows persistent signs of under-replacement on the starting dose of 30 mg 
Chronocort or IRHC they will be monitored and if symptoms do not resolve the participant 
should be withdrawn from study treatment. If a participant shows persistent signs of 
under-replacement during the titration period and has received at least 1 down titration of 
5 mg, a reversion to the previous dose is permitted (i.e. an increase of 5 mg) after discussion 
with the medical monitor. If symptoms persist, no further dose increases can be made, and the 
participant should be withdrawn from study treatment (such cases should be discussed with 
the medical monitor).  
If a participant discontinues study treatment, they should be placed onto the previous 
glucocorticoid treatment and dose they were receiving prior to entry into this study. They 
should complete as many of the assessments scheduled for Visit 6 as possible, preferably 
within 48 hours of stopping study treatment. In all cases except pregnancy (see Section 8.4.5 
for handling of any pregnancies) the participant should be kept in the study, if the participant 
consents to this, and all further safety assessments conducted in line with the protocol 
schedule (note: no efficacy endpoints will be collected once the assessments detailed for 
Visit 6 [early withdrawal] are completed). The date the participant discontinues study 
treatment and the reason for discontinuation will be recorded on the participant’s eCRF. 
Participants who have been randomized to study treatment and who discontinue from study 
treatment are not to be replaced. The handling of safety data collected after the participant has 
discontinued study treatment will be detailed in the SAP. 
Participants who discontinue study treatment are not eligible to enter the long-term extension 
study (DIUR-015), except in the case of pregnancy (see Section 8.4.5). 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request without stating 
a reason and without prejudice to further treatment, or may be withdrawn at any time at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons. 
Participants who become pregnant must be withdrawn from the study (see Section 8.4.5). 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. The 


 
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participant may also request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records. 
If at the baseline visit the participant has had persistent signs of adrenal insufficiency or they 
have not tolerated the 4-week run-in medication, they should be withdrawn from the study at 
this point before randomization. 
If a participant discontinues from the study prior to the last scheduled visit, all efforts should 
be made to perform the EOS assessments (as per Visit 6) at the point the participant 
withdraws from the study (at the latest within 48 hours of the last dose of study medication). 
In particular, the androgen measurements should be taken if possible. 
Participants who discontinue from the study are not eligible to enter the long-term extension 
study (DIUR-015) except in the case of pregnancy (see Section 8.4.5). 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions will be 
taken if a participant fails to return to the clinic for a required study visit: 
• 
The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study at the time of their last assessment, with a primary reason 
of lost to follow-up.  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1. 


 
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8. 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the Schedule of Activities (SoA) 
(Section 1.3). Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor and the medical 
monitor immediately upon occurrence or awareness to determine if the participant 
should continue or discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management 
(e.g. blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time-frame defined in the SoA (Section 1.3).  
• 
At any visit, if multiple assessments are being conducted, vital signs should be 
conducted before any blood tests, and blood samples for androgen testing and optional 
saliva samples for salivary steroid profile must be conducted prior to any dosing. All 
other assessments should be conducted between the 08:00 and 13:00 androgen 
sampling points, where possible.  
• 
If a visit has to be moved (e.g. due to use of ‘stress dosing rules’), the participant 
should return to their usual visit schedule as soon as possible (i.e. all subsequent visits 
should not be moved out as well). 
• 
In some cases (e.g. if the participant lives a long way from the study site or if 
pandemic guidelines dictate) study visits 3 and 4 may be performed as domiciliary 
visits and IMP shipments can be made directly to the participant’s home. However, 
the following visits must be performed at the study site: Screening (Visit 1), Baseline 
(Visit 2), Week 16 (Visit 5), and EOS/early withdrawal visit (Visit 6). If necessary in 
some cases, IMP at Visit 5 can also be delivered to the participant's home. If a 
domiciliary visit is conducted the safety and endocrine blood samples must be sent to 
the central laboratory for analysis and the Investigator must complete the adrenal 
insufficiency checklist. The assessment of hirsutism and acne can be conducted via a 
video call (within ±2 days of the domiciliary visit). If androgen samples are analyzed 
locally for safety reasons the participant must be withdrawn from treatment. 
• 
If a participant discontinues treatment early (see Section 7.1), the assessments 
scheduled for Visit 6 (end of treatment) should be conducted, if possible, preferably 
within 48 hours of stopping study treatment. The participant should be kept in the 
study, if the participant consents to this, and all further safety assessments conducted 
in line with the protocol schedule (note: no efficacy endpoints will be collected once 
the assessments detailed for Visit 6 [early withdrawal] are completed). 


 
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8.1. 
Study Visits 
8.1.1. 
Visit 1 (Screening Visit - Week -4) 
Four weeks prior to the baseline visit, participants will be requested to attend the study site 
for the screening visit (it is mandatory that this visit is conducted at the study site). Prior to 
the visit, the site staff should contact the participant to check that they have been receiving 
their usual CAH medication and ‘stress dosing rules’ have not been applied in the 5 days 
preceding the visit date. If the ‘stress dosing rules’ have been applied, then the visit should be 
postponed until the participant has been receiving their usual CAH medication for 5 days. 
The participant will be told to take their CAH medication at the usual times throughout the 
visit. The ICF should be given to the participant at least 24 hours before the screening visit, 
along with the Investigator’s contact details, so that each participant has sufficient time to 
read the information and ask any questions they may have. If necessary, at Visit 1 the ICF 
can be reviewed again with the participant and the participant given ample opportunity to ask 
any questions before they are asked to sign it. The ICF must be signed at or before Visit 1 and 
prior to any study related procedures. 
Minors will be assented, and parental consent sought in keeping with USA and EU laws and 
local Independent Ethics Committee (IEC) or Institutional Review Board (IRB) requirements. 
Minors will be re-consented on reaching the age of majority if still participating in the study 
at that time. 
The following assessments will be carried out and recorded at this visit:  
• All inclusion and exclusion criteria checked 
• Demographic data 
• Medical history taken (including menstrual history, menopausal status and oral 
contraception use in female participants) 
• Details on concomitant medications taken (CAH medication will be recorded 
separately from other concomitant medications) 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
• Height, weight, and waist circumference will be measured  
• Full physical examination 
• Vital signs (BP, heart rate [HR], respiratory rate and body temperature). BP to be 
recorded after the participant has been semi-supine for 10 minutes. 
• Urine sample for urinalysis  
• Blood samples will be taken for routine biochemistry and hematology  
• Sample taken for PRA or PRC, preferably after the participant has been supine for 
30 minutes 
• Blood sample taken for HbA1c 
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit.  
• Recording of any AEs since informed consent/assent was taken. 
• Blood sampling for measurement of androgen levels (17-OHP and A4)  
The participants will be told not to take their morning dose of IRHC before attending for the 
visit (the morning dose will be taken after the 08:00 hour androgen sample). The androgen 


 
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sampling will commence at 08:00 hours, with 1 other sample taken at 13:00 hours. These 
blood samples are to be taken within ±30 minutes of the stated timepoints, with the exact 
sampling times recorded in the eCRF. Half the sample will be sent to the central laboratory 
for analysis, with the remaining half initially retained at the site before being sent to the 
central laboratory and then on to the biobank for long-term storage and possible future 
research. Participants will then be switched to the run-in medication, which will comprise 
20 mg IRHC in the morning on waking (typically between 06:00 and 08:00 hours) and 10 mg 
in the afternoon (between 15:00 and 17:00 hours) for the next 4 weeks. Once the last blood 
sample has been taken at 13:00 hours and all other assessments have been completed, the 
participant will be allowed home, and instructed to take their first dose of run-in medication 
later that afternoon (between 15:00 and 17:00 hours). The participant will also be issued with 
an emergency treatment pack to be used in the event of illness and implementation of ‘stress 
dosing rules’ (Section 6.1.1). The participant will be asked to return to the clinic in 4 weeks’ 
time for the baseline visit (Visit 2). 
8.1.2. 
Visit 2 (Baseline Visit - Day 1: 4 Weeks After the Screening Visit) 
Prior to the visit, the site staff should contact the participant to check that ‘stress dosing rules’ 
have not been applied in the 5 days preceding the visit date. If ‘stress dosing rules’ have been 
applied, then the visit should be postponed until the participant has been receiving only the 
run-in IRHC medication for 5 days. It is mandatory that this visit is conducted at the study 
site. The participant will be instructed to bring any empty packaging and any unused run-in 
medication and the emergency treatment pack with them to the visit for accountability 
purposes (note: participants take unused study medication and emergency treatment pack 
back home with them to use until the dose titration decision is made and new study 
medication dispensed). The participants will be told not to take their morning dose of IRHC 
before attending for the visit (the morning dose will be taken after the 08:00 hour androgen 
sample and optional saliva sample [where applicable]). Male participants will be asked not to 
take multivitamins or dietary supplements containing biotin or vitamin B7 for 12 hours prior 
to the visit (to avoid interference with LH test results) and also not to ejaculate for the 
preceding 3 days for the sperm count assessment (if the participant has consented to this 
assessment). If the participant has had persistent signs of adrenal insufficiency or they have 
not tolerated the 4-week run-in medication, they should be withdrawn from the study at this 
point before randomization. 
The following assessments will be carried out and recorded at this visit: 
• Limited check of inclusion/exclusion criteria  
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit  
• Participants will be asked about any AEs and concomitant medications changes since 
the last visit 
• Vital signs (BP, HR, respiratory rate and body temperature. BP to be recorded after 
the participant has been semi-supine for 10 minutes) 
• Full physical examination 
• Height, weight, and waist circumference will be measured  
• Assessment of menstrual cycle changes in all pre-menopausal women  


 
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• Assessment of hirsutism by female participants using a VAS and by Investigators 
using Ferriman-Gallwey score  
• Assessment of acne by female participants using a VAS and by Investigators using 
the GEA 
• Assessment of alertness by the participant using a VAS 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
• The following questionnaires will be completed: SF-36®, MAF, and EQ-5D-5L™  
• ECG 
• TART measured by ultrasound in male participants (results read by central 
laboratory) 
• Sperm count measured at home using a testing kit supplied to the male participants 
(only in participants who have consented to this assessment) 
• Urinalysis  
• Blood sample for FSH, osteocalcin, LH, 11-ketotestosterone, total testosterone, 
DHEA, and routine biochemistry and hematology 
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Review of returned run-in medication and emergency treatment pack for compliance 
• Blood sampling for measurement of androgen levels (17-OHP and A4) at 08.00 
(pre-dose) and 13.00 hours  
• Saliva samples collected for exploratory analysis at 08.00 (pre-dose) and 13.00 hours 
(optional). 
The androgen blood samples are to be taken within ±30 minutes of the stated timepoints, with 
the exact sampling times recorded in the eCRF. Half the sample will be sent to the central 
laboratory for analysis, with the remaining half initially retained at the site before being sent 
to the central laboratory and then on to the biobank for long-term storage and possible future 
research. Once the participant’s eligibility for the study has been confirmed, the participant 
will be randomized via the IRT to either Chronocort or to continue with IRHC. The IRT will 
take into account the participant’s fludrocortisone replacement status (requires 
fludrocortisone or does not require fludrocortisone). Participants randomized to Chronocort 
will change to a dosing regimen of 10 mg in the morning on waking (typically between 06:00 
and 08:00 hours) and 20 mg at night just prior to going to bed (typically between 22:00 hours 
and midnight) whereas participants randomized to IRHC will continue the same dosing 
regimen as they were receiving during the run-in period (20 mg in the morning on waking 
[typically between 06:00 and 08:00 hours] and 10 mg in the afternoon [between 15:00 and 
17:00 hours]). Placebo capsules will also be provided to maintain the study blinding. The 
participant will be dispensed with the correct active and placebo study medication and an 
emergency treatment pack in case they need to implement ‘stress dosing rules’, and then they 
will be allowed home. Participants will be instructed to take their first dose of study 
medication that afternoon. Participants will be asked to record the dose, date and time they 
took the first dose of study medication (Chronocort or IRHC) in their electronic participant 
diary.  
Participants will be given an electronic participant diary and will be instructed what to record 
in it. In particular, they will be instructed to complete the alertness VAS on a weekly basis in 
the morning before their morning dose of study medication. The same day of the week should 


 
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be used each week. The participant will be asked to attend the clinic for Visit 3 in 4 weeks’ 
time. 
8.1.3. 
Visit 3 (Titration Visit - Week 4 + 1 Week) 
Four weeks after the previous visit (+ 1 week), the participant will be requested to attend the 
study site for testing of androgen levels (if necessary this visit can be conducted as a 
domiciliary visit). Prior to the visit, the site staff should contact the participant to check that 
‘stress dosing rules’ have not been applied in the 5 days preceding the visit date. If ‘stress 
dosing rules’ have been applied, then the visit should be postponed until the participant has 
been receiving no stress dosing medication for 5 days. The participant will be instructed to 
bring any empty packaging and any unused study medication and the emergency treatment 
pack with them to the visit for accountability purposes (note: participants take unused study 
medication and emergency treatment pack back home with them to use until the dose titration 
decision is made and new study medication dispensed). The participants will be told not to 
take their morning dose of study medication before attending for the visit (the morning dose 
will be taken after the 08:00 hour androgen sample and optional saliva sample [where 
applicable]). Male participants will be asked not to take multivitamins or dietary supplements 
containing biotin or vitamin B7 for 12 hours prior to the visit (to avoid interference with LH 
test results).  
The following assessments will be carried out and recorded at this visit: 
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit 
• Participants will be asked about any AEs (including events considered to be of 
unexpected benefit) and concomitant medications changes since the last visit 
• Vital signs (BP, HR, respiratory rate and body temperature. BP to be recorded after the 
participant has been semi-supine for 10 minutes) 
• Abbreviated physical examination (if indicated by AEs) 
• Height, weight, and waist circumference will be measured 
• Assessment of menstrual cycle changes in all pre-menopausal women  
• Assessment of hirsutism by female participants using a VAS and by Investigators 
using Ferriman-Gallwey score (the Investigator can assess this via a video call if a 
domiciliary visit is conducted for this visit [within ±2 days of the domiciliary visit]) 
• Assessment of acne by female participants using a VAS and by Investigators using 
the GEA (the Investigator can assess this via a video call if a domiciliary visit is 
conducted for this visit [within ±2 days of the domiciliary visit]) 
• Assessment of alertness by the participant using a VAS 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
(the Investigator must complete the checklist even if a domiciliary visit is conducted 
for this visit) 
• The following questionnaires will be completed: SF-36®, MAF, and EQ-5D-5L™  
• Blood sample for HbA1c, FSH, osteocalcin, LH, and routine biochemistry and 
hematology 
• Urinalysis  
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Review of emergency treatment pack for compliance 


 
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• Blood sampling for measurement of androgen levels (17-OHP and A4) at 08.00 
(pre-dose) and 13.00 hours  
• Saliva samples collected for exploratory analysis at 08.00 (pre-dose) and 13.00 hours 
(optional). 
The androgen blood samples are to be taken within ±30 minutes of the stated timepoints, with 
the exact sampling times recorded in the eCRF. Half the sample will be sent for analysis at 
the central laboratory, with the remaining half initially retained at the site before being sent to 
the central laboratory and then on to the biobank for long-term storage and possible future 
research.  
The participant will be asked to attend the clinic for Visit 4 in 6 weeks’ time. Participants will 
be reminded to complete the alertness VAS on a weekly basis in the morning before their 
morning dose of study medication. The same day of the week should be used each week. 
Participants will be discharged once the last androgen sample has been taken and all other 
assessments have been completed. 
Following determination of the Visit 3 androgen levels and completion of the adrenal 
insufficiency checklist, a decision will be made by an independent blinded physician as to 
whether the participant’s dose should be adjusted, and the appropriate IMP packs will be sent 
to the participant, either to collect from their local study site or sent directly to the 
participant’s home (note: the changes will also include the relevant changes to the placebo 
capsules to maintain the blinding). The treatment packs for each participant will always 
contain the same number of capsules as the previous supplies (with placebo capsules masking 
any changes), thus ensuring the participant is not aware of any dose changes. Participants will 
be asked to record the dose, date and time they took the first dose of the revised study 
medication (if applicable) in their electronic participant diary. 
Any dose titrations should be made within 2 to 3 weeks of the visit (dependent on the 
laboratory turnaround time of androgen samples, the time needed by the independent blinded 
physician to evaluate the data, and for the supplies to be sent to the participant). 
8.1.4. 
Telephone Call T3.1 (Visit 3 + 2 to 5 Weeks) 
One week after delivery of the new supplies to the participant, the study site will telephone 
the participant to check the supplies have been received and any old supplies returned. The 
participant will be asked about any AEs and changes in concomitant medications at this call 
and any AEs or changes in concomitant medication reported will be recorded in the eCRF.  
8.1.5. 
Visit 4 (Titration Visit - Week 10 ± 1 Week) 
Six weeks after the previous visit (± 1 week), participants will be requested to attend the 
study site for testing of androgen levels (if necessary this visit can be conducted as a 
domiciliary visit). Prior to the visit, the site staff should contact the participant to check that 
‘stress dosing rules’ have not been applied in the 5 days preceding the visit date. If ‘stress 
dosing rules’ have been applied, then the visit should be postponed until the participant has 
been receiving no stress dosing medication for 5 days. The participant will be instructed to 
bring any empty packaging and any unused study medication and the emergency treatment 
pack with them to the visit for accountability purposes (note: participants take unused study 
medication and emergency treatment pack back home with them to use until the dose titration 


 
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decision is made and new study medication dispensed). The participants will be told not to 
take their morning dose of study medication before attending for the visit (the morning dose 
will be taken after the 08:00 androgen sample and optional saliva sample [where applicable]). 
Male participants will be asked not to take multivitamins or dietary supplements containing 
biotin or vitamin B7 for 12 hours prior to the visit (to avoid interference with LH test results).  
The following assessments will be carried out and recorded at this visit: 
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit 
• Participants will be asked about any AEs (including events considered to be of 
unexpected benefit) and concomitant medications changes since the last visit 
• Vital signs (BP, HR, respiratory rate and body temperature. BP to be recorded after the 
participant has been semi-supine for 10 minutes) 
• Abbreviated physical examination (if indicated by AEs) 
• Height, weight and waist circumference will be measured 
• Assessment of menstrual cycle changes in all pre-menopausal women  
• Assessment of hirsutism by female participants using a VAS and by Investigators 
using Ferriman-Gallwey score (the Investigator can assess this via a video call if a 
domiciliary visit is conducted for this visit [within ±2 days of the domiciliary visit]) 
• Assessment of acne by female participants using a VAS and by the Investigators 
using the GEA (the Investigator can assess this via a video call if a domiciliary visit is 
conducted for this visit [within ±2 days of the domiciliary visit]) 
• Assessment of alertness by the participant using a VAS 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
(the Investigator must complete the checklist even if a domiciliary visit is conducted 
for this visit) 
• The following questionnaires will be completed: SF-36®, MAF, and EQ-5D-5L™  
• Blood sample for HbA1c, FSH, osteocalcin, LH, and routine biochemistry and 
hematology 
• Urinalysis  
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Review of emergency treatment pack for compliance 
• Blood sampling for measurement of androgen levels (17-OHP and A4) at 08.00 
(pre-dose) and 13.00 hours 
• Saliva samples collected for exploratory analysis at 08.00 (pre-dose) and 13.00 hours 
(optional). 
The androgen blood samples are to be taken within ±30 minutes of the stated timepoints, with 
the exact sampling times recorded in the eCRF. Half the sample will be sent for analysis at 
the central laboratory, with the remaining half initially retained at the site before being sent to 
the central laboratory and then on to the biobank for long-term storage and possible future 
research.  
The participant will be asked to attend the clinic for Visit 5 in 6 weeks’ time. Participants will 
be reminded to complete the alertness VAS on a weekly basis in the morning before their 
morning dose of study medication. The same day of the week should be used each week. 


 
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Participants will be discharged once the last androgen sample has been taken and all other 
assessments have been completed. 
Following determination of the Visit 4 androgen levels and completion of the adrenal 
insufficiency checklist, a decision will be made by an independent blinded physician as to 
whether the participant’s dose should be adjusted, and the appropriate IMP packs will be sent 
to the participant, either to collect from their local study site or sent directly to the 
participant’s home (note: the changes will also include the relevant changes to the placebo 
capsules to maintain the blinding). The treatment packs for each participant will always 
contain the same number of capsules as the previous supplies (with placebo capsules masking 
any changes), thus ensuring the participant is not aware of any dose changes. Participants will 
be asked to record the dose, date and time they took the first dose of the revised study 
medication (if applicable) in their electronic participant diary. 
Any dose titrations should be made within 2 to 3 weeks of the visit (dependent on the 
laboratory turnaround time of androgen samples, the time needed by the independent blinded 
physician to evaluate the data, and for the supplies to be sent to the participant). 
8.1.6. 
Telephone Call T4.1 (Visit 4 + 2 to 5 Weeks) 
One week after delivery of the new supplies to the participant, the study site will telephone 
the participant to check the supplies have been received and any old supplies returned. The 
participant will be asked about any AEs and changes in concomitant medications at this call 
and any AEs or changes in concomitant medication reported will be recorded in the eCRF. 
8.1.7. 
Visit 5 (Titration Visit - Week 16 ± 1 Week) 
Six weeks after the previous visit (± 1 week), participants will be requested to attend the 
study site for testing of androgen levels. Prior to the visit, the site staff should contact the 
participant to check that ‘stress dosing rules’ have not been applied in the 5 days preceding 
the visit date. If ‘stress dosing rules’ have been applied, then the visit should be postponed 
until the participant has been receiving no stress dosing medication for 5 days. It is 
mandatory that this visit is conducted at the study site, although if necessary in some cases, 
IMP at this visit can be delivered to the participant's home. The participant will be instructed 
to bring any empty packaging and any unused study medication and the emergency treatment 
pack with them to the visit for accountability purposes (note: participants take unused study 
medication and emergency treatment pack back home with them to use until the dose titration 
decision is made and new study medication dispensed). The participants will be told not to 
take their morning dose of study medication before attending for the visit (the morning dose 
will be taken after the 08:00 hour androgen sample and optional saliva sample [where 
applicable]). Male participants will be asked not to take multivitamins or dietary supplements 
containing biotin or vitamin B7 for 12 hours prior to the visit (to avoid interference with LH 
test results).  
The following assessments will be carried out and recorded at this visit: 
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit 
• Participants will be asked about any AEs (including events considered to be of 
unexpected benefit) and concomitant medications changes since the last visit 


 
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• Vital signs (BP, HR, respiratory rate and body temperature. BP to be recorded after the 
participant has been semi-supine for 10 minutes) 
• Abbreviated physical examination (if indicated by AEs) 
• Height, weight and waist circumference will be measured 
• Assessment of menstrual cycle changes in all pre-menopausal women  
• Assessment of hirsutism by female participants using a VAS and by Investigators 
using Ferriman-Gallwey score  
• Assessment of acne by female participants using a VAS and by Investigators using 
the GEA 
• Assessment of alertness by the participant using a VAS 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
• The following questionnaires will be completed: SF-36®, MAF, and EQ-5D-5L™  
• Blood sample for HbA1c, FSH, osteocalcin, LH, and routine biochemistry and 
hematology 
• Urinalysis  
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Review of emergency treatment pack for compliance 
• Blood sampling for measurement of androgen levels (17-OHP and A4) at 08.00 
(pre-dose) and 13.00 hours 
• Saliva samples collected for exploratory analysis at 08.00 (pre-dose) and 13.00 hours 
(optional). 
The androgen blood samples are to be taken within ±30 minutes of the stated timepoints, with 
the exact sampling times recorded in the eCRF. Half the sample will be sent for analysis at 
the central laboratory, with the remaining half initially retained at the site before being sent to 
the central laboratory and then on to the biobank for long-term storage and possible future 
research.  
Participants will be asked to attend the clinic for Visit 6 in approximately 12 weeks’ time. 
Participants will be reminded to complete the alertness VAS on a weekly basis in the 
morning before their morning dose of study medication. The same day of the week should be 
used each week. Participants will be discharged once the last androgen sample has been taken 
and all other assessments have been completed. 
Following determination of the Visit 5 androgen levels and completion of the adrenal 
insufficiency checklist, a decision will be made by an independent blinded physician as to 
whether the participant’s dose should be adjusted, and the appropriate IMP packs will be sent 
to the participant, either to collect from their local study site or sent directly to the 
participant’s home (note: the changes will also include the relevant changes to the placebo 
capsules to maintain the blinding). The treatment packs for each participant will always 
contain the same number of capsules as the previous supplies (with placebo capsules masking 
any changes), thus ensuring the participant is not aware of any dose changes. Participants will 
be asked to record the dose, date and time they took the first dose of the revised study 
medication (if applicable) in their electronic participant diary. 
Any dose titrations should be made within 2 to 3 weeks of the visit (dependent on the 
laboratory turnaround time of androgen samples, the time needed by the independent blinded 
physician to evaluate the data, and for the supplies to be sent to the participant). 


