A Phase III Extension Study of Efficacy, Safety and Tolerability of Chronocort® in the Treatment of Congenital Adrenal Hyperplasia
Phase: PHASE3
Conditions: Congenital Adrenal Hyperplasia
Sponsor: Neurocrine UK Limited

Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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CLINICAL STUDY PROTOCOL PLUS AMENDMENT 19  
(applicable for USA and France only) 
 
 
A Phase III extension study of efficacy, safety and tolerability of Chronocort® in the 
treatment of congenital adrenal hyperplasia 
 
 
IND No.:  76485 
Protocol No.:  DIUR-006 
EUDRACT No.: 2015-005448-32 
Version No.:  20.0 
 
Date of Protocol:  16 June 2022 
 
STUDY SPONSOR:  
Diurnal Ltd 
Cardiff Medicentre 
Heath Park 
Cardiff 
CF14 4UJ, UK 
 
 
 
Sponsor Signature:
 
 
 
Confidentiality Statement: 
 
This document contains information which is the property of Diurnal Ltd, UK and therefore is provided to you 
in confidence for review by you, your staff, an applicable Independent Ethics Committee/Institutional Review 
Board and Regulatory Authorities. It is understood that this information will not be disclosed to others without 
written approval from Diurnal Ltd. 
 
This study will be conducted in compliance with Good Clinical Practice (GCP), the Declaration of 
Helsinki (with amendments) and in accordance with local legal and regulatory requirements. 

Investigational product: 
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Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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PRINCIPAL COORDINATING INVESTIGATOR SIGNATURE PAGE 
 
 
Principal Coordinating 
Investigator 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
Tel: 
 
Fax: 
 
Email: 
 
 
 
 
 
 
 
 
 
 
I, the undersigned, have reviewed this protocol, plus amendment 19, and including 
appendices, and I will conduct the clinical study as described and will adhere to GCP/ICH 
and all the ethical and regulatory considerations stated. I have read and understood the 
contents of the Investigator’s Brochure. 
 
 
 
 
 
 
Signature: 
 
 
 

Investigational product: 
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Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE  
[NOTE: THIS PAGE MUST BE CUSTOMISED TO EACH STUDY SITE] 
 
 
Principal Investigator 
 
Address: 
 
To be customised as appropriate for each site 
 
 
 
 
 
 
 
Tel: 
 
Fax: 
 
Email: 
 
 
 
 
 
 
 
I, the undersigned, have reviewed this protocol, plus amendment 19, and including 
appendices, and I will conduct the clinical study as described and will adhere to 
GCP/ICH and all the ethical and regulatory considerations stated. I have read and 
understood the contents of the Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
Signature:  ________________________________ 
Date:  _____________________ 
 
Dr ............... [full name to be added] 
 
Principal Investigator 
 
 
 
 
 
 
 

Investigational product: 
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Protocol No.: DIUR-006 
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Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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STATISTICIAN SIGNATURE PAGE 
 
 
Statistician: 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
Tel: 
 
Email: 
 
 
 
 
 
 
 
 
I, the undersigned, have reviewed this protocol, plus amendment 19, and including 
appendices, and I will conduct my role in the clinical study as described and will adhere 
to GCP/ICH and all the ethical and regulatory considerations stated. I have read and 
understood the contents of the Investigator’s Brochure. 
 
 
 
 
 
 
 
Signature
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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1. Protocol Synopsis 
 
PROTOCOL TITLE: 
A Phase III extension study of efficacy, safety and tolerability of 
Chronocort® in the treatment of congenital adrenal hyperplasia 
PROTOCOL No: 
DIUR-006 
PRINCIPAL COORDINATING 
INVESTIGATOR  
 
 
 
 
 
SPONSOR: 
Diurnal Limited 
Cardiff Medicentre 
Heath Park 
Cardiff, CF14 4UJ 
UK 
INVESTIGATIONAL PRODUCT: 
Chronocort® (Hydrocortisone Modified Release Capsule) 
PHASE OF DEVELOPMENT: 
Phase III 
STUDY DESIGN 
Open label extension study 
STUDY CENTRES 
Approved centres who participated in Chronocort® studies 
DIUR-003 and DIUR-005  
INCLUSION CRITERIA 
1. Subjects with congenital adrenal hyperplasia (CAH) who have successfully completed the DIUR-003 
or DIUR-005 clinical trials with the current formulation of Chronocort® 
2. Provision of signed written informed consent. 
EXCLUSION CRITERIA 
1. Co-morbid condition requiring daily administration of a medication (or use of any 
medications/supplements) that interferes with the metabolism of glucocorticoids. 
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the upper limit of 
normal (ULN) or elevated liver function tests (alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST] >2 times ULN]). 
3. Females who are pregnant or lactating. 
4. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH. 
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry 
into the study). 
6. Subjects with a history of bilateral adrenalectomy. 
7. Participation in another clinical trial of an investigational or licensed drug or device within the 3 
months prior to inclusion in this study, except for another clinical trial with the current formulation 
of Chronocort®. 
8. Subjects unable to comply with the requirements of the protocol.  
9. Subjects who routinely work night shifts and so do not sleep during the usual nighttime hours. 
STUDY DURATION: 
The length of the study will be approximately 5.5 years from the date of the first subject entering the study, so 
subjects will be treated for a maximum of 5.5 years (i.e. from August 2016 to February 2022). All subjects 
must be enrolled by 31 October 2018, with no subjects allowed to enter the study after this date. 
NUMBER OF SUBJECTS: 
All eligible subjects from study DIUR-003 (16 subjects) and DIUR-005 (122 subjects) may enter this study, 
giving a maximum of 138 subjects. 
TEST PRODUCT, DOSE AND MODE 
OF ADMINISTRATION: 
Chronocort® will be provided as 5 mg, 10 mg and 20 mg 
capsules for oral administration.  
REFERENCE THERAPY, DOSE 
AND MODE OF ADMINISTRATION: 
 