 
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8.1.8. 
Telephone Call T5.1 (Visit 5 + 2 to 5 Weeks) 
One week after delivery of the new supplies to the participant, the study site will telephone 
the participant to check the supplies have been received and any old supplies returned. The 
participant will be asked about any AEs and changes in concomitant medications at this call 
and any AEs or changes in concomitant medication reported will be recorded in the eCRF. 
8.1.9. 
Telephone Call T5.2 (Week 22 ± 2 Weeks) 
A telephone call will be made to all participants approximately 4 weeks after the last 
telephone call. All participants will be asked about any AEs or any other problems plus any 
changes in concomitant medications since their last visit. Any AEs or changes in concomitant 
medications will be recorded in the eCRF. 
8.1.10. 
Visit 6 (End of Study/Early Withdrawal Visit - 28 Weeks + 1 Week From 
Randomization or at Point of Discontinuing Treatment or Withdrawing 
From the Study) 
This visit is required for all participants either 28 weeks after randomization or at the time a 
participant withdraws early from treatment or from the whole study. The last dose of study 
medication will be taken in the morning of the last dosing day after the 08:00 hour androgen 
sample and optional saliva sample (where applicable) are collected. It is mandatory that this 
visit is conducted at the study site. If a participant who was enrolled under an earlier version 
of the protocol (where the study was up to 52 weeks in duration) had attended Visit 5 at 
Week 16 and is ongoing treatment, they must continue taking the study medication and must 
return at 28 weeks for the EOS (Visit 6) assessments. If they have already had more than 28 
weeks of treatment then they must return as soon as possible (but not within 4 weeks of 
previous blood sampling) for the EOS (Visit 6) assessments according to this amendment. In 
the case of early withdrawal from treatment or from the study, as many assessments as 
possible should be completed within 48 hours of the last dose of the study medication. If the 
participant only discontinues study treatment, they should remain in the study where possible 
and be followed for safety assessments until the scheduled EOS visit (note: no efficacy 
endpoints will be collected once the assessments detailed for Visit 6 [early withdrawal] are 
completed). 
Prior to the visit, the site staff should contact the participant to check that ‘stress dosing rules’ 
have not been applied in the 5 days preceding the visit date. If ‘stress dosing rules’ have been 
applied, then the visit should be postponed until the participant has been receiving no stress 
dosing medication for 5 days. The participant will be instructed to bring any empty packaging 
and any unused study medication and the emergency treatment pack with them to the visit for 
accountability purposes. The participants will be told not to take their morning dose of study 
medication before attending for the visit (the morning dose will be taken after the 08:00 hour 
androgen sample and optional saliva sample [where applicable]). Male participants will be 
asked not to take multivitamins or dietary supplements containing biotin or vitamin B7 for 
12 hours prior to the visit (to avoid interference with LH test results) and also not to ejaculate 
for the preceding 3 days for the sperm count assessment (if the participant has consented to 
this assessment).  


 
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The following assessments will be carried out and recorded at this visit: 
• Record the details of the participant’s glucocorticoid doses for the previous 24 hours 
and throughout the visit  
• Participants will be asked about any AEs and concomitant medications changes since 
the last visit 
• Vital signs (BP, HR, respiratory rate and body temperature. BP to be recorded after 
the participant has been semi-supine for 10 minutes) 
• Full physical examination 
• Height, weight, and waist circumference will be measured 
• Assessment of menstrual cycle changes in all pre-menopausal women 
• Assessment of hirsutism by female participants using a VAS and by Investigators 
using Ferriman-Gallwey score  
• Assessment of acne by female participants using a VAS and by the Investigators 
using the GEA 
• Assessment of alertness by the participant using a VAS 
• Assessment of treatment preference (randomized treatment compared to their usual 
medication) using a VAS 
• Signs and symptoms of adrenal insufficiency using the adrenal insufficiency checklist 
• The following questionnaires will be completed: SF-36®, MAF, and EQ-5D-5L™  
• ECG 
• TART measured by ultrasound in male participants (results read by central 
laboratory) 
• Sperm count measured at home using a testing kit supplied to the male participants 
(only in participants who have consented to this assessment) 
• Urinalysis  
• Sample taken for PRA or PRC, preferably after the participant has been supine for 
30 minutes 
• Blood sample for HbA1c, FSH, osteocalcin, LH, 11-ketotestosterone, total 
testosterone, DHEA, and routine biochemistry and hematology 
• Pregnancy test in WOCBP (either urine or blood as per the site’s usual practice)  
• Review of emergency treatment pack for compliance 
• Blood sampling for measurement of androgen levels (17-OHP and A4) at 08.00 
(pre-dose) and 13.00 hours 
• Saliva samples collected for exploratory analysis at 08.00 (pre-dose) and 13.00 hours 
(optional). 
The androgen blood samples are to be taken within ±30 minutes of the stated timepoints, with 
the exact sampling times recorded in the eCRF. All samples taken at the EOS visit will be 
shipped to the central laboratory in the same shipment. Half of the samples will be analyzed 
and half will be sent on to the biobank for long-term storage and possible future research. 
Once the last blood sample has been taken at 13:00 hours and all other assessments have been 
completed, the participant will be discharged from the clinic. At this point the participants 
can either return to the CAH medication they were taking prior to the study or if they have 
completed the study with up to 28 weeks of randomized treatment, they can enter an 
open-label extension study and receive Chronocort (to be conducted under a separate protocol 


 
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DIUR-015) or they will be offered commercial supplies of Chronocort. The options will be 
dependent on territory. 
8.1.11. 
Telephone Call T6.1 (Visit 6 + 30 Days ± 1 Week) 
Participants who do not enter the open-label extension study will be contacted by telephone 
by the local site staff approximately 30 days after Visit 6 to ask about any AEs that were 
ongoing at Visit 6 and any new SAEs that could be related to the study medication. Any AEs 
or SAEs reported will be recorded in the eCRF and any SAEs will be reported to the 
pharmacovigilance group using the paper SAE form. 
8.1.12. 
Unscheduled Visits or Telephone Calls 
If an unscheduled visit or telephone call is required, e.g. to follow up on an AE, then the 
details should be recorded in the eCRF, along with the results of any tests carried out. If 
laboratory results are needed urgently these can be processed at the local laboratory. 
Additional telephone calls may also be required in between visits to maintain contact with the 
participant and to ensure AEs and use of any ‘stress dosing rules’ are being noted. Any 
additional data obtained in such calls must be recorded in the eCRF, where relevant. 
8.1.13. 
COVID-19 Procedures 
If necessary, appropriate measures will be put in place to enable the study to continue during 
COVID-19 restrictions. These may include domiciliary visits being performed and IMP 
shipments being made directly to the participant’s home. If a domiciliary visit is conducted 
the safety and endocrine blood samples must be sent to the central laboratory for analysis and 
the Investigator must complete the adrenal insufficiency checklist. The assessment of 
hirsutism and acne can be conducted via a video call (within ±2 days of the domiciliary visit). 
If androgen samples are analyzed locally this will unblind the participant and so the 
participant will then be withdrawn from treatment. If local laboratories are used, then normal 
ranges and certification of the local laboratories will be required. Such procedures would be 
agreed between the investigator and Sponsor before implementation. 
8.2. 
Efficacy Assessments 
The timing of each efficacy assessment is shown in the SoA (Section 1.3) and detailed in 
Section 8.1. Wherever possible, all efficacy assessments for a participant should be 
conducted by the same individual.  
8.2.1. 
Efficacy Blood Samples  
The date and time of collection of all blood samples will be recorded in the eCRF. Blood 
samples for the following tests will be taken by suitably qualified study personnel and sent to 
a central laboratory for analysis: 
• 
Androgen testing (17-OHP and A4) at 08:00 and 13:00 hours for all participants at 
Visits 1, 2, 3, 4, 5, and 6. A draw window of ±30 minutes is permitted, but exact times 
of sampling must be recorded in the eCRF. Half of each sample will be sent to the 
central laboratory for analysis, with the remaining half initially retained at the site 
before being sent to the central laboratory and then on to the biobank for long-term 
storage and possible future research (note: samples taken at the EOS visit will all be 


 
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shipped to the central laboratory at the same time and the central laboratory will send 
half the samples to the biobank for long-term storage). The central laboratory will 
analyze 17-OHP and A4 using liquid chromatography tandem mass spectrometry 
(LC-MS-MS) methods, with full details of the assay methods provided in a separate 
manual.  
• 
Blood samples for HbA1c will be taken at screening and then at each visit after 
Visit-2.  
• 
Blood samples for FSH, LH, and osteocalcin will be taken at each visit after Visit 1.  
• 
Serum samples for 11-ketotestosterone and DHEA will be taken at Visits 2 and 6.  
• 
Serum samples for total testosterone will be taken at Visits 2 and 6.  
Participants are required to fast before the collection of the 08:00 androgen sample, but there 
is no requirement to fast for any of the other laboratory tests. 
The maximum amount of blood collected from each participant over the course of the study 
will not exceed approximately 200 mL. Repeat or unscheduled samples may be taken in 
addition for safety reasons or for technical issues with the samples. 
8.2.2. 
Adrenal Insufficiency Checklist  
The adrenal insufficiency checklist (Appendix 5) is completed by the Investigator for all 
participants at Visits 1, 2, 3, 4, 5, and 6. The adrenal insufficiency checklist should only be 
used to determine if symptoms of under- or over-replacement of glucocorticoids have 
occurred since the last visit and this questionnaire should not be used to record AEs due to 
other causes. 
8.2.3. 
Saliva Samples 
Optional saliva samples for exploratory analyses will be taken at 08:00 hours (pre-dose) and 
13:00 hours in the clinic at each study visit after Visit 1 in participants who have consented to 
this procedure. The samples will be collected using a passive drooling method and then split 
into 2 samples and frozen. The samples will then be sent to the central laboratory and then on 
to the biobank for long-term storage and possible future research. The analyses to be 
conducted will be determined at a later date but are likely to include steroid profiling and 
androgens. Samples may be stored for up to 10 years. 
8.2.4. 
Body Weight 
Body weight will be recorded at each visit and the results recorded in the eCRF. Weight will 
be measured with outer clothing and shoes removed.  
8.2.5. 
Waist Circumference  
Waist circumference will be recorded at each visit and the results recorded in the eCRF. 
Waist circumference will be measured midway between the uppermost border of the iliac 
crest and the lower border of the costal margin (rib cage). The tape should be placed around 
the abdomen at the level of this midway point and a reading taken when the tape is snug but 
does not compress the skin (Figure 1). It may be difficult for very overweight participants to 
accurately palpate the bony landmarks, in which case placing the tape at the level of the belly 
button is recommended.  


 
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Figure 1: 
Measuring Tape Position for Waist Circumference 
 
Reproduced from the National Heart, Lung, and Blood Institute as a part of the National Institutes of Health and 
the U.S. Department of Health and Human Services.  
8.2.6. 
Fertility 
Menstrual irregularities including oligomenorrhea (fewer than 9 menstrual cycles per year or 
cycle length >35 days) and secondary amenorrhea (absent menses for ≥3 months) are 
common in females with classic CAH. An electronic participant diary will be used to record 
menstrual cycle details for all pre-menopausal women, but only those who have not had a 
hysterectomy and are not using hormonal contraception will be included in the statistical 
analysis. Restoration of menses in a woman with secondary amenorrhea or normal menstrual 
regularity with cycles occurring every 21 to 35 days, will be captured and documented in the 
electronic patient reported outcomes (ePRO) device. The details in the diary will be reviewed 
at each visit after Visit 1.  
Fertility in men will be assessed at each visit after Visit 1 by measurement of LH (see 
efficacy blood samples Section 8.2.1), and at Visits 2 and 6 by ultrasound for detection of 
TART and sperm count (measured at home using a testing kit supplied to male participants 
who have consented to this assessment) will be assessed. All ultrasounds conducted for 
TART will be assessed by a central reviewer.  
8.2.7. 
Quality of Life Questionnaires 
QoL questionnaires (SF-36®, MAF, and EQ-5D-5L™) will be completed by the participants 
at each visit after Visit 1 using the electronic participant diary and the results will be 
transferred electronically into the database. At the first visit the questionnaires are completed 
(Visit 2), the Investigator or designee will instruct the participant how to complete each 
questionnaire. However, completion of the QoL questionnaires will not be supervised and no 
review or follow-up of responses will be conducted by the site staff. All QoL questionnaires 
will be administered on the study visit days between the first and second blood samplings and 
they will be completed in a quiet environment. The QoL questionnaires will be administered 
in the following order: SF-36®, MAF, and EQ-5D-5L™.  


 
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8.2.8. 
Hirsutism 
Hirsutism will be assessed in female participants at each visit after Visit 1 using a 10 cm 
VAS ranging from ‘No Hair’ to ‘Most Hair Growth Ever Experienced’ which will be 
completed by the participant.  
Example VAS for Hirsutism: 
 
This assessment will be conducted on the study visit days between the first and second blood 
samplings. The VAS will be completed using the electronic participant diary and the results 
will be transferred electronically into the database. A change of ≥1 cm in the VAS will be 
considered clinically relevant. 
Assessment of hirsutism in female participants will also be assessed by the Investigators at 
each visit after Visit 1 using the Ferriman-Gallwey score [Hatch, 1981], with the score being 
entered into the eCRF. 
8.2.9. 
Acne 
Acne will be assessed in women only at each visit after Visit 1 using 2 methods. The 
Investigator will assess the acne objectively using the GEA scale [Dreno, 2011], with the 
score being entered into the eCRF, and the participants will assess their acne subjectively 
using a 10 cm VAS ranging from ‘No Acne’ to ‘Worst Acne Ever’.  
Example VAS for Acne: 
 
Both assessments will be conducted on the study visit days between the first and second 
blood samplings. The VAS will be completed using the electronic participant diary and the 
results will be transferred electronically into the database. A change of ≥1 cm in the VAS will 
be considered clinically relevant. 
8.2.10. 
Alertness 
Alertness will be assessed on a weekly basis in the morning before the participant takes their 
morning dose of study medication. The same day of the week should be used each week. 
When the alertness VAS is conducted at the study visits, it will be completed between the 
first and second blood samplings.  
Alertness will be assessed using the VAS below. The VAS will be completed using the 
electronic participant diary and the results will be transferred electronically into the database. 
A change of ≥1 cm in the VAS will be considered clinically relevant. 
 


 
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8.2.11. 
Preference for Treatment 
At the EOS visit (Visit 6), an assessment of the preference of the randomized treatment to the 
participant’s usual medication (i.e. prior to the run-in period) will be made. 
Example VAS for Treatment Preference: 
 
The assessment will be conducted on the study visit day between the first and second blood 
samplings. The VAS will be completed using the electronic participant diary and the results 
will be transferred electronically into the database. A change of ≥1 cm in the VAS will be 
considered clinically relevant. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
A full physical examination to assess the participant’s general appearance and overall health 
will be carried out at Visits 1, 2, and 6. This physical examination will include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal and neurological 
systems. Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Significant findings that are present prior to randomization must be included in 
the relevant medical history/current medical status section of the eCRF. Significant findings 
made after randomization which meet the definition of an AE must be recorded as AEs in 
the eCRF. At Visits 3, 4, and 5, an abbreviated physical examination will be conducted if 
indicated by AEs, noting any changes from the baseline assessment. Any abnormal findings 
will be recorded on the eCRF.  
Standing height will be measured at each visit and will be measured with the participant’s 
shoes removed. Weight and waist circumference are recorded as efficacy parameters (see 
Section 8.2). Body mass index (BMI) will be calculated within the eCRF. 
 
 
Brain Fog 
unable to 
perform normal 
daily tasks  
Fully Alert 
able to perform 
normal daily tasks 
easily 
The line below is a 10 cm scale from the left-hand side “Brain Fog” to on the right-hand 
side “Fully Alert”. Please mark anywhere on the line your current level of alertness with 
a vertical line, e.g.  


 
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8.3.2. 
Vital Signs 
BP, HR, respiratory rate and body temperature will be measured at Visits 1, 2, 3, 4, 5, and 6. 
Vital signs should be recorded before any blood samples have been taken or at least 1 hour 
after any blood sampling. BP and HR measurements should be preceded by 10 minutes of 
rest (semi-supine position) in a quiet setting without distractions (e.g. television, cell phones). 
BP should be measured in the non-dominant arm. Three measurements for BP, HR and 
respiratory rate will be taken and recorded in the eCRF (3 consecutive readings will be 
recorded at intervals of at least 1 minute), with the average then being calculated within the 
eCRF. The mean arterial BP will also be calculated within the eCRF.  
8.3.3. 
Electrocardiograms 
A single 12-lead ECG will be recorded at Visits 2 and 6 using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. The same 
ECG machine and operator should be used throughout the study for each participant if 
possible. ECGs should be recorded at least 1 hour after any blood samples have been taken. 
ECG measurements should be preceded by 10 minutes of rest (semi-supine position) in a 
quiet setting without distractions (e.g. television, cell phones). The ECGs will be read locally, 
and any abnormal findings recorded on the eCRF as an AE. The original ECG printouts will 
be stored in the participant’s source notes.  
8.3.4. 
Clinical Safety Laboratory Assessments 
• 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and to 
the SoA (Section 1.3) for the timing and frequency. Participants are required to fast 
before the collection of the 08:00 androgen sample, but there is no requirement to fast 
for any of the other laboratory tests. Note: the blood sample for PRA or PRC will be 
collected at screening and at the EOS visit according to local practice but if possible, 
should be taken after the participant has been supine for 30 minutes. All laboratory 
samples will be analyzed by a central laboratory.  
• 
The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or the 
Sponsor’s medical monitor. 
o 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the 
Sponsor notified. 
o 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
o 
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 


 
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management or are considered clinically significant by the Investigator 
(e.g. SAE or AE), then the results must be recorded in the eCRF. 
• Pregnancy tests in WOCBP are conducted at each visit and can be either urine or 
blood as per the site’s usual practice.  
8.3.5. 
Stress Dosing Rules 
All participants will be educated regarding ‘stress dosing rules’. ‘Stress dosing rules’, a 
written guideline detailing what to do during any illness, will be given to all participants (as 
is done for all CAH patients) (Appendix 6). Use of ‘stress dosing rules’ will be recorded in 
the electronic participant diary, including duration, dose of steroid and use of injection, as 
applicable. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3 (Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting). All participants will 
be questioned about the occurrence of any AEs at all study visits and in all telephone calls. 
Any AEs reported by the participant will be recorded in the eCRF and any SAEs will be 
reported to the pharmacovigilance group using the paper SAE form by the Investigator or 
designee. The Investigator and any designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or study 
procedures, or that caused the participant to discontinue from receiving study treatment or 
from the whole study (see Section 7 [Discontinuation of Study Treatment and Participant 
Discontinuation/Withdrawal]). Note that signs and symptoms of adrenal insufficiency 
recorded on the adrenal insufficiency checklist do not need to be reported as AEs unless they 
are considered unrelated to the participant’s CAH (i.e. they are due to another reason) or they 
meet the criteria for reporting as an SAE.  
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected for all participants from the time of signing the ICF up to 
the EOS visit (Visit 6) in participants who are entering the open-label extension study or 
early withdrawal visit (if applicable), or to the final telephone call T6.1 (approximately 
30 days following the last visit) in participants who are not entering the open-label extension 
study. AEs must be reported equally for both study treatments, regardless of whether the 
Investigator thinks the AEs are related to the study treatment. Any AEs or SAEs still ongoing 
at the final visit will be followed until resolution or stabilization if resolution is not expected. 
Medical occurrences that begin before the start of study treatment but after the ICF is signed 
will be recorded on the Medical History/Current Medical Conditions section of the eCRF, not 
the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
After the final visit or telephone call, Investigators are not obligated to actively seek AEs or 
SAEs in former study participants. However, if the Investigator learns of any SAE, including 
a death, at any time after a participant has been discharged from the study, and he/she 


 
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considers the event to be reasonably related to the study treatment or study participation, the 
Investigator must promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to enquire about 
AE occurrences.  
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(as defined in Section 8.4.8), will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IECs/IRBs, and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators, as necessary. 
• An Investigator who receives a safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IEC/IRB, if 
appropriate according to local requirements. 
8.4.5. 
Pregnancy 
Female subjects who are pregnant or lactating will not be allowed to enter the study and all 
female participants of childbearing potential and all male participants must agree to the use of 
an accepted method of contraception during the study (Appendix 4). If a participant becomes 
pregnant during the study, they should be withdrawn from the study - not due to safety 
reasons but because pregnancy may interfere with the study endpoints. However, participants 
who withdraw from the study due to pregnancy may be eligible to enter the long-term 
extension study (DIUR-015) at the discretion of the Investigator providing that at least 
6 weeks has lapsed after the pregnancy is complete (i.e. at least 6 weeks post-partum 


 
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regardless of outcome or at least 6 weeks after abortion or termination) or at least 6 weeks 
after they have finished lactating and are no longer breast feeding (whichever is longer). 
As soon as the pregnancy is confirmed, the Investigator will conduct as many of the 
evaluations included in the EOS visit (Visit 6) as possible and the participant will be asked to 
sign a pregnancy consent form to enable information on the course of the pregnancy to be 
collected. The Investigator will transition the participant onto the appropriate standard of care 
therapy. AEs will be collected for 30 days after the EOS visit and a follow-up telephone call 
will be conducted at 30 days. No other data will be collected while the participant is off study 
due to the pregnancy unless the Investigator considers any AEs are related to study treatment, 
in which case every reasonable attempt will be made to follow up until resolution of the 
event.  
The outcome of the pregnancy will be collected via a Pregnancy Report Form that must be 
sent to Pharmalex: diurnalclinicalsafety@pharmalex.com.  
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such.  
8.4.6. 
Cardiovascular and Death Events 
Cardiovascular events will be reported in the same manner as other AEs/SAEs. All deaths 
will be reported as SAEs in this study, regardless of the cause.  
8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs 
None in this study. 
8.4.8. 
Adverse Events of Special Interest  
Some of the AEs likely to occur in participants with CAH are of special interest (adverse 
events of special interest [AESI]). These AESIs will be recorded in the eCRF and will also be 
reported to the Sponsor using the SAE/AESI form (see Appendix 3 for further details). These 
events will include, but not be limited to: 
• 
any events causing implementation of ‘stress dosing rules’ 
• 
Addisonian crisis, with Addisonian or adrenal crisis being defined as follows (based 
on Allolio, 2015): 
 
(A):  
Major impairment of general health with at least 2 of the following  
 
signs/symptoms: 
Hypotension (systolic blood pressure <100 mmHg) 
Nausea or vomiting 
Severe fatigue 
Fever 
Somnolence 
Hyponatremia (<132 mmol/L) or hyperkalemia (as judged by characteristic 
ECG changes) 


 
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Hypoglycemia 
AND 
(B):  
Parenteral glucocorticoid (hydrocortisone) administration followed by clinical 
 
improvement including: 
Outpatient care only 
Hospital care (general ward) 
Admission to intensive care unit 
OR 
Death from adrenal crisis (with or without parenteral glucocorticoid 
administration) 
• 
any other event that is considered to be an unexpected benefit (note: events recorded 
as efficacy assessments e.g. change in menses, acne and hirsutism, should not be 
recorded as AESIs to avoid duplication) 
8.5. 
Treatment of Overdose 
For this study, any dose of Chronocort or IRHC greater than 60 mg within a 24-hour time 
period will be considered an overdose. In the event of an overdose, the participant should 
immediately contact the Investigator or Study Nurse for advice. There is no antidote available 
for Chronocort or IRHC, however, it should be noted that the active ingredient is 
hydrocortisone intended for replacement therapy in cortisol deficient patients. The 
Investigator should then: 
1. Contact the Sponsor’s medical monitor immediately. 
2. Closely monitor the participant for any AEs/SAEs or laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor’s medical monitor based on the clinical evaluation of the 
participant. 
8.6. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Genetics 
Genetics evaluations are not being conducted in this study. However, if retrospective genetic 
information to confirm the diagnosis of CAH is available, this should be recorded in the 
eCRF. 


 
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8.9. 
Biomarkers 
17-OHP and A4 are used as biomarkers of disease control and are evaluated as efficacy 
endpoints in this study (see Section 8.2.1 for full details). 
8.10. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.11. 
Health Economics 
Health economics parameters are not evaluated in this study. 


 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
9.1.1. Primary Analysis 
A participant is a biochemical responder if: 
i) 
they are in biochemical control at 08:00 hours after 28 weeks of randomized 
treatment (Visit 6) 
where ‘biochemical control’ is defined as a 17-OHP concentration equal to or less 
than the upper limit of optimal control and a A4 concentration equal to or less 
than the upper limit of the reference range - if either or both these conditions are 
not met the participant is not in biochemical control. 
and 
ii) 
their total daily dose after 28 weeks of randomized treatment is 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)  
The primary null hypothesis is that the response rate in the Chronocort arm is worse than or 
equal to the response rate in the IRHC arm minus 15 percentage points. 
The primary alternate hypothesis is that the response rate in the Chronocort arm is better than 
the response rate in the IRHC arm minus 15 percentage points.  
Biochemical non-inferiority of Chronocort to IRHC will be declared if the 95% CI for the 
difference in response rates between the 2 treatment arms (Chronocort minus IRHC) is 
wholly above minus 15 percentage points. 
9.1.2. First Key Secondary Analysis 
A participant is a dose responder if: 
i) 
their total daily dose after 28 weeks of randomized treatment is not more than 
25 mg 
and 
ii) 
they are in biochemical control at 08:00 hours after 28 weeks of randomized 
treatment (Visit 6)  
where ‘biochemical control’ is defined as a 17-OHP concentration equal to or less 
than the upper limit of optimal control and a A4 concentration equal to or less 
than the upper limit of the reference range - if either or both these conditions are 
not met the participant is not in biochemical control. 
The first key secondary null hypothesis is that the response rate in the Chronocort arm is 
worse than or equal to the response rate in the IRHC arm. 
The first key secondary alternate hypothesis is that the response rate in the Chronocort arm is 
better than the response rate in the IRHC arm.  


 
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Dose superiority of Chronocort to IRHC will be declared if the 95% CI for the difference in 
response rates between the 2 treatment arms (Chronocort minus IRHC) is wholly above zero, 
provided that biochemical non-inferiority of Chronocort to IRHC has been declared under the 
primary efficacy objective. 
9.1.3. Second Key Secondary Analysis 
The second key secondary null hypothesis is that the mean total daily dose after 28 weeks of 
randomized treatment in the Chronocort arm is higher than or equal to the mean total daily 
dose after 28 weeks of randomized treatment in the IRHC arm. 
The second key secondary alternate hypothesis is that the mean total daily dose after 
28 weeks of randomized treatment in the Chronocort arm is lower than the mean total daily 
dose after 28 weeks of randomized treatment in the IRHC arm.  
Superiority of Chronocort to IRHC with respect to the total daily dose after 28 weeks of 
randomized treatment will be declared if the 95% CI for the difference in means between the 
2 treatment arms (Chronocort minus IRHC) is wholly below zero, provided that dose 
superiority of Chronocort to IRHC has been declared under the first key secondary efficacy 
objective. 
9.2. 
Sample Size Determination 
Sufficient participants will be screened and enrolled into the run-in period to achieve 
approximately 50 participants randomly assigned to either Chronocort or IRHC at Visit 2 (25 
participants per treatment arm, regardless of baseline strata), or until a cut-off date of 
30 April 2023, whichever is reached first. Individual study sites should not randomize more 
than 8 participants without first consulting the Sponsor.  A sample size of 25 participants per 
treatment arm will provide at least 80% power to demonstrate non-inferiority of Chronocort 
to IRHC when the biochemical response rate in the IRHC arm is 40%, the non-inferiority 
margin is 15%, and the biochemical response rate in the Chronocort arm is 68% using a 
1-sided continuity corrected z-test with unpooled variance and a 1-sided alpha of 2.5%. 
Note: "Enrolled" means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified. 
Note: Basing the sample size calculation on a continuity corrected z-test provides a 
conservative estimate of sample size relative to the test, based on a logistic model adjusted 
for stratification factors, which will actually be used. 
Note: The anticipated response rates in the treatment arms are based on the corresponding 
results in Study DIUR-005.  


 
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9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened Set 
All participants who sign the ICF. 
Safety Analysis Set (SAF) 
All participants who received, either as part of the run-in or 
post-randomization periods, at least 1 dose of Chronocort or IRHC. 
Participants will be analyzed according to the treatment they 
actually received. The SAF is a subset of the Screened Set. 
Full Analysis Set (FAS) 
All participants with CAH who were randomized into the study and 
who received at least 1 dose of post-randomization study treatment 
(Chronocort or IRHC). Participants in the FAS will be analyzed 
according to randomized treatment. The FAS is a subset of the SAF. 
Efficacy Evaluable Set 
(EES) 
All participants in the FAS who had Visit 2 and Visit 6 (EOS), 
17-OHP and A4 measurements taken at 08:00 hours, and who have 
no critical protocol deviations that affect the assessment of efficacy. 
The EES is a subset of the FAS. 
9.4. 
Statistical Analyses 
The SAP will be developed and finalized before screening of the first participant to the study. 
It will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. Minor changes to the analyses 
specified in this section need not trigger a protocol amendment but must be documented in 
the CSR. 
9.4.1. General Considerations 
All baseline, disposition, protocol compliance, exposure, efficacy and safety variables will be 
listed and summarized by treatment arm. The standard summary statistics for continuous 
baseline and outcome variables are: N, mean, standard deviation (SD), median, quartiles, 
minimum and maximum.  
The standard summary statistics for categorical baseline and outcome variables are count and 
proportion (expressed as percentage). 
9.4.2. 
Efficacy Analyses 
Standard methodology for comparisons: Unless otherwise stated, continuous outcome 
variables will be compared between treatment arms using analysis of variance (ANOVA) 
adjusting for the standard explanatory variables. If a non-normal distribution is anticipated or 
observed, then consideration will be given to using a logarithmic transformation or a 
non-parametric analysis. Analyses of change from baseline will always include the baseline 
value as a covariate. 
Unless otherwise stated, binary outcome variables will be compared between treatment arms 
using logistic regression adjusted for the standard explanatory variables. 


 
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Standard explanatory variables: The standard explanatory variables are (i) whether or not 
the participant was in biochemical control at baseline, (ii) whether or not the participant was 
receiving fludrocortisone at baseline and (iii) their interaction. Randomization of participants 
to treatment arm is stratified by fludrocortisone treatment and the analyses will include the 
stratification of biochemical control. 
Analyses will be stratified or adjusted, as appropriate, on the basis of (i) the participant’s 
fludrocortisone replacement status at baseline (requires fludrocortisone or does not require 
fludrocortisone) and (ii) whether they are in biochemical control at baseline or not (based on 
the androgen results from the baseline visit [Visit 2]). Participants with 17-OHP equal to or 
below the upper limit for optimal control at 08:00 hours and A4 equal to or below the upper 
limit of the reference range will be classified as ‘in biochemical control’. Participants with 
17-OHP above the upper limit for optimal control and/or A4 above the upper limit of the 
reference range will be classified as ‘not in biochemical control’. 
Analysis 
Statistical Analysis Methods 
Primary analysis 
Non-inferiority: a 95% CI will be calculated for the difference (Chronocort 
minus IRHC) in biochemical responder rates. Biochemical non-inferiority 
will be declared if the 95% CI lies wholly above minus 15%. The primary 
analysis will be conducted using the FAS.  
First key secondary 
analysis 
Superiority analysis: a 95% CI will be calculated for the difference 
(Chronocort minus IRHC) in dose responder rates. Dose superiority will be 
declared if the 95% CI lies wholly above zero, provided that biochemical 
non-inferiority of Chronocort to IRHC has been declared under the primary 
efficacy objective. The first key secondary analysis will be conducted using 
the FAS.  
Second key 
secondary analysis 
Superiority analysis: a 95% CI will be calculated for the difference 
(Chronocort minus IRHC) in mean total daily dose after 28 weeks of 
randomized treatment. Superiority with respect to total daily dose after 
28 weeks of randomized treatment will be declared if the 95% CI lies 
wholly below zero, provided that dose superiority of Chronocort to IRHC 
has been declared under the first key secondary objective. The second key 
secondary analysis will be conducted using the FAS.  
Other analyses of 
the primary 
outcome variable 
and of the key 
secondary outcome 
variables (classed 
as secondary 
outcome analyses) 
Analyses of the primary outcome variable other than the primary analysis 
and analyses of the key secondary outcome variables other than the key 
secondary analyses, such as: 
• analysis at other timepoints 
• assessment of the effect of baseline and disease characterizing 
variables, including stratification variables 
• analysis using the EES and subgroups 
are deemed to be supplementary analyses and will be performed using the 
same statistical methodology as will be used for the primary analysis and 
key secondary analyses. Calculated p-values will be indicative rather than 
substantive. 
Other secondary 
outcome variables 
and exploratory 
Analysis of any other secondary outcome variables and of exploratory 
outcome variables will be performed using the standard statistical 
methodology. Calculated p-values will be indicative rather than substantive. 


 
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outcome variables 
9.4.2.1. 
Primary Efficacy Analysis 
Assessment 
17-OHP and A4 plasma concentration obtained from the 08:00 hours blood 
sample at Visit 6 (EOS) and daily dose of hydrocortisone. 
Estimand 
The difference (Chronocort arm minus IRHC arm) in the proportion of 
participants who are biochemical responders at 08:00 hours at Visit 6 
(EOS). 
Population 
The FAS, being representative of the target CAH population. 
Outcome Variable 
The primary efficacy outcome variable is whether or not the participant is a 
biochemical responder after 28 weeks of randomized treatment.  
A biochemical responder is a participant who: 
i) is in biochemical control at the 08:00 hour assessment after 
28 weeks of randomized treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal to or below the upper 
limit for optimal control and an A4 concentration equal to or below 
the upper limit of the reference range) 
and 
ii) is receiving after 28 weeks of randomized treatment 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). 
Intercurrent Events 
(1) participants who withdraw from treatment before Visit 6 (EOS) or who 
do not meet the criteria for being a biochemical responder are deemed 
not to be a biochemical responder. 
(2) participants receiving rescue medication (under ‘stress dosing rules’) 
will continue in the study with unchanged procedures, except that 
Visit 6 (EOS) will be delayed if necessary, to 5 days after the use of 
rescue medication. 
Summary Statistic 
The proportion of participants in each treatment arm who are biochemical 
responders at 08:00 hours at Visit 6 (EOS). 
Analysis 
The difference (Chronocort arm minus IRHC arm) in the proportion of 
participants who are biochemical responders is estimated using logistic 
regression [Ge, 2011], and fludrocortisone use at baseline, biochemical 
control at baseline, and their interaction as explanatory variables. 
Interpretation 
Biochemical non-inferiority of Chronocort to IRHC will be declared if the 
95% CI for the difference in proportions lies wholly above minus 
15 percentage points.  
 
 
 
 
 
 
 
 


 
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Sensitivity Analysis: The main statistical analysis assumes that the treatment effect is 
constant over the standard explanatory variables. Sensitivity analyses will investigate whether 
the treatment effect varies with the explanatory variables.  
Other Analyses: Any other analyses of 17-OHP and A4 concentrations, not otherwise 
specified as a secondary analysis, are supplementary analyses. 
9.4.2.2. 
First Key Secondary Analysis 
Assessment 
17-OHP and A4 plasma concentration obtained from the 08:00 hours blood 
sample at Visit 6 (EOS) and daily dose of hydrocortisone. 
Estimand 
The difference (Chronocort arm minus IRHC arm) in the proportion of 
participants who are dose responders at 08:00 hours at Visit 6 (EOS). 
Population 
The FAS, being representative of the target CAH population. 
Outcome Variable 
The primary efficacy outcome variable is whether or not the participant is a 
dose responder after 28 weeks of randomized treatment.  
A dose responder is a participant who: 
i) is receiving after 28 weeks of randomized treatment a total daily 
dose of hydrocortisone of not more than 25 mg 
and 
ii) is in biochemical control at the 08:00 hour assessment after 
28 weeks of randomized treatment (where in biochemical control 
is defined as both a 17-OHP concentration equal to or below the 
upper limit for optimal control and an A4 concentration equal to 
or below the upper limit of the reference range). 
Intercurrent Events 
(1) participants who withdraw from treatment before Visit 6 (EOS) or who 
do not meet the criteria for being a dose responder are deemed not to be 
a dose responder. 
(2) participants receiving rescue medication (under ‘stress dosing rules’) 
will continue in the study with unchanged procedures, except that 
Visit 6 (EOS) will be delayed if necessary, to 5 days after the use of 
rescue medication. 
Summary Statistic 
The proportion of participants in each treatment arm who are dose 
responders at 08:00 hours at Visit 6 (EOS). 
Analysis 
The difference (Chronocort arm minus IRHC arm) in the proportion of 
participants who are dose responders is estimated using logistic regression 
[Ge, 2011], and fludrocortisone use at baseline, biochemical control at 
baseline, and their interaction as explanatory variables. 
Interpretation 
Dose superiority of Chronocort to IRHC will be declared if the 95% CI for 
the difference in proportions lies wholly above zero, provided that 
biochemical non-inferiority of Chronocort to IRHC has been declared. 
Sensitivity Analysis: The main statistical analysis assumes that the treatment effect is 
constant over the standard explanatory variables. Sensitivity analyses will investigate whether 
the treatment effect varies with the explanatory variables.  
Other Analyses: Any other analyses of dose response, not otherwise specified as a secondary 
analysis, are supplementary analyses. 


 
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9.4.2.3. 
Second Key Secondary Analysis 
Assessment 
Total daily dose of hydrocortisone at Visit 6 (EOS). 
Estimand 
The difference (Chronocort arm minus IRHC arm) in the mean total daily 
dose at Visit 6 (EOS). 
Population 
The FAS, being representative of the target CAH population. 
Outcome Variable 
Total daily dose of hydrocortisone at Visit 6 (EOS). 
Intercurrent Events 
(1) participants who die or withdraw from treatment before Visit 6 (EOS) 
will have their Visit 6 (EOS) dose imputed within a repeated measures 
model. 
(2) participants receiving rescue medication (under ‘stress dosing rules’) 
will continue in the study with unchanged procedures, except that 
Visit 6 (EOS) will be delayed if necessary, to 5 days after the use of 
rescue medication. 
Summary Statistic 
The mean total daily dose in each treatment arm at Visit 6 (EOS). 
Analysis 
The mean difference (Chronocort arm minus IRHC arm) in total daily dose 
after 28 weeks of randomized treatment is estimated using a repeated 
measures model with timepoints 10, 16, and 28 weeks after randomization 
using fludrocortisone use at baseline, biochemical control at baseline, and 
their interaction as explanatory variables. 
Interpretation 
Superiority of Chronocort to IRHC with respect to total daily dose after 
28 weeks of randomized treatment will be declared if the 95% CI for the 
difference in means lies wholly below zero, provided that dose superiority 
of Chronocort to IRHC has been declared. 
Sensitivity Analysis: The main statistical analysis assumes that the treatment effect is 
constant over the standard explanatory variables. Sensitivity analyses will investigate whether 
the treatment effect varies with the explanatory variables.  
Other Analyses: Any other analyses of total daily dose, not otherwise specified as a 
secondary analysis, are supplementary analyses. 
9.4.2.4. 
Other Secondary Efficacy Analyses 
 
Outcome Variables 
Outline Analyses 
Whether or not the participant is a biochemical 
responder at 4, 10, and 16 weeks after 
randomization. 
The same analysis will be used as for the 
primary outcome variable (except that at 
4 weeks there has been no opportunity for a 
dose titration so the condition on dose is not 
used). 
Whether or not the participant is a dose 
responder at 10 and 16 weeks after 
randomization. 
The same analysis will be used as for the first 
key secondary outcome variable. 
Total daily dose at 10 and 16 weeks after 
randomization. 
The same analysis will be used as for the second 
key secondary outcome variable. 
Whether or not the participant is in biochemical 
control (provided total daily dose is not greater 
than 30 mg) at 4, 10, 16, and 28 weeks after 
randomization. 
The same analysis will be used as for the 
primary outcome variable. 
The difference in range as calculated as the 
difference between the 08:00 and 13:00 17-OHP 
Standard methodology for comparisons. 


 
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levels at 4, 10, 16, and 28 weeks after 
randomization. 
The difference in range as calculated as the 
difference between the 08:00 and 13:00 A4 
levels at 4, 10, 16, and 28 weeks after 
randomization. 
Standard methodology for comparisons. 
The mean of the 08:00 and 13:00 levels for each 
androgen at 4, 10, 16, and 28 weeks after 
randomization. 
Standard methodology for comparisons. 
The total daily glucocorticoid dose at 4, 10, 16, 
and 28 weeks after randomization. 
Standard methodology for comparisons. 
Additionally, the mean total daily dose by 
treatment will be calculated for participants in 
and not in biochemical control at the EOS visit. 
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in menstrual 
regularity 
Standard methodology for comparisons (only in 
pre-menopausal women without hysterectomy 
and not using hormonal contraception) 
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in LH levels 
Standard methodology for comparisons (men 
only) 
The change from baseline to 28 weeks of 
randomized treatment in size of TART 
Standard methodology for comparisons (men 
only) 
The change from baseline to 28 weeks of 
randomized treatment in sperm count 
Standard methodology for comparisons (men 
only) 
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective 
hirsutism using the Ferriman-Gallwey score 
Standard methodology for comparisons (women 
only) 
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in objective 
acne using the Global Evaluation Acne (GEA) 
scale 
Standard methodology for comparisons (women 
only) 
The change from screening to 4, 10, 16, and 28 
weeks of randomized treatment in HbA1c levels 
Standard methodology for comparisons  
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in waist 
circumference 
Standard methodology for comparisons  
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in body weight 
Standard methodology for comparisons  
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using 
the self-completed SF-36® total score and the 
sub-domain of vitality 
Standard methodology for comparisons  
The change from baseline to 4, 10, 16, and 28 
weeks of randomized treatment in QoL using 
the MAF 
Standard methodology for comparisons  
The change from baseline to 4, 10, 16, and 28 
weeks in subjective hirsutism and acne using a 
participant-reported VAS. 
Standard methodology for comparisons (women 
only). 
The change from baseline to 4, 10, 16, and 28 
weeks in QoL using the EQ-5D-5L™. 
Standard methodology for comparisons. 


 
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9.4.2.6. 
Safety Analyses 
All safety analyses will be performed on the SAF. 
Endpoint 
Statistical Analysis Methods 
AEs 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 or later and summarized descriptively. Only 
TEAEs will be included in the main safety analysis. A TEAE is defined as 
any AE that has an onset on or after the first dose of study treatment and 
before the last dose of study treatment + 30 days or is any pre-existing AE 
that has worsened in severity on or after the first dose of study treatment and 
before the last dose of study treatment + 30 days. The incidence, nature, 
severity, relatedness, duration, outcome, seriousness and expectedness of 
TEAEs will be tabulated. AEs of special interest will be additionally 
separately tabulated. 
Need for additional 
glucocorticoid doses 
Use of hydrocortisone from the stress dosing packs or use of any additional 
glucocorticoid treatment during the study will be summarized descriptively. 
Other safety 
assessments 
For laboratory parameters, vital signs, and ECGs, change from baseline will 
be calculated at each scheduled post-baseline visit and summary statistics 
will be presented both for absolute values (at baseline and each scheduled 
post-baseline visit) and changes from baseline by treatment arm, and visit. 
Shift tables of baseline to minimum and maximum on-treatment will be 
produced for the appropriate parameters displaying the number and 
percentage of participants in each of the categories (High, Low and Normal) 
relative to the category of their baseline assessment. Results considered 
clinically significant by the Investigator will be summarized at each visit. 
Physical examination results, and their change from baseline, will be 
summarized at each visit. 
9.4.2.7. 
Compliance  
Percentage treatment compliance between visits and overall will be listed and summarized by 
treatment arm. 


 
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9.4.2.8. 
Study Conduct  
Protocol deviations will be classified as ‘major’ or ‘minor’ and will be listed and summarized 
by treatment arm. 
9.4.2.9. 
Other Analyses  
None. 
9.5. 
Interim Analyses  
No formal interim analysis is planned. However, safety data will be generated at regular 
intervals for review by the independent DSMB (see Section 9.6). Details of these DSMB 
outputs will be specified in the DSMB Organizational Meeting Presentation and Minutes and 
DSMB Charter. Any outputs provided to the DSMB will be unblinded, but outputs provided 
to other team members will use a dummy randomization list with generic labels. 
9.6. 
Data Safety Management Board 
An independent DSMB will meet on a regular basis during the study to review safety data. 
The DSMB will operate in accordance with a charter, which is a separate controlled 
document. During the course of the study, if unblinded analyses indicate that AEs are 
occurring more frequently than anticipated, the DSMB will notify the Sponsor, who will 
notify regulatory authorities expeditiously as appropriate. 
 


 
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10. 
Supporting Documentation and Operational Considerations 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
o Applicable ICH GCP Guidelines. 
o Applicable laws and regulations. 
• 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IEC/IRB by the Investigator 
and reviewed and approved by the IEC/IRB before the study is initiated. 
• 
Any substantial amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• 
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IECs/IRBs annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IEC/IRB. 
o Notifying the IEC/IRB of SAEs or other significant safety findings as required by 
IEC/IRB procedures. 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IEC/IRB, European regulation 536/2014 for clinical studies (if applicable), and 
all other applicable local regulations. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• 
Minors will be assented and parental consent sought in keeping with local laws and local 
IEC/IRB requirements. Minors will be re-consented on reaching the age of majority if 
still participating in the study at that time. 
• 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (as defined in the relevant country) will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 


 
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(HIPAA) requirements, where applicable, and the IEC/IRB or study site.  
• 
The medical record must include a statement that written informed consent/assent was 
obtained before the participant was entered in the study and underwent any 
study-specific assessments, and the date the written consent/assent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must generally be re-consented to the most current version of the ICF(s) 
during their participation in the study (i.e. if the change affects procedures or adds new 
safety information) but re-consent may not be required for minor administrative changes. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
A participant who is re-screened is not required to sign another ICF if the re-screening occurs 
within 30 days from the previous ICF signature date. 
Data Protection 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IEC/IRB members, and by inspectors from regulatory 
authorities. 
Committees Structure 
Data Safety Management Board 
This study will include a DSMB which is constituted to safeguard the interests of study 
participants, assist and advise the Sponsor, assess the safety of the study treatments, monitor 
the overall conduct of the clinical study, and uphold data integrity. A separate charter will be 
created to outline the roles and responsibilities of the DSMB, including the timing of 
meetings, methods of providing information to and from the DSMB, frequency and format of 
meetings, recommendations on safety and statistical issues, and relationships with the 
Sponsor and study project team.  
Data Review Meeting 
The Sponsor will convene a Data Review Meeting after the data has been cleaned and the 
database soft-locked but before final database lock and analysis has commenced. The review 
will be performed within the framework of the requirements of the ICH Guideline E9. The 
terms of reference for the Data Review Meeting will include, but will not be limited to: 
• 
the determination of whether protocol deviations are ‘major’ or ‘minor’, or not a protocol 
deviation at all 
• 
the allocation of participants to analysis sets 
• 
a review of missing data and of outliers 
• 
a review of whether additional covariates need to be included in the analyses 


 
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• 
revisions to SAP in light of any Data Review Meeting findings  
All persons taking part in the Data Review Meeting must only have access to datasets masked 
to treatment allocation. Treatment arm allocations will be scrambled using a dummy 
randomization list and presented using generic treatment labels (for example, “Group A” and 
“Group B”). 
Dissemination of Clinical Study Data 
The Sponsor will comply with regulatory requirements on disclosure and dissemination of 
clinical study data in line with its SOPs. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on eCRFs unless transmitted 
directly to the Sponsor or designee electronically (e.g. laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.  
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• 
The Investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• 
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g. Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification (SDV) to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements.  
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator after study completion for as long as local 
regulations or institutional policies require. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Remote Monitoring Visits 
If remote monitoring is being conducted, SDV against the source documents will be 
conducted using remote access to the participants electronic medical records or using scanned 
documents, if either are permitted. All participant identifiers must be redacted prior to 
scanning (further details are provided in the Clinical Monitoring Plan). However, it should be 
noted that sending copies of medical records, even pseudonymized, is not authorized in 
France, in accordance with the national recommendations published on the ANSM website 


 
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(https://www.ansm.sante.fr/Activites/Essais-cliniques/COVID-19-Ongoing-clinical-
trials/(offset)/1). 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
The information in original documents and records (e.g. patient files, laboratory results, 
etc.) are defined as source data and will be reviewed by the monitor for SDV. SDV 
ensures accuracy and credibility of the data obtained. During monitoring visits, reported 
data are reviewed with regard to being accurate, complete and verifiable from source 
documents. 
Study and Site Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The Sponsor reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. Reasons for the 
early closure of a study site by the Sponsor or Investigator may include but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• 
Inadequate recruitment of participants by the Investigator. 
• 
Discontinuation of further study treatment development. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organizations used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the 
participants and should assure appropriate therapy and follow-up. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multi-site studies only in their entirety and not as individual site 
data. In this case, a Coordinating Investigator will be designated by mutual agreement. 


 
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• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
The Sponsor will also publish the study results in an appropriate public registry that complies 
with the regulations and rules applicable to the study. 
 


 
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Appendix 2: Clinical Laboratory Tests 
The tests detailed in the table below will be performed by the central laboratory. The results 
will either be entered into the eCRF by the site staff or transferred electronically by the 
central laboratory. The Investigator must document their review of each laboratory safety 
report. Participants are required to fast before the collection of the 08:00 androgen sample, 
but there is no requirement for the participant to be fasting for any of the other laboratory 
tests.  
Protocol-Required Safety and Efficacy Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean cell hemoglobin 
(MCH) 
Mean cell hemoglobin 
concentration (MCHC)  
Red cell distribution width 
(RDW) 
White blood cell 
(WBC) count with 
differential (absolute 
and %): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
count 
Hemoglobin 
Hematocrit 
HbA1c 
Clinical 
Chemistry 
Blood urea 
nitrogen 
(BUN) 
Potassium 
AST/serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT/serum glutamic-
pyruvic transaminase 
(SGPT) 
Total protein 
Inorganic 
phosphorus 
Calcium 
Alkaline phosphatase 
Lactate 
dehydrogenase 
(LDH) 
Chloride 
Total 
carbon 
dioxide 
(CO2) 
Albumin 
Total creatine kinase 
(CK) 
Total 
magnesium 
FSH 
LH 
Uric acid 
Osteocalcin 
DHEA 
11-ketotestosterone 
Total testosterone 
Androgens (17-OHP and A4) 
 
Plasma renin activity (PRA) or plasma renin concentration (PRC) after the 
participant has been supine for 30 minutes if possible 
Routine 
Urinalysis 
• Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and 
urobilinogen. 
• Microscopic examination (if blood or protein is abnormal). 
Other 
Screening 
Tests 
• Urine or blood human chorionic gonadotropin (hCG) pregnancy test (as 
needed for WOCBP). 
NOTES: 
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN at any time 
may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE. 
 
 
 


 
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Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e. not related 
to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• ‘Lack of efficacy’ or ‘failure of expected pharmacological action’ per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
 


 
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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital or hospitalization for elective surgery). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g. hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
 


 
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d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medically Important Events 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF and 
any SAEs will be reported to the pharmacovigilance group using the SAE/AESI 
Report Form. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor or designee. In this case, all participant identifiers, with 
the exception of the participant number, will be redacted on the copies of the 
medical records before submission to the Sponsor or designee. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
 
 


 
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Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report. However, it is very important 
that the Investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• All AEs will be assigned one of the following assessments of causality (note: both 
Chronocort and IRHC and the stress dosing medication are considered study 
treatments in this context): 
o Definitely related to the study treatment  
o Probably related to the study treatment 
o Possibly related to the study treatment  


 
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o Unlikely to be related to the study treatment 
o Not related to the study treatment 
• All AEs judged by either the Investigator or the Sponsor as having a reasonable 
suspected causal relationship to a study treatment or are due to an interaction with a 
study treatment, qualify as adverse drug reactions (ADRs). 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the Investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF and 
the SAE/AESI Report Form. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information. 
Reporting of SAEs and AESIs 
SAE and AESI Reporting via Paper Form 
The SAE or AESI information should be reported by email using the SAE/AESI Report 
Form to the Sponsor’s Medical Monitor and to the pharmacovigilance contact below: 
Pharmalex 
Email: diurnalclinicalsafety@pharmalex.com 
 
The medical monitor will be allocated by the Contract Research Organization and the 
contact details provided to each site. 


 
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Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Female participants presenting with oligomenorrhea or amenorrhea who are aged ≤55 years 
should be considered potentially fertile and therefore should undergo pregnancy testing like 
all other female participants. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Pre-menopausal female with 1 of the following: 
• documented hysterectomy 
• documented bilateral salpingectomy 
• documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
2. Post-menopausal female 
• A post-menopausal state is defined as a woman over 55 years who has not had 
menses for 12 months without an alternative medical cause. A high FSH level in 
the post-menopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormone replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status before study enrollment. 
Contraception Guidance 
Couples should agree not to try to become pregnant during this study. It should be noted that 
Chronocort treatment may result in improved fertility and so appropriate precautions against 
pregnancy should be taken. 
Male participants 
• Male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following:  
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
o Agree to use a male condom when having penile-vaginal intercourse with a 
WOCBP who is not currently pregnant. 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
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for the duration of the study. Men must also refrain from donating sperm for the duration of 
the study and for 7 days after the last dose of study treatment. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. The methods of contraception must remain the same throughout the study in both 
nature and dose. The type of contraception should have been ongoing for ≥90 days prior to 
the study and at least 7 days after the final dose. If <90 days prior to the study, additional use 
of a double barrier method until 90 days is reached is required.  
Contraceptive Methods 
Highly Effective Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• oral  
• intra-vaginal  
• trans-dermal.  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• oral  
• injectable.  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• intra-uterine device 
• intra-uterine hormone-releasing system. 
• Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  


 
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Barrier methods of contraception 
Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. The following should be noted:  
Failure rates indicate that, when used alone, the diaphragm and condom are not highly 
effective forms of contraception. Therefore, the use of additional spermicides does confer 
additional theoretical contraceptive protection. However, spermicides alone are inefficient 
at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are 
not a barrier method of contraception and should not be used alone.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating in 
clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for 7 days after the last dose of study treatment. 
Pregnancy testing 
• WOCBP should only be included after a confirmed negative highly sensitive urine 
pregnancy test (or blood test if required according to usual site practices) taken at the 
screening visit (Visit 1). 
• Additional pregnancy testing should be performed at every clinic visit from Visit 2 
onwards.  
• Pregnancy testing will be performed if pregnancy is suspected.  
Collection of Pregnancy Information  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study.  
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy to Pharmalex (diurnalclinicalsafety@pharmalex.com). The female partner 
will also be followed up to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. Generally, the 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure.  
Female Participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant’s pregnancy to Pharmalex (diurnalclinicalsafety@pharmalex.com). The 
participant will be followed up to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 


 
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termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• Any post-study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in 
Section 8.4.1. While the Investigator is not obligated to actively seek this information 
in former study participants, he/she may learn of an SAE through spontaneous 
reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment and will be followed up as detailed above (with consent 
of the participant). However, participants who withdraw from the study due to 
pregnancy may be eligible to enter the long-term extension study (DIUR-015) at the 
discretion of the Investigator providing that at least 6 weeks has lapsed after the 
pregnancy is complete (i.e. at least 6 weeks post-partum regardless of outcome or at 
least 6 weeks after abortion or termination) or at least 6 weeks after they have finished 
lactating and are no longer breast feeding (whichever is longer). 
 


 
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Appendix 5: Adrenal Insufficiency Checklist 
This questionnaire should be used to determine if symptoms of under- or over-replacement 
of glucocorticoids have occurred in the preceding 4 weeks. Symptoms unrelated to CAH, but 
due to other causes, e.g. nausea with migraine, should be recorded on the eCRF AE page. 
Version FINAL 1.0 – 01 Sept 2015 
 
 
Date of assessment (mm/dd/yyyy):
Please ask subject:
Have you experienced any of the following symptoms 
more than once per week in the last 4 weeks?
Symptoms
Yes
If Yes, do you believe 
this to be related to 
under or over 
replacement of 
glucocorticoid? 
Please state 
over/under.
No
Any 
clinically 
significant 
findings? 
Y/N
Sudden weight loss
Sudden weight gain
Lack of appetite
Increased appetite
Nausea
Vomiting
Headache
Blurred vision
Fatigue
Weakness
Dizziness
Lightheadedness
Syncope (sudden loss
of consciousness)
Sleeping difficulties
Increased acne
Other
If yes to Other please specify:


 
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Appendix 6: Stress Dosing Rules 
Each site should follow their own stress dosing rules, or if these are not available then the 
following rules should be used: 
ADRENAL INSUFFICIENCY 
Your body does not make adequate cortisol or aldosterone. Cortisol is a hormone which has 
many purposes in the body including maintaining blood pressure. Normally cortisol is 
secreted in the body in small amounts every day by the adrenal glands. In addition to the 
usual production of cortisol, the body normally has the ability to increase cortisol production 
in response to various stressors such as infection or trauma. Aldosterone is a hormone which 
is important in regulating salt and water balance. Sufficient aldosterone is necessary to 
prevent dehydration. These two hormones are being replaced in your body by medications.  
 
Extra hydrocortisone must be given during times of extreme physical stress such as illness 
with fever and significant trauma.  
 
For illnesses which result in:  
 
Fever greater than or equal to 100°F (37.7°C)/ minor illnesses: take 10 mg hydrocortisone 
three times a day in addition to the usual daily dose of study medication. 
 
Fever greater than or equal to 101°F (38.3°C)/ more severe illness: take 20 mg 
hydrocortisone three times a day in addition to the usual daily dose of study medication. 
 
Vomiting: If you vomit, wait one half-hour and then take 20 mg of hydrocortisone for stress 
dosing rules from your packet provided. If you vomit the study medication dose do not take 
another dose of study medication until the next dose is due. Call the study team to let us 
know you are sick. If you are vomiting and cannot keep the medication down (vomit less than 
1 hour after the dose), you need to administer injectable hydrocortisone. Do not delay giving 
injectable hydrocortisone. Drink SMALL amounts of clear liquids frequently, as tolerated. 
Call your doctor or go to an emergency room if your symptoms worsen or you do not 
improve within one hour. 
 
Watch for signs of acute cortisol deficiency: headache, nausea, abdominal pain, dehydration, 
confusion, weakness, fatigue.  
 
An injectable form of hydrocortisone must be kept in an easily accessible location for 
emergencies (i.e., purse, briefcase, desk at work). It may be kept for several years in the 
unmixed form at room temperature. It should not be exposed to extreme hot or cold (i.e., do 
not store in the glove compartment of a car). Check the expiration date routinely and obtain a 
prescription refill when needed. Also make sure you have the needle necessary to inject the 
medication.  
 
Your dose of hydrocortisone for injection is 100 mg – 2 mL by intramuscular injection 
to the thigh.  
 


 
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Other points to remember:  
 
• When you are sick, drink sugar and salt containing liquids (e.g., non-diet soda, 
Gatorade, Lucozade, soup). 
 
• If you need to have surgery, extensive dental work, or you have been in an accident, 
extra doses of hydrocortisone will be needed, usually by intramuscular injection or 
intravenous administration. Notify any physician or dentist that you have ADRENAL 
INSUFFICIENCY, so proper amounts of hydrocortisone can be given prior to a 
procedure.  
 
• It is essential that you wear a medical identification bracelet or necklace to alert 
people in times of emergency that you have adrenal insufficiency and are taking 
medication. It is also a good idea to have a wallet card or something on your driver’s 
licence identifying you as having ADRENAL INSUFFICIENCY.  
 
• Call your doctor for:  
Fever for more than three days 
Changes in behavior, such as acting confused 
 
• If you are living with someone, let them know to seek medical help on your behalf if 
you are unresponsive or difficult to arouse. 
 
Ensure that you have a list of important phone numbers:  
Nurse: 
Doctor: 
Pharmacy: 
 


 
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Appendix 7: Abbreviations 
Abbreviation 
Definition 
17-OHP 
17-hydroxyprogesterone 
A4 
Androstenedione 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
AE  
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAH 
Congenital adrenal hyperplasia 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
CO2 
Carbon dioxide 
CONSORT 
Consolidated Standards of Reporting Trials 
CSR 
Clinical Study Report 
CYP3A4 
Cytochrome P450 3A4 
DHEA 
Dehydroepiandrosterone 
DSMB 
Data Safety Management Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EES 
Efficacy Evaluable Set 
EOS 
End of study 
ePRO 
Electronic patient reported outcome 
EQ-5D-5L™ 
5-level Standardized Health Questionnaire 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
GEA 
Good Clinical Practice 
Global Evaluation Acne 
HbA1c 
Glycated hemoglobin 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
IEC 
International Council for Harmonization 
Independent Ethics Committee 
IMP 
Investigational medicinal product  


 
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IRB 
Institutional Review Board 
IRHC 
Immediate-release hydrocortisone 
IRT 
Interactive response technology 
LC-MS-MS 
Liquid chromatography tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LPLV 
Last participant last visit 
MAF 
Multidimensional Assessment of Fatigue 
MCH 
Mean cell hemoglobin 
MCHC 
Mean cell hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
PK 
Pharmacokinetic(s) 
PRA 
Plasma renin activity 
PRC 
Plasma renin concentration 
QoL 
Quality of life 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SF-36® 
Medical Outcome Study 36-Item Short Form Health Survey 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reactions 
TART 
Testicular adrenal rest tumors 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
Note: A participant in this clinical study is an individual subject who agrees to participate in 
the study as either as recipient of an investigational medicinal product or as a control. 
 
 
 


 
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Appendix 8: Protocol Amendment History 
Amendment 1 (04-May-2021) 
Overall Rationale for the Amendment: 
In developing the detailed titration guidelines for the investigator, it was determined that 
there was the potential for unblinding by allowing the investigators to know the androgen 
levels (17-OHP and A4) so this was amended so only the central independent blinded 
physician has access to the androgen results. In addition, the choices for participants at the 
end of the study was amended to allow access to commercial Chronocort, depending on the 
territory. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 2 (27-Jan-2022) 
Overall Rationale for the Amendment: 
Following review by the FDA and the French Regulatory Authority (ANSM) several changes 
have been made to the protocol. In addition, a few other changes have been made to amend 
errors or to reflect how the study will be run. All these changes are detailed below: 


 
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Amendment 3 (04-Mar-2022) 
Overall Rationale for the Amendment: 
Following a second review by the French Regulatory Authority (ANSM) an additional 
change has been made to the protocol. In addition, a few other changes have been added that 
have arisen during the study start-up process. All these changes are detailed below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Amendment 4 (23-Mar-2022) 
Overall Rationale for the Amendment: 
The schedule of assessments was incorrect, so this plus a few other minor changes have been 
implemented. All these changes are detailed below: 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 5 (09-Feb-2023) 
Overall Rationale for the Amendment: 
Following a change in the Sponsor’s regulatory strategy, the 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). In addition, the visit windows for the telephone calls have been 
widened for practical reasons. Elsewhere other clarifications have been added. All the 
changes are marked in the tracked changes version of the protocol, with the key changes 
summarized below: 


 
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11. 
References 
Allolio B. Extensive expertise in endocrinology. Adrenal crisis. Eur J Endocrinol. 
2015;172(3):R115-24. 
Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, et al. Health status of adults 
with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 
2010;95(11):5110-21. 
Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis 
and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice 
guideline. J Clin Endocrinol Metab. 2016;101(2):364-89. 
 
 
Chakhtoura Z, Bachelot A, Samara-Boustani D, Ruiz JC, Donadille B, Dulon J, et al. Impact 
of total cumulative glucocorticoid dose on bone mineral density in patients with 
21-hydroxylase deficiency. Eur J Endocrinol. 2008;158(6):879-87. 
Debono M, Mallappa A, Gounden V, Nella AA, Harrison RF, Crutchfield CA, et al. 
Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying 
optimal monitoring times and novel disease biomarkers. Eur J Endocrinol. 
2015;173(6):727-37.  
Dreno B, Poli F, Pawin H, Beylot C, Faure M, Chivot M, et al. Development and evaluation 
of a Global Acne Severity Scale (GEA Scale) suitable for France and Europe. J Eur Acad 
Dermatol Venereol. 2011:25(1);43-48. 
Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, et al. Clinical 
characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin 
Endocrinol Metab. 2012;97(12):4429-38. 
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-adjusted difference in 
proportions from clinical trials using logistic regression and weighted risk differences. Ther 
Innov Regul Sci. 2011;45(4):481-93.  
Ghizzoni L, Bernasconi S, Virdis R, Vottero A, Ziveri M, Volta C, et al. Dynamics of 
24-hour pulsatile cortisol, 17-hydroxyprogesterone, and androstenedione release in 
prepubertal patients with nonclassic 21-hydroxylase deficiency and normal prepubertal 
children. Metabolism 1994;43(3):372-7. 
Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with 
congenital adrenal hyperplasia. Nat Rev Endocrinol. 2014;10(2):115-24. 
Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, etiology, and 
management. Am J Obstet Gynecol. 1981;140(7):815-30.  
Jones CM, Mallappa A, Reisch N, Nikolaou N, Krone N, Hughes BA, et al. Modified-release 
and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal 
hyperplasia. J Clin Endocrinol Metab. 2017;102(6):1797-806. 
Maguire AM, Ambler GR, Moore B, McLean M, Falleti MG, Cowell CT. Prolonged 
hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone 
deficiency. Pediatrics. 2007;120(1):e164-71. 


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Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D, et al. A phase 2 study 
of Chronocort®, a modified-release formulation of hydrocortisone, in the treatment of adults 
with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015;100(3):1137-45. 
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-36. 
Merke DP. Approach to the adult with congenital adrenal hyperplasia due to 21-hydroxylase 
deficiency. J Clin Endocrinol Metab. 2008;93(3):653-60.  
Pang S, Clark A, Neto EC, Giugliani R, Dean H, Winter J, et al. Congenital adrenal 
hyperplasia due to 21-hydroxylase deficiency: Newborn screening and its relationship to the 
diagnosis and treatment of the disorder. Screening. 1993;2(2-3);105-39. 
Reichstein T, Steiger M. Desoxy-cortico-sterone (21-oxy-progesteron) aus delta 5-3-oxy-atio-
cholensaure. Helv Chim Acta. 1937;20(1):1164-79. 
Schnaider-Rezek GS, Lemos-Marini SH, Baptista MT, Guerra-Junior G, Morcillo AM, Mello 
MP, et al. Metabolic evaluation of young women with congenital adrenal hyperplasia. Arq 
Bras Endocrinol Metabol. 2011;55(8):646-52. 
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital 
adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical 
practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133-60. 
Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital 
adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical 
practice guideline. J Clin Endocrinol Metab. 2018;103(11):4043-88.  
Storbeck KH, Schiffer L, Baranowski ES, Chortis V, Prete A, Barnard L, et al. Steroid 
metabolome analysis in disorders of adrenal steroid biosynthesis and metabolism. Endocr 
Rev. 2019;40(6):1605-25. 
Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin 
North Am. 2001;30(1):15-30.  

SAP_001.pdf: 
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Statistical Analysis Plan 
Title: 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 
Protocol Number: DIUR-014 
Protocol Version: 6.0 / 09 February 2023 
Sponsor: Diurnal  
SAP Version 4.0 
SAP Issue Date: 22 Feb 2024 
SAP Authors: 
 
 
 
 
NCT#: NCT05063994


 
  
 
 
 
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Revision History 
Version Issue Date 
Revision / Addition 
Rationale 
1.0 
30-Nov-2021 
Initial Release Version 
 
2.0 
12-Jul-2022 
Version 2.0 
Updated for Protocol 
Version 5.0. 
In addition, definition of 
Efficacy Evaluable Set 
updated to only exclude 
subjects with major 
protocol deviations that 
are deemed to have an 
effect on the assessment 
of efficacy.
3.0 
26-Jun-2023 
Version 3.0 
Updated for Protocol 
Version 6.0.
4.0 
22-Feb-2024 
Version 4.0 
Update for Protocol 
Version 7.0, updates prior 
to the Database Lock
 
 
 


 
  
 
 
 
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I confirm that I have reviewed this document and agree with the content. 
 
Approvals 
Syneos Health Approval 
 
 
 
 
 
 
Name, Title 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
 
Name, Title 
 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
Diurnal Ltd Approval 
 
 
 
 
 
Name, Title 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 


 
  
 
 
 
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Table of Contents 
APPROVALS ................................................................................................................................ 3 
1 
INTRODUCTION ....................................................................................................... 6 
2 
STUDY OBJECTIVES & ENDPOINTS/OUTCOME VARIABLES ........................ 8 
3 
SAMPLE SIZE .......................................................................................................... 15 
4 
RANDOMIZATION & UNBLINDING ................................................................... 16 
5 
PLANNED ANALYSES ........................................................................................... 17 
5.1 
Analysis Sets .............................................................................................................. 18 
5.2 
Derived Data .............................................................................................................. 18 
5.2.1 
Race ............................................................................................................................ 19 
5.2.2 
Baseline ...................................................................................................................... 19 
5.2.3 
Duration / Study Day / Time ...................................................................................... 19 
5.2.4 
Quality of Life: SF-36, MAF, EQ-5D........................................................................ 19 
5.2.5 
Participants Recruited before Implementation of Protocol Version 6.0 .................... 20 
5.2.6 
Conventions for Missing and Partial Dates................................................................ 20 
5.2.7 
Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications ................................................................................................................ 20 
5.2.8 
Missing Last Dates of Study Drug Dosing ................................................................ 22 
5.2.9 
Missing Diagnosis Dates ............................................................................................ 22 
5.2.10 
Exposure to Study Drug ............................................................................................. 22 
5.2.11 
Inexact Values ............................................................................................................ 22 
5.2.12 
Electrocardiogram (ECG) Data .................................................................................. 22 
5.2.13 
Visit Windows............................................................................................................ 23 
5.2.14 
Unscheduled Visits .................................................................................................... 23 
5.2.15 
Randomization Strata ................................................................................................. 23 
5.3 
General Considerations .............................................................................................. 23 
5.3.1 
Tables and Listings .................................................................................................... 23 
5.3.2 
Decimal Places ........................................................................................................... 24 
5.4 
Participant Disposition ............................................................................................... 25 
5.5 
Protocol Deviations .................................................................................................... 25 
5.6 
Demographic and Other Baseline Characteristics ..................................................... 26 
5.7 
Medical History.......................................................................................................... 26 
5.8 
Other Baseline Characteristics ................................................................................... 26 
5.9 
Covid-19 Visit Impact ................................................................................................ 27 
5.10 
Exposure to Study Drug ............................................................................................. 27 
5.11 
Efficacy Analyses ...................................................................................................... 27 


 
  
 
 
 
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5.11.1 
Statistical Hypotheses ................................................................................................ 27 
5.11.2 
Estimands ................................................................................................................... 30 
5.11.3 
Estimand Related Data Handling ............................................................................... 33 
5.11.4 
Analysis of the Primary Efficacy Endpoint ............................................................... 36 
5.11.5 
Key Secondary Efficacy Endpoints and Analyses ..................................................... 37 
5.11.6 
Other Secondary Efficacy Endpoints ......................................................................... 39 
 
 
5.11.8 
Multiplicity................................................................................................................. 42 
5.12 
Safety Analyses .......................................................................................................... 43 
5.12.1 
Summary .................................................................................................................... 43 
5.12.2 
Adverse Events .......................................................................................................... 44 
5.12.3 
Prior, Concomitant and Subsequent Medication........................................................ 46 
5.12.4 
Rescue Medication ..................................................................................................... 47 
5.12.5 
Need for Additional Glucocorticoid Doses ................................................................ 47 
5.12.6 
Laboratory Data ......................................................................................................... 47 
5.12.7 
Vital Signs .................................................................................................................. 48 
5.12.8 
Electrocardiogram Data ............................................................................................. 48 
5.12.9 
Physical Examination ................................................................................................. 48 
6 
INTERIM ANALYSIS .............................................................................................. 48 
7 
DATA SAFETY MONITORING BOARD ANALYSIS .......................................... 48 
8 
CHANGES TO PLANNED PROTOCOL ANALYSIS ............................................ 49 
9 
CHANGES TO PLANNED ANALYSIS FROM SAP VERSION 1.0 ..................... 49 
10 
REFERENCES........................................................................................................... 51 
11 
APPENDICES ........................................................................................................... 52 
11.1 
Quality of Life Derivation.......................................................................................... 52 
11.1.1 
SF-36 Scoring Information ........................................................................................ 52 
11.1.2 
Multidimensional Assessment of Fatigue (MAF) ...................................................... 56 
11.1.3 
EQ-5D ........................................................................................................................ 56 
 
 
 
 
 
 
 
 
 


 
  
 
 
 
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1 
INTRODUCTION 
This document details the planned statistical analyses for the Diurnal, protocol “DIUR-014” 
study titled “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”. 
The proposed analyses are based on the contents of the final version 7.0 of the protocol (dated 30 
October 2023).  
Congenital adrenal hyperplasia (CAH) is most commonly caused by 21-hydroxylase deficiency 
that results in cortisol deficiency, with or without aldosterone deficiency, and androgen excess. 
Patients are currently treated with glucocorticoid replacement therapy, but immediate release 
formulations fail to replicate the natural cortisol circadian rhythm, and patients often struggle to 
take a midday dose, resulting in patients being poorly controlled. Chronocort® is a newly 
developed modified release oral formulation of hydrocortisone, and it is designed to closely 
replicate the normal serum levels of the endogenous cortisol circadian rhythm, offering the 
prospect of an improved treatment outcome and a novel treatment paradigm.  
The proposed study will evaluate whether a twice daily dosing regimen of Chronocort®, with 
two-thirds of the total daily dose given at night and one-third in the morning (which can more 
closely replicate circadian cortisol levels) will improve control of adrenal androgen production 
(as measured by 17-hydroxyprogesterone [17-OHP] and androstenedione [A4]) compared to a 
similarly titrated regimen of twice daily immediate release hydrocortisone replacement therapy 
(IRHC) in conditions broadly resembling routine clinical practice. The study design is presented 
in the schema in Figure 1. 
This is a randomized, double blind, active controlled, titrated, parallel arm, multicenter study.  
After a 4-week run-in period, participants will be randomized on a 1:1 basis to either 
Chronocort® or IRHC (Cortef®, Pfizer Inc.).  
Version 1.0 of the statistical analysis plan (SAP) was developed and finalized before the first 
participant is screened and contained a full description of the statistical methods to be used. 
Versions 2.0 and 3.0 have updated the SAP in line with the subsequent protocol amendments.  
Version 4.0 incorporated additional considerations for statistical analysis based on blinded 
review of the data prior to the database lock. Any changes from the analyses planned in Version 
1.0 of the SAP are detailed in Section 9. 
 
 


 
  
 
 
 
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Figure 1 
EOS = end of study; IRHC = immediate-release hydrocortisone; IR
T 
= interactive response technology 
Note: timelines not to scale 
 
 


 
  
 
 
 
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2 
STUDY OBJECTIVES & ENDPOINTS/OUTCOME VARIABLES 
Objectives 
Outcome Variables and Analyses Supporting the 
Objectives 
Primary Efficacy 
 
 To compare Chronocort to IRHC in terms 
of biochemical responder rate after 28 
weeks of randomized treatment. 
 
 
 
 
 
 
 
 The primary efficacy outcome variable is whether 
or not the participant is a biochemical responder 
after 28 weeks of randomized treatment.  
A biochemical responder is a participant who: 
i) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (wherein biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 
upper limit of the reference range),  
and 
ii) is receiving after 28 weeks of randomized 
treatment 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). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are biochemical responders 
28 weeks after randomization will be estimated in 
the Full Analysis Set (FAS). Participants who die 
or withdraw from treatment before 28 weeks will 
be classified as not a biochemical responder. 
Participants receiving rescue medication under the 
'stress dosing rules' within 5 days before the 
scheduled visit at 28 weeks after randomization 
will have their visit delayed appropriately1. 
Biochemical non-inferiority of Chronocort to 
IRHC will be declared if the 95% confidence 
interval (CI) for the difference in proportions lies 
wholly above minus 15 percentage points. 
 
 
 
 
Key Secondary Efficacy 
 


 
  
 
 
 
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 1) To compare Chronocort to IRHC in 
terms of dose responder rate after 28 weeks 
of randomized treatment.  
 
 
 
 
 
 
 The first key secondary efficacy outcome variable 
is whether or not the participant is a dose 
responder after 28 weeks of randomized 
treatment.  
A dose responder is a participant who: 
i) is receiving after 28 weeks of randomized 
treatment a total daily dose of hydrocortisone 
of not more than 25 mg, and 
ii) is in biochemical control at the 08:00 hours 
assessment after 28 weeks of randomized 
treatment (where in biochemical control is 
defined as both a 17-OHP concentration equal 
to or below the upper limit for optimal control 
and an A4 concentration equal to or below the 
upper limit of the reference range). 
The difference (Chronocort minus IRHC) 
between the proportion of participants in each 
treatment arm who are dose responders 28 weeks 
after randomization will be estimated in the FAS. 
Participants who die or withdraw from treatment 
before 28 weeks will be classified as not a dose 
responder. Participants receiving rescue 
medication under the 'stress dosing rules' within 
5 days before the scheduled visit at 28 weeks 
after randomization will have their visit delayed 
appropriately1. 
Dose superiority of Chronocort to IRHC will be 
declared if the 95% CI for the difference in 
proportions lies wholly above zero, provided that 
biochemical non-inferiority of Chronocort to 
IRHC has been declared under the primary 
efficacy objective.
 2) To compare Chronocort to IRHC in 
terms of total daily dose after 28 weeks of 
randomized treatment. 
 The second key secondary efficacy outcome 
variable is the total daily dose (mg) after 
28 weeks of randomized treatment.  
The difference (Chronocort minus IRHC) 
between the mean total daily dose after 28 weeks 
of randomized treatment in each treatment arm 
will be estimated in the FAS. Superiority of 
Chronocort to IRHC with respect to total daily 
dose after 28 weeks of randomized treatment will 
be declared if the 95% CI for the difference in 
means lies wholly below zero, provided that 
biochemical non-inferiority of Chronocort to 
IRHC has been declared under the primary 


 
  
 
 
 
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efficacy objective and dose superiority of 
Chronocort to IRHC has been declared under the 
first key secondary efficacy objective.
Other Secondary Efficacy 
 
 To compare Chronocort to IRHC in terms 
of biochemical responders at 4, 10 and 16 
weeks after randomization. 
 
 
 The outcome variables whether or not the 
participant is a biochemical responder at 08:00 
hours at 4, 10 and 16 weeks after randomization 
are compared between treatment arms by 
calculating the difference in proportion of 
participants responding. These outcome variables 
are to be analyzed in the same manner as the 
primary efficacy outcome variable. 
 To compare Chronocort to IRHC in terms 
of dose responders at 10 and 16 weeks after 
randomization. 
 The outcome variables whether or not the 
participant is a dose responder at 08:00 hours at 
10 and 16 weeks after randomization are 
compared between treatment arms by calculating 
the difference in proportion of participants 
responding. These outcome variables are to be 
analyzed in the same manner as the key 
secondary outcome variable. 
 To compare Chronocort to IRHC in terms 
of total daily dose at 10 and 16 weeks after 
randomization. 
 The outcome variables total daily dose at 10 and 
16 weeks after randomization are compared 
between treatment arms by calculating the 
difference in mean total daily dose. These 
outcome variables are to be analyzed in the same 
manner as the second key secondary outcome 
variable. 
 To compare Chronocort to IRHC in terms 
of biochemical control at 4, 10, 16 and 28 
weeks after randomization. 
 The outcome variables whether or not the 
participant is in biochemical control (provided 
total daily dose is not more than 30 mg) at 08:00 
hours at 4, 10, 16 and 28 weeks after 
randomization are compared between treatment 
arms by calculating the difference in proportion 
of participants in control. 
 To compare Chronocort to IRHC in terms 
of the impact on 17-OHP range. 
 The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of 17-OHP levels at 4, 10, 16 and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 


 
  
 
 
 
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 To compare Chronocort to IRHC in terms 
of the impact on A4 range. 
 The difference in range as calculated as the 
difference between the 08:00 and 13:00 
measurements of A4 levels at 4, 10, 16 and 28 
weeks after randomization and their changes from 
baseline will be summarized and compared 
between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on mean 17-OHP and A4. 
 The mean of the 08:00 and 13:00 measurements 
of 17-OHP levels and A4 levels at 4, 10, 16 and 
28 weeks after randomization and their changes 
from baseline will be summarized and compared 
between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on glucocorticoid dose. 
 The total daily glucocorticoid dose at 4, 10, 16 
and 28 weeks after randomization will be 
summarized and compared between treatment 
arms. 
 The relationship between daily glucocorticoid 
dose and biochemical control at 28 weeks after 
randomization will be explored. 
 To compare Chronocort to IRHC in terms 
of changes in menstrual regularity. 
 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in menstrual 
regularity (only in pre-menopausal women 
without hysterectomy and not using hormonal 
contraception) will be summarized and compared 
between treatment arms.  
 To compare Chronocort to IRHC in terms 
of the impact on luteinizing hormone (LH) 
levels. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in LH levels (men 
only) will be summarized and compared between 
treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on testicular adrenal rest 
tumors (TART) size. 
 The change from baseline to 28 weeks of 
randomized treatment in size of TART (men 
only) will be summarized and compared between 
treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on sperm count. 
 The change from baseline to 28 weeks of 
randomized treatment in sperm count (men only) 
will be summarized and compared between 
treatment arms. 


 
  
 
 
 
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 
To compare Chronocort to IRHC in terms 
of the impact on subjective hirsutism in 
female participants. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in subjective 
hirsutism (women only) will be summarized and 
compared between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on objective hirsutism in 
female participants. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in objective 
hirsutism using the Ferriman-Gallwey score 
(women only) will be summarized and compared 
between treatment arms. 
 
To compare Chronocort to IRHC in terms 
of the impact on subjective acne in female 
participants. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in subjective acne 
using a visual analogue scale (VAS) (women 
only) will be summarized and compared between 
treatment arms. 
 
To compare Chronocort to IRHC in terms 
of the impact on objective acne in female 
participants. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in objective acne 
using the Global Evaluation Acne (GEA) scale 
(women only) will be summarized and compared 
between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on glycated hemoglobin 
(HbA1c) levels. 
 The change from screening to 4, 10, 16 and 28 
weeks of randomized treatment in HbA1c levels 
will be summarized and compared between 
treatment arms. 


 
  
 
 
 
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 To compare Chronocort to IRHC in terms 
of the impact on waist circumference. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in waist 
circumference will be summarized and compared 
between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on body weight. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in body weight 
will be summarized and compared between 
treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on quality of life (QoL) using 
the self-completed Medical Outcome Study 
36-Item Short Form Health Survey (SF-
36®) total score and the sub-domain of 
vitality. 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in QoL using the 
self-completed SF-36® total score and the 
sub-domain of vitality will be summarized and 
compared between treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on QoL using the 
Multidimensional Assessment of Fatigue 
(MAF). 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in QoL using the 
MAF will be summarized and compared between 
treatment arms. 
 To compare Chronocort to IRHC in terms 
of the impact on QoL using the 5-level 
Standardized Health Questionnaire 
(EQ-5D-5L™). 
 The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in QoL using the 
EQ-5D-5L™ will be summarized and compared 
between treatment arms. 
Compliance 
 
 To assess compliance over the study 
period. 
 The percentage overall treatment compliance  will 
be summarized. 
Exploratory Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
  
 
 
 
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Safety 
  
 To assess the safety and tolerability of 
Chronocort relative to IRHC. 
 The incidence, nature, severity, relatedness, 
duration, outcome, seriousness and expectedness 
of treatment emergent adverse events (TEAEs) 
will be tabulated by treatment arm. AEs of special 
interest will additionally be tabulated separately, 
with particular note of adrenal crises.
 To assess the need for use of additional 
glucocorticoid doses (stress dosing rules). 
 The use of medication from the stress dosing 
packs or use of any additional glucocorticoid 
treatment during the study will be tabulated by 
treatment arm.
 To evaluate the safety of Chronocort 
compared to IRHC by assessment of 
routine safety laboratory assessments, 
physical examination, vital signs, and 
electrocardiogram (ECG). 
 Safety hematology, biochemistry, urinalysis, and 
vital signs conducted at each post-randomization 
visit and the physical examination and ECG 
assessments conducted after 28 weeks of 
randomized treatment, and their changes from 
baseline, will be summarized by treatment arm.
1 This description aligns with the ICH E9 requirement for the definition of an Estimand. 
Outcome variables are underlined 
Note: The reference range for A4 is up to 150 ng/dL (5.2 nmol/L) for men and up to 200 ng/dL (7.0 nmol/L) for 
women (based on the luteal phase) (based on data from The Mayo Clinic). 
The optimal range for 17-OHP in adults (post-pubertal males or females aged >16 years) is up to 1200 ng/dL (36.4 
nmol/L).  
 
3 
SAMPLE SIZE 
Sufficient participants will be screened to achieve approximately 50 participants randomly 
assigned to either Chronocort or IRHC (25 participants per treatment arm, regardless of baseline 
strata), or until a cut-off date of 30 April 2023, whichever is reached first. Individual study sites 
should not randomize more than 8 participants without first consulting the Sponsor. A sample 
size of 25 participants per treatment arm will provide at least 80% power to demonstrate non-
inferiority of Chronocort to IRHC when the biochemical response rate in the IRHC arm is 40%, 
the non-inferiority margin is 15%, and the biochemical response rate in the Chronocort arm is 
68% using a 1-sided continuity corrected z-test with unpooled variance and a 1-sided alpha of 
2.5%. Sample size is calculated using PASS 2022 (v22.0.3). 


 
  
 
 
 
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Note: Basing the sample size calculation on a continuity corrected z-test provides a conservative 
estimate of sample size relative to the test, based on a logistic model adjusted for stratification 
factors, which will actually be used. 
Note: Post-hoc analysis of study DIUR-005 showed that ~40% of participants receiving the 
control treatment (that is: their pre-randomization treatment) would have been down-titrated by 
the proposed rules for the current study at four weeks after randomization.  Estimating therefore 
the response rate for the IRHC as 40% and expecting that no participants withdrawn completely 
from hydrocortisone treatment would qualify for down-titration, the estimated treatment benefit 
of IRHC is a gain in response rate of 40%.  Setting the non-inferiority margin as minus 15% thus 
retains five eighths of the anticipated treatment benefit of IRHC. 
4 
RANDOMIZATION & UNBLINDING 
This is a double-blinded study with 2 treatment arms.  The blinded treatment to be taken by a 
participant will be assigned using an IRT on a 1:1 basis (Chronocort:IRHC). Before the study is 
initiated, the login information and instructions for use of the IRT will be provided to each site. 
The randomization list will be generated by the study statistician using a computer-generated 
central randomization list using balanced blocks. The site will access the IRT at the baseline visit 
(Day 1) and they will record the randomization number allocated to the participant on the 
applicable eCRF. Randomization will be balanced within site and stratified by the participant's 
fludrocortisone replacement status (requires fludrocortisone/does not require fludrocortisone).  
Potential bias will be reduced by the following steps:  
 Records will be kept of any participants screened, whether or not they enter the study. 
This will enable an assessment of the representative nature of the participants 
randomized. 
 Both study treatments will be over-encapsulated so that they look the same, so both the 
participant and the Investigator will not know which treatment group the participant has 
been randomized to. 
 The titration of each participant’s dose of study treatment will be the same in both arms 
and will be based on the adrenal insufficiency checklist and androgen sampling, thus 
ensuring that opportunities for optimization and control of androgens are the same in both 
arms. 
 The dose titration decisions will be made by an independent blinded physician who will 
be unaware of the treatment allocation to each participant. 
 The treatment packs for each participant will be pre-packed and packs issued by the IRT 
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After each visit, new supplies will be provided to the participant that contains the same 
number of capsules as the previous supplies (with placebo capsules masking any 
changes), regardless of whether the dose was titrated or not, thus ensuring the participant 
is not aware of any dose changes. 
 The primary endpoint is an objective biochemical measure that is not subject to bias. 
 Efforts will be made to ensure that all participants remain in the study and are evaluable.  
 There will be rigorous monitoring of sites to ensure compliance with all study procedures. 
 The statistical analysis plan (SAP) version 1.0 has been completed before screening of the 
first participant to the study. While it is not reasonable to assume that updates will not 
occur to the SAP after this point and prior to unblinding of the study, an initial record of 
planned analysis prior to any participant activity is provided. 
 Treatment will be allocated using block randomization. The block size will be determined 
by the statistician and will not be communicated to the study team. 
 To minimize bias whilst the study is ongoing, the study team will remain blinded to 
aggregated and individual data prior to database lock and any data reviews will use a 
dummy randomization list with generic labels. 
 Participants and Investigators will be requested not to reveal details of the study on social 
media. 
 
Participants will be allocated an identifying number sequentially per site at the screening visit 
(Visit 1) 
 
 When the participant is randomized 
at the baseline visit (Visit 2), a separate randomization number will be allocated, which will be 
used internally for the purposes of treatment allocation and stratum identification. The screening 
number will still be used for participant identification purposes, so there may be gaps in 
participant ID numbers for screen failures. Randomization numbers will be assigned sequentially 
within each stratum and site as soon as participants fully satisfy all of the inclusion and none of 
the exclusion criteria. Screening and randomization numbers once assigned to a participant must 
not be re-assigned to another participant. Re-screened participants should be assigned the same 
participant number as they were assigned during their initial screening visit. 
5 
PLANNED ANALYSES 
The SAP supersedes the protocol in case of any differences; a list of any changes from the 
analyses presented in the protocol is provided in Section 8. The SAP provides a robust plan of 
the analyses to be conducted for the trial; however, it is recognized that no SAP prepared in 
advance of the data can be absolutely definitive, and the final Clinical Study Report (CSR) may 


 
  
 
 
 
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contain additional tables or statistical tests if warranted by the data obtained. The justification for 
any such additional analyses will be fully documented in the final CSR. 
The SAP describes all the analyses and summaries that will be performed on the total participant 
populations. In addition, all analyses and summaries will be repeated on the subgroup of French 
participants only. 
5.1 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened Set 
All participants who sign the ICF. 
Safety Analysis Set (SAF) 
All participants who received, either as part of the run-in or 
post-randomization periods, at least 1 dose of Chronocort or 
IRHC. Participants will be analyzed according to the treatment 
they actually received. The SAF is a subset of the Screened Set. 
Full Analysis Set (FAS) 
All participants with CAH who were randomized into the study 
and who received at least 1 dose of post randomization study 
treatment (Chronocort or IRHC). Participants in the FAS will be 
analyzed according to randomized treatment. The FAS is a subset 
of the SAF. 
Efficacy Evaluable Set 
(EES) 
All participants in the FAS who had Visit 2 and Visit 6 (EOS) 
17-OHP and A4 measurements taken at 08:00 hours, and who 
have no critical protocol deviations that affect the assessment of 
efficacy. The EES is a subset of the FAS. 
Participants excluded from the analysis sets and the reason for their exclusion will be listed, and 
further details regarding exclusion decisions will be documented during the Data Review 
Meeting. 
5.2 
Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 


 
  
 
 
 
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5.2.1 Race 
Where more than one race category has been selected for a participant, these race categories will 
be combined into a single category labeled “Multiple Race” in the summary tables. The listings 
will reflect the original selected categories.  
5.2.2 Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the participant receives the first dose of study drug following randomization. Generally, this will 
be the assessment performed at the Baseline visit (V2). 
For androgens / biochemical control status and difference / average of 8:00 and 13:00 17-OHP 
and A4 results, baseline will be defined as value obtained at Baseline visit (V2).  
5.2.3 Duration / Study Day / Time  
Study day will be calculated as the number of days from first dose of study drug after 
randomization  
 date of event – date of first dose of study drug + 1, for events on or after first dose  
 date of event – date of first dose of study drug, for events before first dose  
As the protocol baseline is at Day 1 (i.e. there is no Day 0), any derivation of target day for a 
scheduled visit and/or applicable visit windows per protocol is in line with this approach. 
Durations of events related to an anchor point of start of the event will be calculated in a similar 
manner, replacing date of first dose of study drug with date of start of the event. 
5.2.4 Quality of Life: SF-36, MAF, EQ-5D 
QoL questionnaires (SF-36®, MAF, and EQ-5D-5L™) will be completed by the participants at 
Visits 2, 3, 4, 5 and 6 through an electronic data collection tool. No missing data will be allowed 
by the system and therefore no missing data imputation method will be needed.   
The scores for the SF-36 questionnaire for each domain and total will be calculated using the 
Optum software. The total scores for MAF and EQ-5D will be derived programmatically as per 
their respective user guides. See Section 11.1 for further details of derivation. 


 
  
 
 
 
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5.2.5 Participants Recruited before Implementation of Protocol Version 6.0 
The week 28 visit was not scheduled prior to protocol version 6.0. Therefore some participants 
recruited before the implementation of protocol version 6.0 may be missing the week 28 
assessment. In such cases, should the week 34 assessment be available, this will be used for the 
week 28 assessment. Therefore, where a week 34 assessment is available, no imputation for the 
missing week 28 assessment will occur. Furthermore, for participants recruited before the 
implementation of protocol version 6.0, if such a participant does not have a week 28 
assessment, but their end of study is between week 16 and week 34, then the end of study is 
mapped to week 28. 
Note, the following conventions will apply for the efficacy and safety analyses. 
For efficacy data, all summaries will be presented by all available scheduled visits. In these 
summaries, week 28 and week 34 will be presented separately. In addition, a further summary, 
and where applicable analysis, will be performed for week 28 where week 34 assessments are 
mapped to week 28 as described above. Note, this will be the main analysis for inference. 
For safety data, all summaries will be presented by all available scheduled visits. No mapping of 
week 34 to week 28 will occur. 
5.2.6 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual participant listings will be presented as recorded on the 
eCRF (i.e., not completed as per the below rules). 
5.2.7 Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the participant has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the participant’s 
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 If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the participant’s last clinic visit in the study if in the same year. 
 If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the participant’s last clinic 
visit in which case the date of participant’s last clinic visit in the study will be used 
instead. 
Missing start date will be imputed as follows: 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
 If the stop date occurs before the start of study drug, the start date of the event / 
concomitant medication will be imputed as the participant’s screening date or the stop 
date of the event / concomitant medication whichever is the earlier. 
Partial start date (year present, but month and day missing) 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date 
will be imputed as the date of the first dose of study drug. If the year is different from the 
year of first dosing “01-Jan” will be used. 
 If the stop date occurs before the start of study drug, the start date of the event / 
concomitant medication will be imputed as the “01-Jan” of the same year. 
 
Partial start date (month and year present, but day missing) 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the first dose of study drug in 
which case the date of first dose of study drug will be used.  
 If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the 
concomitant medication / event corresponds to the date of the first dose of study drug. The time 
will be imputed as the same time as the first dose of study drug. In all other cases the time will 
not be imputed. 


 
  
 
 
 
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5.2.8 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study 
drug will be taken for analysis purposes as the date when the participant would have run out of 
study drug assuming full compliance from the date the study drug was last dispensed or the date 
of participant’s last clinic visit in the study or early withdrawal or death whichever the earlier. 
If only the month and year of the last dose was recorded, then the date of last dosing will be 
taken for analysis purposes as the date the participant would have run out of study drug assuming 
full compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of participant’s last clinic visit in the study or early withdrawal or 
death whichever the earlier. 
5.2.9 Missing Diagnosis Dates   
If the month and year are present but the day is missing, for the purpose of calculating duration 
of disease at baseline/randomization, the diagnosis date will be set to first day of the relevant 
month. If only the year is recorded the diagnosis date will be set as “01-Jan” for that year.  
5.2.10 Exposure to Study Drug 
The following derivations will be implemented with respect to study drug exposure: 
 Total treatment duration (days) = (date of last dose of study drug – date of first dose 
of study drug)+1 
 Total glucocorticoid exposure (days) = sum of all periods of glucocorticoid treatment, 
where each period is calculated as (date of last dose of glucocorticoid in period of 
treatment – date of start of glucocorticoid treatment during period) +1 
 
5.2.11 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
5.2.12 Electrocardiogram (ECG) Data 
For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented. For overall interpretation if more than 
one value is recorded, the most severe (worst case) of the respective readings will be taken. 


 
  
 
 
 
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5.2.13 Visit Windows 
There are no plans to derive visit windows, and visits will be used in the analyses as reported on 
the eCRF. For participants prematurely withdrawing from the study, the early withdrawal visit 
will be remapped to the next scheduled visit after the last dose. Note, for participants with an end 
of study visit between weeks 28 and 34, the end of study visit will be remapped to week 28 for 
the analysis combining the week 28 and 34 results, see Section 5.2.5. Note, for participants 
recruited before implementation of protocol version 6.0 (see Section 5.2.5), week 34 assessments 
used in lieu of week 28 assessments will be used for analysis for the EES, as will any 
assessments from an end of study visit between week 28 and week 34. 
5.2.14 Unscheduled Visits 
Only scheduled post-baseline values will be tabulated. Post-baseline repeat / unscheduled 
assessments will in general be disregarded, although unscheduled visits will be included in the 
derivation of shifts to “worst” post-baseline value.  All post-baseline assessments (scheduled and 
unscheduled) will be listed in the relevant appendices to the CSR.   
5.2.15 Randomization Strata 
Randomization of participants to treatment arm is stratified by fludrocortisone treatment and 
where applicable, the analyses will be stratified by baseline biochemical control status. 
5.3 General Considerations 
5.3.1 Tables and Listings 
All data listings, summaries, figures and statistical analyses will be generated using SAS [SAS 
Institute Inc., Cary, NC, 27513, USA] version 9.4 or higher1. 
Summaries will be presented by treatment group (Chronocort vs IRHC).  
Overall columns are to be included within the table shells as follows: 
Disposition 
Treatment group and overall 
Demography and Baseline 
Characteristics 
Treatment group and overall 
Prior, Concomitant, Subsequent 
and Rescue Medications 
Treatment group and overall 
Exposure to Study Drug  
Treatment group only


 
  
 
 
 
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Efficacy 
Treatment group only 
AEs 
Treatment group and overall 
Other safety 
Treatment group only 
 
Listings will be sorted in the following order: treatment group, participant, parameter, and visit 
unless otherwise stated. All data will be listed; participants who were not randomized will be 
displayed after the randomized treatment groups as “Not randomized to study treatment”.  
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, quantiles and minimum and maximum. For tabulations of changes 
from baseline data for efficacy endpoints, the lower and upper 95% confidence limits for the 
mean for the individual treatments will be presented.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the participant population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
5.3.2 Decimal Places 
Decimal places for derived data described in Section 5.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer, for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal 
places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the 
minimum and maximum will be displayed to the same number of decimal places as reported in 
the raw data. Percentages will be displayed with one decimal place.  
P-values will be quoted to 3 decimal places. P-values < 0.001 will be presented as “p<0.001”. 
Where this value is less than 0.05 (two-sided test), 0.025 (one-sided test), 0.01 or 0.001, attention 
will be drawn to this fact using the conventional “*”, “**” or “***” annotation, respectively. 
These conventions will be footnoted in the table or figure shell.  


 
  
 
 
 
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5.4 
Participant Disposition 
Participant disposition will be summarized descriptively as follows:  
 The number and percentage of participants achieving the following criteria will be 
summarized by treatment group and overall for the Screened Set:  
o Entering the study or failed screening, with reasons 
o Multiple screened and a) entering the study or b) persistent failed screening 
o Received IRHC in the run-in period but were not randomized, with reasons 
o Randomized 
o Included and excluded from each analysis set, with reasons for exclusion 
o Completed or prematurely discontinued treatment, with reasons (including the 
number of participants with premature discontinuation of study treatment, that 
continued study assessments) 
o Completed or prematurely discontinued study, with reasons 
 As a separate summary, the number of participants included in each analysis set will be 
summarized for each region, country and study site by treatment group and overall for the 
Screened Set.  
 The number of participants who complete each phase of the study and the number of 
participants present at each scheduled visit will be summarized by treatment group and 
overall for the FAS.  
Participant disposition will be listed for the Screened Set. The reasons for exclusion from each of 
the analysis sets will also be listed. 
5.5 
Protocol Deviations 
A critical protocol deviation is a protocol deviation (PD) with the potential to compromise the 
efficacy analysis. Critical PDs may include, but are not limited to: 
 Randomization criteria violations. 
 Inclusion/exclusion criteria violations. 
 Inadequate compliance with study drug. 
 Prohibited medications taken. 
 Significant deviations from the study drug administration schedule. 
 Other protocol deviations that could affect participants’ efficacy outcomes. 
A Data Review Meeting will be convened after the data has been cleaned and the database soft-
locked but before final database lock and analysis has commenced. As part of the review, a 
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at all. The review will also document the allocation of participants to analysis sets, among other 
items.  
A listing of all PDs defined as major and/or critical will be presented. Participants experiencing 
at least one major and/or critical PD, and the reasons for deviation will be summarized by 
treatment group and overall. 
5.6 
Demographic and Other Baseline Characteristics 
Demographic and other baseline variables will be summarized by treatment group, split by 
baseline biochemical control status, using the FAS. The comparability of treatment groups with 
respect to participant demographics and baseline characteristics will be assessed in a descriptive 
manner; no formal statistical testing will be performed. 
Standard continuous or categorical variable summaries will be presented by randomized 
treatment group for the following variables. Participant listings will also be presented.  
 Demographic data (e.g. age, sex, race, ethnicity, height (cm), weight (kg), BMI (kg/m2), 
fludrocortisone replacement status [as stratified for randomization, and actual if 
different], baseline biochemical control) 
 Disease history (e.g. duration since diagnosis, hospitalization and number of adrenal 
crises within the 12 months prior to randomization, previous CAH medication) 
 Medical history by MedDRA System Organ Class (SOC) and Preferred Term (PT) 
All variables collected only at baseline or prior to baseline will be summarized here. Variables 
that are collected pre and post-baseline (e.g. vital signs, labs, physical exam, ECGs and efficacy) 
will be presented at Screening and/or Baseline in the by-visit tables within their respective 
analysis section (i.e. under efficacy or safety).  
5.7 
Medical History 
Separate tabulations of previous and ongoing conditions at screening will be presented by 
treatment group and overall for the FAS. Conditions will be presented according to Medical 
Dictionary for Regulatory Activities (MedDRA, version 20.0 or later) primary system organ 
class and preferred term. The dictionary version used will be displayed in the footnote of the 
presented data displays. 
5.8 
Other Baseline Characteristics 
Pregnancy test performed at screening, baseline and at other scheduled visits for females of 
childbearing potential will be listed only. 


 
  
 
 
 
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5.9 
Covid-19 Visit Impact 
At each visit, using the FAS, a summary will be provided of any impact on the visit due to 
Covid-19. The number of participants with an impact will be summarized, as well as what the 
impact was (missed visit, interrupted and/or out of window in person visit at site, remote visit, 
other).  
5.10 Exposure to Study Drug  
Extent of exposure will be presented using total treatment duration (days) by treatment group for 
the SAF. 
The number and percentage of participants experiencing a study drug dose change (either 
increase or decrease) during the study, plus reasons for change, will be summarized by treatment 
group for the SAF. Total glucocorticoid exposure during the study will also be summarized by 
treatment group for the SAF. 
5.11 Efficacy Analyses 
Analyses will be stratified or adjusted, as appropriate, on the basis of (i) the participant's 
fludrocortisone replacement status (requires fludrocortisone/does not require fludrocortisone) 
and (ii) whether they are in biochemical control at baseline or not (based on the androgen results 
from the baseline visit [Visit 2]).  
5.11.1 Statistical Hypotheses 
5.11.1.1 Primary Efficacy Endpoint: Biochemical Response after 28 Weeks of Randomized 
Study Treatment 
A participant is a biochemical responder if: 
i) 
they are in biochemical control at 08:00 hours after 28 weeks of randomized 
treatment (Visit 6)  
where 'biochemical control' is defined as a 17-OHP concentration equal to or less than 
the upper limit of optimal control and a A4 concentration equal to or less than the 
upper limit of the reference range - if either or both these conditions are not met the 
participant is not in biochemical control, AND 
ii) 
their total daily dose after 28 weeks of randomized treatment is not more than 25 mg 
(if the participant was in biochemical control at baseline) and not more than 30 mg (if 
the participant was not in biochemical control at baseline).  


 
  
 
 
 
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The primary null hypothesis is that the response rate in the Chronocort arm is worse than or 
equal to the response rate in the IRHC arm minus 15 percentage points. The primary alternate 
hypothesis is that the response rate in the Chronocort arm is better than the response rate in the 
IRHC arm minus 15 percentage points. Biochemical non-inferiority of Chronocort to IRHC will 
be declared if the 95% CI for the difference in response rates between the 2 treatment arms 
(Chronocort minus IRHC) is wholly above minus 15 percentage points. 
5.11.1.2 First Key Secondary Efficacy Endpoint: Dose Response after 28 Weeks of 
Randomized Study Treatment 
A participant is a dose responder if: 
i) 
their total daily dose after 28 weeks of randomized treatment is not more than 25 mg, 
AND 
ii) 
they are in biochemical control at 08:00 hours after 28 weeks of randomized 
treatment (Visit 6) 
where 'biochemical control' is defined as a 17-OHP concentration equal to or less than 
the upper limit of optimal control and a A4 concentration equal to or less than the 
upper limit of the reference range - if either or both these conditions are not met the 
participant is not in biochemical control. 
The first key secondary null hypothesis is that the response rate in the Chronocort arm is worse 
than or equal to the response rate in the IRHC arm. The first key secondary alternate hypothesis 
is that the response rate in the Chronocort arm is better than the response rate in the IRHC arm.  
Dose superiority of Chronocort to IRHC will be declared if the two-sided 95% CI for the 
difference in response rates between the 2 treatment arms (Chronocort minus IRHC) is wholly 
above zero, provided that biochemical non-inferiority of Chronocort to IRHC has been declared 
under the primary efficacy objective. 
5.11.1.3 Second Key Secondary Efficacy Endpoint: Mean Total Daily Dose of 
Hydrocortisone after 28 Weeks of Randomized Study Treatment 
The second key secondary null hypothesis is that the mean total daily dose of hydrocortisone 
after 28 weeks of randomized treatment in the Chronocort arm is higher than or equal to the 
mean total daily dose after 28 weeks of randomized treatment in the IRHC arm. The second key 
secondary alternate hypothesis is that the mean total daily dose after 28 weeks of randomized 
treatment in the Chronocort arm is lower than the mean total daily dose after 28 weeks of 
randomized treatment in the IRHC arm.  


 
  
 
 
 
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Superiority of Chronocort to IRHC (with respect to the total daily dose after 28 weeks of 
randomized treatment) will be declared if the two-sided 95% CI for the difference in means 
between the 2 treatment arms (Chronocort minus IRHC) is wholly below zero, provided that 
biochemical non-inferiority of Chronocort to IRHC has been declared under the primary efficacy 
objective, and dose superiority of Chronocort to IRHC has been declared under the first key 
secondary efficacy objective. 
5.11.1.4 Overview of Analyses for Efficacy Endpoints  
Analysis 
Statistical Analysis Methods 
Primary analysis 
Non-inferiority: a 95% CI will be calculated for the difference (Chronocort 
minus IRHC) in biochemical responder rates. Biochemical non-inferiority will 
be declared if the 95% CI lies wholly above minus 15%. The primary analysis 
will be conducted using the FAS.  
First key secondary 
analysis 
Superiority analysis: a 95% CI will be calculated for the difference (Chronocort 
minus IRHC) in dose responder rates. Dose superiority will be declared if the 
95% CI lies wholly above zero, provided that biochemical non-inferiority of 
Chronocort to IRHC has been declared under the primary efficacy objective. The 
first key secondary analysis will be conducted using the FAS.  
Second key 
secondary analysis 
Superiority analysis: a 95% CI will be calculated for the difference (Chronocort 
minus IRHC) in mean total daily dose after 28 weeks of randomized treatment. 
Superiority with respect to total daily dose after 28 weeks of randomized 
treatment will be declared if the 95% CI lies wholly below zero, provided that 
biochemical non-inferiority of Chronocort to IRHC has been declared under the 
primary efficacy objective and dose superiority of Chronocort to IRHC has been 
declared under the first key secondary objective. The second key secondary 
analysis will be conducted using the FAS.  
Other analyses of 
the primary 
outcome variable 
and of the key 
secondary outcome 
variables (classed 
as secondary 
outcome analyses) 
Analyses of the primary outcome variable other than the primary analysis and 
analyses of the key secondary outcome variables other than the key secondary 
analyses, such as: 
 analysis at other timepoints 
 assessment of the effect of baseline and disease characterizing variables, 
including stratification variables 
 analysis using the EES and subgroups. 
are deemed to be supplementary analyses and will be performed using the same 
statistical methodology as will be used for the primary analysis and key 
secondary analyses. Calculated p-values will be indicative rather than 
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Other secondary 
outcome variables 
and exploratory 
outcome variables 
Analysis of any other secondary outcome variables and of exploratory outcome 
variables will be performed using the standard statistical methodology. 
Calculated p-values will be indicative rather than substantive. 
5.11.2 Estimands 
5.11.2.1 Primary Efficacy Endpoint 
Treatment Conditions of Interest
Chronocort vs IRHC
Population 
Participants Aged 16 Years and Over with Congenital Adrenal 
Hyperplasia
Assessment 
17-OHP and A4 plasma concentration obtained from the 08:00 
hours blood sample at Visit 6 (EOS) and daily dose of 
hydrocortisone
Outcome Variable 
The proportion of participants in each treatment arm who are 
biochemical responders at 08:00 hours at Visit 6 (EOS). See Section 
5.11.1.1 for details on criteria for biochemical response
Population-Level Summary 
The difference (Chronocort arm minus IRHC arm) in the proportion 
of participants who are biochemical responders at 08:00 hours at 
Visit 6 (EOS)
Analysis 
The difference (Chronocort arm minus IRHC arm) in the proportion 
of participants who are biochemical responders is estimated using 
logistic regression (Ge, 2011) with treatment, fludrocortisone use at 
baseline, biochemical control at baseline, and the interaction of 
fludrocortisone use and biochemical control at baseline as 
explanatory variables. 
Intercurrent Events (ICEs) 
(i) 
Participants who withdraw from treatment before Visit 
6 (EOS) or who do not meet the criteria for being a 
biochemical responder are deemed not to be a 
biochemical responder. 
(ii) 
Participants receiving rescue medication (under 'stress 
dosing rules') will continue in the study with unchanged 
procedures, except that Visit 6 (EOS) will be delayed if 
necessary, to 5 days after the use of rescue medication
Strategies to Handle ICEs 
(i) 
Discontinuation of study treatment before Visit 6 
(EOS), for any reason  
Composite strategy 
(ii) 
Receipt of rescue medication under ‘stress-dosing rules’ 
Treatment policy strategy 
Where under the treatment policy strategy, available data occurring on or after the ICE will be 
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after the ICE will be considered as biochemical non-response. Additionally, any missing Visit 6 
biochemical response data will be multiple imputed per Section 5.11.3.1.   
Interpretation: Biochemical non-inferiority of Chronocort to IRHC will be declared if the 95% 
CI for the difference in proportions lies wholly above minus 15 percentage points. Confirmatory 
testing will occur on the primary estimand. 
Choice of Non-Inferiority Margin: See Section 3 for details on the choice of the NI margin. 
5.11.2.2 First Key Secondary Efficacy Endpoint 
Treatment Conditions of Interest
Chronocort vs IRHC
Population 
Participants Aged 16 Years and Over with Congenital Adrenal 
Hyperplasia
Assessment 
17-OHP and A4 plasma concentration obtained from the 08:00 
hours blood sample at Visit 6 (EOS) and daily dose of 
hydrocortisone
Outcome Variable 
The proportion of participants in each treatment arm who are dose 
responders at 08:00 hours at Visit 6 (EOS). See Section 5.11.1.2 for 
details on criteria for dose response.
Population-Level Summary 
The difference (Chronocort arm minus IRHC arm) in the proportion 
of participants who are dose responders at 08:00 hours at Visit 6 
(EOS)
Analysis 
The difference (Chronocort arm minus IRHC arm) in the proportion 
of participants who are dose responders is estimated using logistic 
regression (Ge, 2011), with treatment, fludrocortisone use at 
baseline, biochemical control at baseline, and the interaction of 
fludrocortisone use and biochemical control at baseline as 
explanatory variables.
ICEs 
(i) 
Participants who withdraw from treatment before Visit 
6 (EOS) or who do not meet the criteria for being a 
dose responder are deemed not to be a dose responder. 
(ii) 
Participants receiving rescue medication (under 'stress 
dosing rules') will continue in the study with unchanged 
procedures, except that Visit 7 will be delayed if 
necessary, to 5 days after the use of rescue medication
Strategies to Handle ICEs 
(i) 
Discontinuation of study treatment before Visit 6 
(EOS), for any reason  
Composite strategy 
(ii) 
Receipt of rescue medication under ‘stress-dosing rules’ 
Treatment policy strategy 
Note: Handling strategies for ICEs will be the same as for the primary efficacy endpoint. 


 
  
 
 
 
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Interpretation: Dose superiority of Chronocort to IRHC will be declared if the 95% CI for the 
difference in proportions lies wholly above zero, provided that biochemical non-inferiority of 
Chronocort to IRHC has been declared. 
5.11.2.3 Second Key Secondary Efficacy Endpoint 
Treatment Conditions of Interest
Chronocort vs IRHC
Population 
Participants Aged 16 Years and Over with Congenital Adrenal 
Hyperplasia
Assessment
Total daily dose of hydrocortisone at Visit 6 (EOS)
Outcome Variable
The mean total daily dose in each treatment arm at Visit 6 (EOS).
Population-Level Summary 
The difference (Chronocort arm minus IRHC arm) in the mean total 
daily dose of hydrocortisone at Visit 6 (EOS)
Analysis 
The mean difference (Chronocort arm minus IRHC arm) in total 
daily dose after 28 weeks of randomized treatment is estimated 
using a repeated measures model on timepoints 10, 16 and 28 
weeks after randomization with treatment, timepoint, treatment by 
timepoint interaction, fludrocortisone use at baseline, biochemical 
control at baseline, and the interaction of fludrocortisone use and 
biochemical control at baseline as explanatory variables.
ICEs 
(i) 
Participants who withdraw from treatment before Visit 
6 (EOS) will have their total daily dose imputed. 
(ii) 
Participants receiving rescue medication (under 'stress 
dosing rules') will continue in the study with unchanged 
procedures, except that Visit 6 (EOS) will be delayed if 
necessary, to 5 days after the use of rescue medication
Strategies to Handle ICEs 
(i) 
Discontinuation of study treatment before Visit 6 
(EOS), for any reason 
Treatment policy strategy 
(ii) 
Receipt of rescue medication under ‘stress-dosing rules’ 
Treatment policy strategy 
Where under the treatment policy strategy, available data occurring on or after the ICE will be 
analyzed as observed. Data missing at 28 weeks (or any other visit) will be imputed as per 
Section 5.11.3.3.   
Interpretation: Superiority of Chronocort to IRHC with respect to total daily dose after 28 
weeks of randomized treatment will be declared if the 95% CI for the difference in means lies 
wholly below zero, provided that biochemical non-inferiority of Chronocort to IRHC has been 
declared under the primary efficacy objective and dose superiority of Chronocort to IRHC has 
been declared under the first key secondary efficacy objective. 


 
  
 
 
 
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5.11.3 Estimand Related Data Handling 
5.11.3.1 Primary Efficacy Endpoint – Biochemical Response at Visit 6 (EOS) 
For the imputation of biochemical response where a composite variable strategy is employed, 
any biochemical response data occurring on or after the applicable ICE will be considered as 
biochemical non-response. This imputation will occur first, before any imputation of missing 
data occurs. 
For the imputation of missing data, the binary response status will be multiple imputed. The 
number of imputations will be 50, representing the set of 50 plausible values obtained from a 
prediction model based primarily on observed data (i.e. applying a MAR approach in general). 
The fully conditional specification (FCS) method will be used for dealing with arbitrary non-
monotone missing data patterns. The FCS is based on an iterative algorithm; at each iteration and 
for each variable of the prediction model, there is a prediction step and an imputation step. As 
imputations will be for binary components, the models used for prediction and imputation will be 
logistic regression models. 
The full MI approach will comprise of 4 steps, as follows: 
 Prediction Step: the current (iteration) values of the observed and imputed values are 
used to derive the predictive distribution of the missing values under MAR conditions  
 Imputation Step: updated imputations are generated by draws from the predictive 
distribution defined by the updated logistic regression model  
 Analysis Step: The analysis as described in Section 5.11.4.1 is conducted for each of the 
50 imputations 
 Combining Step: Rubin’s rule (SAS PROC MIANALYZE) is used to combine the 50 
point estimates and standard errors, in order to provide a single point estimate and 
confidence interval that can be compared to the respective Non-inferiority delta in the 
null hypotheses described in Section 5.11.1 to provide rejection or acceptance. 
5.11.3.1.1 Prediction Step 
The prediction step attempts to predict the biochemical response based on observed data that may 
have an influence on it (assuming MAR). 
The prediction model will include the following variables, to attempt to estimate the missing value 
as closely as possible based on available characteristics.  


 
  
 
 
 
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Timepoint 
Variables 
Variable Used for 
Randomization (per IWRS) 
 Fludrocortisone replacement status (requires 
fludrocortisone or does not require fludrocortisone) 
Baseline Assessments 
 Participant’s assessment of biochemical control 
 Sex 
Assessments at V4, V5, V6 
and V7 
 Participant’s biochemical response status 
Other 
 Randomized study treatment (Chronocort or IRHC) 
5.11.3.1.2 Multiple Imputation Step for All Missing Data (MAR) 
Within the Bayesian framework, the task of imputing missing values is achieved by drawing 
random values from the posterior predictive distribution of the missing primary efficacy endpoint 
data (predicted by the logistic regression prediction model specified above). This posterior 
predictive distribution is a function of the observed data and regression parameters (or function of 
regression parameters) under MAR conditions. 
When the last variable in the sequence of variables listed above in the prediction model has been 
imputed, the algorithm cycles again through each variable, repeating the chain of regression 
estimation and imputation draw steps. These cycles are repeated 200 times (“burn-in” iterations) 
and finally there will be 50 draws from the predictive distribution for missing values. SAS PROC 
MI will be used for this process.  
 
Example SAS Code for Prediction and Imputation Steps: 
 
   
 
   
  
       
 
   
  
       
 
 
 
 
The LOGISTIC option LIKELIHOOD=AUGMENT may be used when the maximum likelihood 
parameter estimates do not exist. This option adds observations in each response group to the 
likelihood function. Each added observation contributes the same weight, with the number of 


 
  
 
 
 
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parameters in the logistic regression model as the total added weight. Existence of maximum 
likelihood estimates will be checked after general unblinding with the actual randomization. 
5.11.3.1.3 Analysis Step 
Each of the imputations will be analyzed using a logistic regression model, as described in 
Sections 5.11.4.1 and 11.2.  
5.11.3.1.4 Combining Step 
SAS Proc MIANALYZE will be used to combine the 50 point estimates for the common 
response probability difference and standard errors, allowing appropriate statistical inference as 
described below: 
 
   
 
   
 
   
 
 
5.11.3.2 First Key Secondary Efficacy Endpoint – Dose Response at Visit 6 
The approach for dose response will be similar to that described in Section 5.11.3.1 for 
biochemical response. The primary analysis conducted using MAR approach for imputation will 
be presented for this endpoint, similar to the primary efficacy endpoint. 
5.11.3.3 Second Key Secondary Efficacy Endpoint – Total Daily Dose of Hydrocortisone at 
28 weeks 
For the second key secondary efficacy endpoint, where an ICE occurs, every effort will be taken 
to ascertain the total daily dose of hydrocortisone (or equivalent) at 28 weeks whether on study 
or not. Where hydrocortisone is not used, and instead an alternative treatment (such as 
prednisone, prednisolone or dexamethasone) is received, the dose of the treatment received will 
be converted to hydrocortisone equivalent as follows [Nebesio et al. 2016]:  
 Dexamethasone x 80 
 Prednisolone/one x 5  
This could occur at pre Run-in Baseline, and for participants that discontinue study treatment. 
Where missing data exists for total daily hydrocortisone dose after discontinuation, no explicit 
imputation will be done. 


 
  
 
 
 
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5.11.4 Analysis of the Primary Efficacy Endpoint 
5.11.4.1 Main Analysis of the Primary Efficacy Endpoint 
The main analysis of the primary endpoint is based on the proportion of participants achieving 
biochemical response at V6, with ICE handling per Section 5.11.2.1 and imputing missing data 
using the MI approach described in Section 5.11.3.1.  
The primary estimand will be analyzed using a logistic regression model. The model will include 
the following factors: treatment arm (Chronocort versus IRHC, reference IRHC), the 
participant's fludrocortisone replacement status at baseline (requires fludrocortisone or does not 
require fludrocortisone) and whether they are in biochemical control at baseline or not (based on 
the androgen results from the baseline visit [Visit 2]), plus the interaction of these variables. The 
estimated response rate for each treatment arm, and the corresponding difference in rates along 
with the 2-sided 95% CI for the difference will be presented using the procedure described by Ge 
et al. (2011). See Section 11.2 for further details of the analysis. 
1) In case issues related to convergence of the model or other issues that may be expected 
based on the frequency counts within the combinations of the factors involved lead to 
warnings (such as, for example, complete or quasi- separation, model less than full rank, 
etc.) and/or prevent the model from producing valid results (execution stops, some terms 
in the model not estimated, unusually large standard errors obtained, etc.), an initial 
assessment of the distribution of response/non-response outcomes will occur in order to 
ascertain the possible best next steps. However, a priori, in lieu of such knowledge, the 
following steps will be implemented in order specified below: Exclude the interaction 
term; 
2) Exclude the interaction term and one of the main effects (fludrocortisone replacement 
status at baseline or biochemical control at baseline, whichever produces combinations 
with lower counts); 
3) Exclude both factors and their interaction. 
At each step, the model will be rerun and evaluated for continued occurrence of issues. The 
decisions made at each step of the model selection process will be fully documented. 
17-OHP and A4 results will be listed, and results from visits outside the protocol specified visit 
window will be flagged. 
5.11.4.2 Sensitivity and Supportive Analyses 
The main statistical analysis assumes that the treatment effect is constant over the standard 
explanatory variables. Additional sensitivity analyses will investigate whether the treatment 


 
  
 
 
 
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effect varies with the explanatory variables: including, but not limited to, subgroup analyses by 
biochemical control status at baseline, fludrocortisone use at baseline, region or country as 
appropriate and pre-treatment corticosteroid. Separate summary tables will be presented for each 
subgroup and a measure of treatment-by-subgroup interaction together with confidence interval 
and P-value provided.  Forest plots will additionally be presented to provide a visual comparison 
of the differences in treatment effect between subgroups.  
All subgroup analyses will be performed as unstratified/unadjusted. 
Summary tables split by biochemical control at baseline will also be presented for disposition, 
demography and baseline characteristics and exposure to study drug, (Participants with baseline 
17-OHP equal to or below the upper limit for optimal control at 08:00 hours and baseline A4 
equal to or below the upper limit of the reference range will be classified as ‘in biochemical 
control’. Participants with baseline 17-OHP above the upper limit for optimal control and/or 
baseline A4 above the upper limit of the reference range will be classified as ‘not in biochemical 
control’.) 
Supportive analysis: The main statistical analysis will additionally be performed on the EES. 
Other analyses: Any other analyses of 17-OHP and A4 concentrations and dose, not otherwise 
specified as a secondary analysis, are supplementary analyses. The number and percentage of 
participants in receipt of rescue medication overlapping with a scheduled visit, as well as the 
number and percentage of participants with moved Visit 6 assessment due to stress dosing rules 
will be summarized by treatment group, split by baseline biochemical control status. 
All observed data for the primary endpoint will additionally be summarized descriptively by 
visit, with no imputation. 
5.11.5 Key Secondary Efficacy Endpoints and Analyses 
The high-level handling approaches for the secondary endpoints are as follows. All observed data 
for these endpoints will additionally be summarized descriptively by visit, with no imputation. 
Endpoint 
Analysis Set 
Modelling Method 
Data Handling 
Percentage of 
Participants Dose 
Response after 28 
Weeks of Randomized 
Study Treatment 
FAS and EES 
Logistic Regression 
As per Primary efficacy 
endpoint.  


 
  
 
 
 
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Endpoint 
Analysis Set 
Modelling Method 
Data Handling 
Mean Total Daily Dose 
after 28 Weeks of 
Randomized Study 
Treatment 
FAS and EES 
MMRM 
Treatment policy strategy for 
participants who stop 
treatment before visit 6.  
Treatment policy strategy for 
participants whose visit 6 is 
delayed because of 
administering rescue 
medication. Present all visits 
up to and including V6. 
5.11.5.1 Percentage of Participants Achieving Dose Response after 28 Weeks of 
Randomized Study Treatment 
The percentage of participants achieving dose response over the course of the study will be 
analyzed in a similar manner to the primary efficacy endpoint (logistic regression) on the FAS.  
5.11.5.2 Mean Total Daily Dose after 28 Weeks of Randomized Study Treatment 
Mean Total Daily Dose will be analyzed on the FAS using a repeated measures mixed model 
with factors for treatment arm (Chronocort versus IRHC, reference IRHC), the participant's 
fludrocortisone replacement status at baseline (requires fludrocortisone or does not require 
fludrocortisone) and whether they are in biochemical control at baseline or not (based on the 
androgen results from the baseline visit [Visit 2]) and their interaction, as well as the treatment-
visit interaction. A restricted maximum likelihood method will be specified, along with an 
unstructured covariance matrix. The estimate of the least-squared means difference at each visit 
and the corresponding 95% CI for the difference will be presented. Example SAS code for the 
analysis is provided in Section 11.3. 
Considerations for model adjustments specified in Section 5.11.4 also apply to the analysis of 
this key secondary efficacy endpoint. 
5.11.5.3 Sensitivity and Supportive Analyses for the Key Secondary Efficacy Endpoints 
Sensitivity analyses:  
The main statistical analysis assumes that the treatment effect is constant over the standard 
explanatory variables. Additional sensitivity analyses will investigate whether the treatment 
effect varies with the explanatory variables: including, but not limited to, subgroup analyses by 
biochemical control status at baseline, fludrocortisone use at baseline, region or country as 
appropriate and pre-treatment corticosteroid. Separate summary tables will be presented for each 
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and P-value provided.  Forest plots will additionally be presented to provide a visual comparison 
of the differences in treatment effect between subgroups. 
Supportive analysis: The main statistical analysis for each of the key secondary endpoints will 
additionally be performed on the EES. 
5.11.6 Other Secondary Efficacy Endpoints 
5.11.6.1 Standard Explanatory Variables for Other Secondary Efficacy Endpoints 
The standard explanatory variables are (1) whether or not the participant was in biochemical 
control at baseline, (2) whether or not the participant was receiving fludrocortisone at baseline 
and (3) their interaction. Randomization of participants to treatment arm is stratified by 
fludrocortisone treatment and the analyses will include the stratification of biochemical control. 
Analyses will be stratified or adjusted, as appropriate, on the basis of (i) the participant's 
fludrocortisone replacement status at baseline (requires fludrocortisone or does not require 
fludrocortisone) and (ii) whether they are in biochemical control at baseline or not (based on the 
androgen results from the baseline visit [Visit 2]). Participants with 17-OHP equal to or below 
the upper limit for optimal control at 08:00 hours and A4 equal to or below the upper limit of the 
reference range will be classified as ‘in biochemical control’. Participants with 17-OHP above 
the upper limit for optimal control and/or A4 above the upper limit of the reference range will be 
classified as ‘not in biochemical control’. 
Considerations for model adjustments specified in Section 5.11.4 also apply to the analysis of 
other secondary efficacy endpoints. 
5.11.6.2 Standard Methodology for Comparisons of Other Secondary Efficacy Endpoints 
Unless otherwise stated, continuous outcome variables will be compared between treatment arms 
using analysis of covariance (ANCOVA) adjusting for the standard explanatory variables. Unless 
otherwise stated, a treatment policy approach will be assumed for all ICEs, with no imputation of 
missing data. If a non-normal distribution is anticipated or observed, then consideration will be 
given to using a logarithmic transformation or a non-parametric analysis. Analyses of change 
from baseline will always include the baseline value as a covariate. Example code is provided in 
Section 11.4. 
Unless otherwise stated, binary outcome variables will be compared between treatment arms 
using logistic regression adjusted for the standard explanatory variables. Unless otherwise stated, 
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missing data. The procedure described by Ge et al. (2011) will be used to estimate the standard 
error and resulting confidence interval around the covariate adjusted difference in proportions 
5.11.6.3 Analyses of Other Secondary Efficacy Endpoints 
Outcome Variables 
Outline Analyses 
Whether or not the participant is a biochemical 
responder at 4, 10 and 16 weeks after 
randomization. 
The same analysis will be used as for the primary 
estimand of the primary outcome variable (except 
that at 4 weeks there has been no opportunity for a 
dose titration so the condition on dose is not used).
Whether or not the participant is a dose 
responder at 10 and 16 weeks after 
randomization.
The same analysis will be used as for the primary 
estimand of the first key secondary outcome 
variable.
Total daily dose at 10 and 16 weeks after 
randomization. 
The same analysis will be used as for the primary 
estimand of the second key secondary outcome 
variable.
Whether or not the participant is in biochemical 
control (provided total daily dose is not greater 
than 30mg) at 4, 10, 16 and 28 weeks after 
randomization.
The same analysis will be used as for the primary 
estimand of the primary outcome variable.   
The difference in range as calculated as the 
difference between the 08:00 and 13:00 17-OHP 
levels at 4, 10, 16 and 28 weeks after 
randomization.
Standard methodology for comparisons. 
The difference in range as calculated as the 
difference between the 08:00 and 13:00 A4 
levels at 4, 10, 16 and 28 weeks after 
randomization.
Standard methodology for comparisons. 
The mean of the 08:00 and 13:00 levels for each 
androgen at 4, 10, 16 and 28 weeks after 
randomization.
Standard methodology for comparisons. 
The total daily glucocorticoid dose at 4, 10, 16 
and 28 weeks after randomization. 
Standard methodology for comparisons. Total 
glucocorticoid daily dose will be calculated as mean 
total daily dose of study medication and other 
additional glucocorticoids over the time interval 
since previous visit. Additionally, the mean total 
daily dose by treatment will be calculated for 
participants in and not in biochemical control at the 
end of study visit. 


 
  
 
 
 
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Outcome Variables 
Outline Analyses 
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in menstrual 
regularity 
Standard methodology for comparisons (only in 
pre-menopausal women without hysterectomy and 
not using hormonal contraception). 
 
Note, post treatment menstrual regularity will be 
derived from the menstrual cycle log using the 
following definitions: 
 
Oligomenorrhoea is defined as fewer than 9 
menstrual cycles per year or cycle length 
>35 days 
 
Amenorrhoea is defined as absent menses 
for ≥3 months. 
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in LH levels
Standard methodology for comparisons (men only) 
The change from baseline to 28 weeks of 
randomized treatment in size of TART 
Descriptive statistics only (men with TART at 
baseline). Percentage change from baseline will be 
summarized.
The change from baseline to 28 weeks of 
randomized treatment in sperm count
Standard methodology for comparisons (men only) 
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in objective 
hirsutism using the Ferriman-Gallwey score
Standard methodology for comparisons (women 
only) 
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in objective 
acne using the Global Evaluation Acne (GEA) 
scale
Standard methodology for comparisons (women 
only) 
The change from screening to 4, 10, 16 and 28 
weeks of randomized treatment in HbA1c levels
Standard methodology for comparisons  
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in waist 
circumference
Standard methodology for comparisons  
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in body weight
Standard methodology for comparisons  
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in QoL using 
the self-completed SF-36® total score and the 
sub-domain of vitality
Standard methodology for comparisons  
The change from baseline to 4, 10, 16 and 28 
weeks of randomized treatment in QoL using 
the MAF
Standard methodology for comparisons  
The change from baseline to weeks 4, 10, 16 
and 28 in subjective hirsutism and acne using a 
participant-reported VAS.
Standard methodology for comparisons (women 
only). 


 
  
 
 
 
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Outcome Variables 
Outline Analyses 
The change from baseline to weeks 4, 10, 16 
and 28 in QoL using the EQ-5D-5L™.
Standard methodology for comparisons. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.11.8 Multiplicity 
The results of the key secondary analysis (dose response) will only be considered substantive if 
the primary estimand of the primary analysis demonstrates non-inferiority, otherwise the results 
will be considered indicative. Similarly, the analysis of the second key secondary efficacy 
endpoint (total daily dose) will be considered substantive if the primary estimand of the primary 
efficacy endpoint and key first secondary endpoint demonstrate success. 
All other analyses of secondary endpoints, analyses of exploratory endpoints and sensitivity and 
supportive analyses will be considered as descriptive evidence of efficacy and will be analyzed 
without any procedures to account for multiple comparisons. 


 
  
 
 
 
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5.12 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Analysis Set. 
5.12.1 Summary 
All safety analyses will be performed on the SAF. 
Endpoint 
Statistical Analysis Methods 
AEs 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 or later and summarized descriptively. Only TEAEs 
will be included in the main safety analysis. A TEAE is defined as any AE that 
has an onset on or after the first dose of study drug and before the last dose of 
study drug + 30 days or is any pre-existing AE that has worsened in severity on 
or after the first dose of study drug and before the last dose of study drug + 30 
days. The incidence, nature, severity, relatedness, duration, outcome, 
seriousness and expectedness of TEAEs will be tabulated. AEs of special 
interest will be additionally separately tabulated. 
Prior, concomitant 
and subsequent 
medications 
Medications will be coded using WHO Drug dictionary and summarized 
descriptively using ATC level and preferred term. See Section 5.12.3 for 
further details. 
Rescue medications 
Rescue medications will be coded and summarized similarly to prior and 
concomitant medications. An additional summary of the use of rescue 
medication overlapping with each visit will be presented. See Section 5.12.4 
for further details. 
Need for additional 
glucocorticoid doses 
Use of hydrocortisone from the stress dosing packs or use of any additional 
glucocorticoid treatment during the study will be summarized descriptively. 
Other safety 
assessments 
For laboratory parameters, vital signs, and ECGs, change from baseline will be 
calculated at each scheduled post-baseline visit and summary statistics will be 
presented both for absolute values (at baseline and each scheduled post-
baseline visit) and changes from baseline by treatment arm, and visit. Shift 
tables of baseline to minimum and maximum on-treatment will be produced for 
the appropriate parameters displaying the number and percentage of 
participants in each of the categories (High, Low and Normal) relative to the 
category of their baseline assessment. Results considered clinically significant 
by the Investigator will be summarized at each visit. Physical examination 
results, and their change from baseline, will be summarized at each visit. 
 


 
  
 
 
 
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5.12.2 Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
 Any AE that has an onset on or after the first dose of study drug and before last dose of 
study drug + 30 days. 
 Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
and before the last dose of study drug + 30 days.  
A TEAE which starts or worsens on or after the first dose of IRHC in the run-in period but before 
the first dose of randomized study treatment is allocated to the run-in period.  A TEAE which starts 
or worsens after the first dose of randomized study treatment is allocated to the treatment actually 
received during the randomized treatment period.  A TEAE which starts or worsens in the run-in 
period and worsens in the randomized treatment period is allocated to both periods. 
A treatment-related AE is defined as an AE that is recorded by the Investigator as definitely, 
probably, possibly or likely to be related to the study drug. If an AE has missing relationship it is 
assumed to be related to the study drug for analysis purposes. Maximum severity will be 
assumed for an AE with missing severity.  
TEAEs will be summarized separately for the run-in period and after randomization. In the list of 
AE tables below, only the first 2 will be done for both the run-in period and after randomization. 
All the others will just be done after randomization. 
The following tables will be presented for AEs by treatment group: 
 Overall incidence and the number of AEs, Serious Adverse Events (SAEs), Treatment 
related TEAEs, TEAEs leading to withdrawal of study drug, TEAEs leading to early 
withdrawal from study, TEAEs leading to study drug dose increase or decrease, TEAEs 
leading to study drug dose interruption, TEAEs leading to use of rescue medication, 
Treatment Emergent AEs of Special Interest (TEAESIs), non-treatment emergent AEs 
occurring > 30 days after last dose of study drug, and AEs leading to death – run-in 
period and after randomization 
 TEAEs by system organ class (SOC) and preferred term (PT), incidence and number of 
events – run-in period and after randomization 
 Treatment related TEAEs by SOC and PT, incidence and number of events – after 
randomization only 
 Serious TEAEs by SOC and PT, incidence and number of events – after randomization 
only 
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 Treatment related TEAEs by SOC, PT and maximum severity, incidence – after 
randomization only 
 TEAEs by SOC, PT and relationship, incidence  – after randomization only 
 TEAEs leading to withdrawal of study drug by SOC and PT, incidence – after 
randomization only 
 TEAEs leading to study drug dose increase or decrease by SOC and PT, incidence – after 
randomization only 
 TEAEs leading to study drug dose interruption by SOC and PT, incidence – after 
randomization only 
 TEAEs leading to use of rescue medication by SOC and PT, incidence – after 
randomization only 
 TEAEs leading to early withdrawal from study by SOC and PT, incidence – after 
randomization only 
 TEAESIs (including events of unexpected benefit, adrenal crises, signs and symptoms of 
adrenal insufficiency and over-treatment) by SOC and PT, incidence – after 
randomization only 
 Non-treatment emergent AEs occurring > 30 days after last dose of study drug by SOC 
and PT, incidence – after randomization only 
 Listing of Serious TEAEs (presented in the Table section of the appendices)  
 Listing of Deaths (presented in the Table section of the appendices). 
In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by 
the same participant will be counted as multiple events.  
For incidence summaries by SOC and PT, a participant will be counted only once at the SOC 
level and once at each PT level within the SOC level, even if the participant experienced more 
than one AE within a specific SOC and PT. For summaries by SOC, PT, and severity, a 
participant is typically counted once at each severity level for which the event occurred at the 
SOC level and at each severity level for which the event occurred for each unique PT within that 
SOC level. Therefore, participants may contribute to multiple severity levels within a PT or 
SOC. 
All AEs will be listed.   


 
  
 
 
 
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5.12.3 Prior, Concomitant and Subsequent Medication 
Medications/procedures will be coded using the World Health Organization Drug Dictionary 
(WHODrug). The dictionary version used will be displayed in the footnote of the presented data 
displays. 
5.12.3.1 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
treatment group and overall, for the SAF.  
Prior medications are defined as all medications with stop date after the signing of the informed 
consent form but before first dose of randomized study drug. Concomitant medications are 
defined as medications that either start after the first dose of randomized study drug, or started 
before the first dose of randomized study drug and continue to be taken after the first dose of 
randomized study drug. For details on imputation of missing/partial start and stop dates of 
prior/concomitant medications, see Section 5.2.7. 
Participant incidence will be tabulated for concomitant medications by Anatomic Therapeutic 
Class (ATC) level 3 and preferred term for the SAF, by treatment group and overall. Participants 
will be counted only once for each ATC or preferred term in the event that they have multiple 
records of the same ATC or preferred term in the database. Prior medications will only be 
included in data listings. 
Prior and concomitant medications will be listed with the occurrence (prior versus concomitant) 
identified. 
Medications for CAH taken in the 26 weeks before the start of the run-in period will be 
separately listed and summarized. 
5.12.3.2 Subsequent Medication 
Medications that start after the last dose of randomized study drug but before 28 weeks after 
randomization are considered subsequent medications. Subsequent medications will be analyzed 
in the same way as concomitant medications (using ATC and preferred term, by treatment group 
and overall for the SAF), and will be included in the above listings of 
prior/concomitant/subsequent.  


 
  
 
 
 
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5.12.4 Rescue Medication 
Medication to be used when the 'stress dosing rules' are implemented will be supplied by the 
study site as part of an emergency treatment pack. The content will typically include (according 
to local practice): 
 
A one-week supply of 10 mg oral hydrocortisone tablets (to allow dosage of up to 60 mg 
daily)  
 
Hydrocortisone for injection plus syringes and needles  
 
The standard information guidance regarding 'stress dosing rules'. 
Participants receiving rescue medication will be presented in a data listing. The extent of receipt 
of rescue medication in relation to efficacy assessments will be covered under Section 5.11.4.2. 
The Data Review will document further details of all medications regarded as rescue, and their 
timing. 
Medications defined as rescue will be analyzed in the same way as concomitant medications (using 
ATC and preferred term, by treatment group and overall, for the SAF); however the number of 
separate uses (similar to presentation of the number of events for the AEs) will also be included. 
Rescue medications will be listed separately to prior, concomitant, and subsequent medications. 
5.12.5 Need for Additional Glucocorticoid Doses 
Use of hydrocortisone from the stress dosing packs or use of any additional glucocorticoid 
treatment during the study will be summarized descriptively. 
5.12.6 Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology, urinalysis, and serum chemistry 
parameter. Each measurement (continuous data) will be classed as below, within, or above 
normal range, based on ranges supplied by the laboratory used. Shift tables in relation to the 
normal range from baseline to end of study/early withdrawal visit, and worst high/low on-
treatment during the study will be presented. For the worst high/low shifts, all lab assessments 
will be considered (both scheduled and any unscheduled). 
A listing of any clinically significant laboratory measurements recorded throughout the study 
will be presented. 


 
  
 
 
 
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5.12.7 Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Pulse rate (bpm)  
 Respiration rate (breath / min) 
 Body temperature (degrees Celsius) 
5.12.8 Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated at each follow-up:  
 Heart rate (bpm) 
 PR interval (ms) 
 RR interval (ms)  
 QRS complex (ms)   
 QT interval (ms)  
 QTc interval (ms)  
In addition, shift tables relating to the overall interpretation (Normal, Abnormal NCS, and 
Abnormal CS) from baseline to end of study/early withdrawal visit will be presented by 
treatment group.  
5.12.9 Physical Examination 
The body systems within the physical examination data at the end of the study will be 
summarized by treatment group (Normal; Abnormal NCS, Abnormal CS). Changes from 
baseline will also be tabulated. Details of clinically significant findings will be listed.  
6 
INTERIM ANALYSIS 
No formal interim analysis is planned.  
7 
DATA SAFETY MONITORING BOARD ANALYSIS 
An independent DSMB will meet on a regular basis during the study to review safety data. The 
DSMB will operate in accordance with a charter, which is a separate controlled document.  


 
  
 
 
 
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Safety data will be generated at regular intervals for review by the independent DSMB (see 
Section 9.6 of the study protocol). Details of these DSMB outputs will be specified in the Kick-
Off Meeting slides and minutes and the DSMB Charter. Any outputs provided to the DSMB will 
be unblinded (a separate statistical team will provide the unblinded outputs to the DSMB). 
Outputs provided to other team members to remain in a blinded capacity will use a dummy 
randomization list with generic labels. 
During the course of the study, if unblinded analyses indicate that AEs are occurring more 
frequently than anticipated, the DSMB will notify the Sponsor, who will notify regulatory 
authorities expeditiously as appropriate. 
8 
CHANGES TO PLANNED PROTOCOL ANALYSIS 
 Section 2: Analysis of Biochemical Response Rate at Week 4 was specified in the 
Protocol but not including a criterion for dose as the participant is still receiving the 
initial dose at Week 4.  This analysis has been removed as it is identical to the analysis of 
Biochemical Control Rate at Week 4.  
 No comparative analysis will be performed for the endpoint The change from baseline to 
28 weeks of randomized treatment in size of TART (men only). Only summaries 
including percentage change from baseline will be provided. 
 No compliance calculation will be performed. The extent by which participants did not 
follow the instructions for the return of unused and empty medication containers rendered 
calculations of compliance uninterpretable. 
 
9 
CHANGES TO PLANNED ANALYSIS FROM SAP VERSION 1.0 
 In line with protocol amendment 6.0, the primary analysis timepoint has been updated 
from week 52 to week 28 
 Sensitivity analyses of primary efficacy endpoint and first key secondary endpoint of 
MNAR multiple imputation and tipping point analysis have been removed. 
 Analysis of second key secondary endpoint will now be mixed model repeated measures 
analysis. Analysis using MAR multiple imputation has been removed. 
 Description of steps to be implemented in case of issues with statistical models, including 
potential exclusion of interaction term and/or other factors, was added.  
 It was specified that all subgroup analyses will be performed as unstratified/unadjusted. 
 Additional considerations for baseline derivation were added. 


 
  
 
 
 
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 The compliance calculation and analysis was removed. 
 
Updates to match to protocol version 7.0. 
 
 
 


 
  
 
 
 
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10 REFERENCES 
Brand, J. P. L. (1999). “Development, Implementation, and Evaluation of Multiple Imputation 
Strategies for the Statistical Analysis of Incomplete Data Sets.” Ph.D. thesis, Erasmus 
University. 
 
 
Drano B et al. Development and evaluation of a Global Acne Severity Scale. 
Ge M, Durham LK, Meyer RD, et al. Covariate-adjusted difference in proportions from clinical 
trials using logistic regression and weighted risk differences. Drug Inf J 2011;45:481–93. 
(GEA Scale) suitable for France and Europe Journal of the European Academy of Dermatology 
and Venereology 2011, 25, 43–48. 
Hatch R. et al. Hirsutism: Implications, etiology, and management AJOG 1981  VOLUME 140, 
ISSUE 7, P815-830.  
Nebesio et al. Differential effects of hydrocortisone, prednisone, and dexamethasone on 
hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal 
hyperplasia. International Journal of Pediatric Endocrinology (2016) 2016:17. DOI 
10.1186/s13633-016-0035-5 
Ratitch, B., and O’Kelly, M. (2011). “Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures.” In Proceedings of PharmaSUG 2011 (Pharmaceutical Industry 
SAS Users Group). Paper SP04. Cary, NC: SAS Institute Inc.  
Rubin, D. B. (1976). “Inference and Missing Data.” Biometrika 63:581–592. 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons. 
Van Buuren, S. (2007). “Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification.” Statistical Methods in Medical Research 16:219–242. 
 
 
 
 


 
  
 
 
 
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11 APPENDICES 
11.1 Quality of Life Derivation  
11.1.1 SF-36 Scoring Information 
Derivation of summary scores, including appropriate handling of missing items, will be 
performed using the scoring software provided by the owner of the scale (Optum software, 
owned by QualityMetric®). Details of the specific derivations are held by QualityMetric. 
The SF-36 (v2.0) consists of 36 items, as follows: 
- 
1:In general, would you say your health is  
- 
2:Compared to one year ago, how would you rate your health in general now  
- 
3A:Vigorous activities, such as running, lifting heavy objects, participating in strenuous 
sports  
- 
3B:Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or 
playing golf  
- 
3C:Lifting or carrying groceries  
- 
3D:Climbing several flights of stairs  
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3E:Climbing one flight of stairs  
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3F:Bending, kneeling, or stooping  
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3G:Walking more than a mile  
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3H:Walking several hundred yards  
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3I:Walking one hundred yards  
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3J:Bathing or dressing yourself  
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4A:As a result of your physical health, cut down on the amount of time you spent on work 
or other activities  
- 
4B:As a result of your physical health, accomplished less than you would like  
- 
4C:As a result of your physical health, were limited in the kind of work or other activities  
- 
4D:As a result of your physical health, had difficulty performing the work or other 
activities (for example, it took extra effort)  
- 
5A:As a result of any emotional problems, cut down the amount of time you spent on 
work or other activities  
- 
5B:As a result of any emotional problems, accomplished less than you would like  
- 
5C:As a result of any emotional problems, did work or other activities less carefully than 
usual  
- 
6:During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors, or 
groups  
- 
7:How much bodily pain have you had during the past 4 weeks  
- 
8:During the past 4 weeks how much did pain interfere with your normal work (including 
both work outside the home and housework)  


 
  
 
 
 
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9A:How much of the time during the past 4 weeks: did you feel full of life  
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9B:How much of the time during the past 4 weeks: have you been very nervous  
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9C:How much of the time during the past 4 weeks: have you felt so down in the dumps 
that nothing could cheer you up  
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9D:How much of the time during the past 4 weeks: have you felt calm and peaceful  
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9E:How much of the time during the past 4 weeks: did you have a lot of energy  
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9F:How much of the time during the past 4 weeks: have you felt downhearted and 
depressed  
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9G:How much of the time during the past 4 weeks: did you feel worn out  
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9H:How much of the time during the past 4 weeks: have you been happy  
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9I:How much of the time during the past 4 weeks: did you feel tired  
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10:During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting your friends, relatives, etc.)  
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11A:I seem to get sick a little easier than other people  
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11B:I am as healthy as anybody I know  
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11C:I expect my health to get worse  
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11D:My health is excellent  
From the responses to these questions, the physical component score (PCS) and mental 
component score (MCS) are derived from the following subscores: 
Scale 
Item 
Coding 
Range of Raw 
Score 
Normalization* 
Physical 
Functioning 
Items 3a to 3j 
Yes, limited a lot = 1 
Yes, limited a little = 2 
No, not limited = 3 
10 (Worst) – 30 
(Best) 
(S-10)/20x100 
Role-
Physical 
Items 4a to 4d 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 
4 (Worst) – 20 
(Best) 
(S-4)/16x100 
Bodily Pain 
Item 7 
None = 6 
Very Mild = 5.4 
Mild = 4.2 
Moderate = 3.1 
Severe = 2.2 
Very Severe = 1 
2 (Worst) – 12 
(Best) 
(S-2)/10x100 
Item 8 if both 
items 7 and 8 
are answered 
Not at all and Item 7 is 
“None” = 6 
Not at all and Item 7 is not 
“None” = 5 


 
  
 
 
 
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Scale 
Item 
Coding 
Range of Raw 
Score 
Normalization* 
A little bit = 4 
Moderately = 3 
Quite a bit = 2 
Extremely = 1 
Item 8 if item 7 
is not answered 
Not at all = 6 
A little bit = 4.75 
Moderately = 3.5 
Quite a bit = 2.25 
Extremely = 1 
General 
Health 
Item 1 
Excellent = 5  
Very good = 4.4  
Good = 3.4  
Fair = 2  
Poor = 1 
5 (Worst) – 25 
(Best) 
(S-5)/20x100 
Items 11a and 
11c 
Definitely true = 1  
Mostly true = 2  
Don't know = 3  
Mostly false = 4 Definitely 
false = 5 
Items 11b and 
11d 
Definitely true = 5 Mostly 
true = 4  
Don't know = 3  
Mostly false = 2  
Definitely false = 1 
Vitality 
Items 9a and 9e 
All of the time = 5  
Most of the time = 4  
Some of the time = 3  
A little of the time = 2  
None of the time = 1 
4 (Worst) – 20 
(Best) 
(S-4)/16x100 
Items 9g and 9i 
All of the time = 1  
Most of the time = 2  
Some of the time = 3  
A little of the time = 4  
None of the time = 5 
Social 
Functioning 
Item 6 
Not at all = 5  
Slightly = 4  
Moderately = 3  
2 (Worst) – 10 
(Best) 
(S-2)/8x100 


 
  
 
 
 
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Scale 
Item 
Coding 
Range of Raw 
Score 
Normalization* 
Quite a bit = 2  
Extremely = 1 
Item 10 
All of the time = 1  
Most of the time = 2  
Some of the time = 3  
A little of the time = 4  
None of the time = 5 
Role-
Emotional 
Items 5a to 5c 
All of the time = 1  
Most of the time = 2  
Some of the time = 3  
A little of the time = 4  
None of the time = 5 
3 (Worst) – 15 
(Best) 
(S-3)/12x100 
Mental 
Health 
Items 9b, 9c and 
9f 
All of the time = 1  
Most of the time = 2  
Some of the time = 3  
A little of the time = 4  
None of the time = 5 
5 (Worst) – 25 
(Best) 
(S-5)/20x100 
Items 9d and 9h 
All of the time = 5  
Most of the time = 4  
Some of the time = 3  
A little of the time = 2  
None of the time = 1 
Note: * S = raw score = sum of item scores after coding 
Each scale score is then standardized based on the latest US population figures (held by Optum) 
to produce the following standardized Scale Scores: 
- 
Physical Functioning 
- 
Role-physical 
- 
Bodily pain 
- 
General health 
- 
Vitality 
- 
Social functioning 
- 
Role-emotional 
- 
Mental heath 
Finally, the SF-36 PCS and MCS transformed scores are derived. Additionally, norm-based 
transformation of the 8 scale scores will occur. 


 
  
 
 
 
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11.1.2 Multidimensional Assessment of Fatigue (MAF) 
The items of the MAF will be scored as follows (per American College of Rheumatology 
guidance): 
- 
Items 1, 4 – 14: 10pt scale from 1 = ‘not at all’ to 10 = ‘a great deal’ 
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Item 2: 10pt scale from 1 = ‘mild’ to 10 = ‘severe’ 
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Item 3: 10pt scale from 1 = ‘no distress’ to 10 = ‘a great deal of distress’ 
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Timing items 15 and 16: Categorical responses: 1 to 4 
- 
To calculate the Global Fatigue Index (GFI), convert item 15 to a 0 - 10 scale by 
multiplying each score by 2.5 and then sum items 1, 2, and 3, and average 4 - 14, and 
newly scored item 15. Do not assign a score to items 4 - 14 if the respondent gave a 
response of "do not do any activity for reasons other than fatigue." If a respondent selects 
“no fatigue” on item 1, assign a zero to items 2 - 16. Item 16 is not included in the GFI. 
A higher score indicates more severe fatigue, fatigue distress, or impact on activities of daily 
living. 
11.1.3 EQ-5D 
The EQ-5D is a standardized PRO for use as a general measure of health outcome. The EQ-5D 
has 5 questions used to create a descriptive “health state” and a VAS to capture a patient’s 
overall health rating. The 5 questions and derivation of the total score are as follows. 
Additionally, the 5 questions will be mapped to an index value using the crosswalk link function 
based on the published EQ-5D-5L Crosswalk Index Value Set. 
Question 
Coding 
Mobility (EQ5D0201) I have no problems walking = 1 
I have slight problems walking = 2 
I have moderate problems walking' = 3 
I have severe problems walking = 4 
I am unable to walk = 5 
Self-Care 
(EQ5D0202) 
I have no problems washing and dressing myself = 1 
I have slight problems washing and dressing myself = 2 
I have moderate problems washing and dressing myself = 3 
I have severe problems washing and dressing myself = 4 
I am unable to wash and dress myself = 5 


 
  
 
 
 
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Question 
Coding 
Usual Activities 
(EQ5D0203) 
I have no problems doing my usual activities = 1 
I have slight problems doing my usual activities = 2  
I have moderate problems doing my usual activities = 3  
I have severe problems doing my usual activities = 4 
I am unable to do my usual activities = 5 
Pain/Discomfort 
(EQ5D0204) 
I have no pain or discomfort = 1 
I have slight pain or discomfort = 2 
I have moderate pain or discomfort = 3  
I have severe pain or discomfort = 4 
I have extreme pain or discomfort = 5 
Anxiety/Depression 
(EQ5D0205) 
I am not anxious or depressed = 1 
I am slightly anxious or depressed = 2  
I am moderately anxious or depressed = 3  
I am severely anxious or depressed = 4 
I am extremely anxious or depressed = 5 
EQ-5D Total Score 
Determine ‘health state’ which for example if all questions were 
answered ‘1’ then it would be 
11111 per participant per visit where: 
 EQ5D0201 outcome x 10000 
 EQ5D0202 outcome x 1000 
 EQ5D0203 outcome x 100 
 EQ5D0204 outcome x 10 
 EQ5D0205 outcome x 1 
EQ-5D Index 
Corresponding index value from the US country value set from the 
Euroquol list, based on the 'health state'. The crosswalk value set 
can be found here. 
 
 
 


 
  
 
 
 
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