None. 

Investigational product: 
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OBJECTIVES: 
Primary Objective: Safety and tolerability of Chronocort® over time, as assessed by signs and symptoms of 
adrenal insufficiency or over-treatment, use of sick day rules, adrenal crisis, adverse events (AEs), laboratory 
measures and clinical observation. 
Secondary Objectives: 
The long-term efficacy of Chronocort® will be assessed over time by the measurement of: 
1. Total daily dose of Chronocort®  in mg/day of hydrocortisone and by body surface area (BSA) 
during the study and the incidence of dose titrations 
2. 17-hydroxyprogesterone (17-OHP) and androstenedione (A4), measured at two time points (at 
09:00 and 13:00 hours) for: 
a. 
Disease control at each visit as assessed by both 17-OHP and A4 levels in the optimal 
and normal range, respectively, at both time points and by the proportion of dose given 
at night 
b. 17-OHP and A4 standard deviation scores (SDS) 
c. 
Change in absolute values compared to pre-Chronocort®  baseline values 
3. Changes compared to pre-Chronocort® baseline in:  
a. 
Bone turnover markers  -  serum C-terminal cross-linked telopeptide (CTX), osteocalcin 
b. Testosterone (total) 
c. 
Fasting insulin and blood glucose levels, and glycated haemoglobin (HbA1c) 
d. High sensitivity c-reactive protein (hsCRP) and plasma renin activity (PRA) 
e. 
Body composition (dual energy X-ray absorptiometry [DEXA]) (fat mass, lean mass 
and total bone density) (except in Germany) 
f. 
Quality of life – SF-36®, Multidimensional Assessment of Fatigue (MAF), EQ-5D™ 
Note: Pre-Chronocort® baseline means prior to the first dose of continuous Chronocort® which is: 
• 
The reassessed baseline under DIUR-006 for subjects entering from study DIUR-003 and those subjects from 
DIUR-005 who had a gap between completing study DIUR-005 and starting study DIUR-006, 
• 
Visit 4 (Week 24) from the feeder study for subjects who received standard glucocorticoid replacement therapy 
in study DIUR-005 and immediately entered DIUR-006, 
• 
Prior to the first  Chronocort® dose in study DIUR-005 for subjects who received Chronocort® in study 
DIUR-005 (i.e. DIUR-005 baseline visit) and immediately entered DIUR-006. 
METHODOLOGY: 
Subjects completing study DIUR-005 and those who have already completed study DIUR-003 will be offered 
the opportunity either to continue Chronocort® therapy or to switch from their current glucocorticoid therapy 
to Chronocort® in this open-label study.  
All subjects will have a screening visit prior to the baseline assessment to allow DIUR-006 procedures to be 
fully explained and informed consent to be given by the subject. For subjects from DIUR-003 and any subjects 
from DIUR-005 who had a gap between completing study DIUR-005 and starting study DIUR-006 during 
which they received standard glucocorticoid therapy, this screening visit will include safety blood tests. Any 
subjects not meeting the inclusion/exclusion criteria following these blood tests will be not be entered into the 
study. 
All subjects will then return for the baseline visit. For subjects entering from study DIUR-003 and any subjects 
from DIUR-005 who had a gap between completing study DIUR-005 and starting study DIUR-006 during 
which they received standard glucocorticoid therapy, the full set of baseline assessments will be completed, 
including 2 blood samples (one at 09:00 and one at 13:00 hours) for 17-OHP and A4 (note: baseline DEXA 
scan only needed for subjects entering from study DIUR-003). For subjects entering immediately from study 
DIUR-005, test results from their last visit in the feeder study (V4) will be used for this baseline assessment, 
with the 09:00 and 13:00 hour results taken from the 24-hour hormone profiles conducted at the visit. Any 
subjects not meeting the inclusion/exclusion criteria following these blood tests will be withdrawn from this 
study. 
Once the baseline assessments are completed, the subjects will be given sufficient Chronocort® to use until the 
next visit at Week 4. Subjects entering immediately from study DIUR-005 who were previously on 
Chronocort®  will continue on the same dose of Chronocort® that they were receiving at the end of the feeder 
study. Subjects from study DIUR-005 on standard therapy, subjects from DIUR-005 who had a gap between 
completing study DIUR-005 and starting study DIUR-006 during which they received standard glucocorticoid 
therapy, and subjects from study DIUR-003 will have their initial dose of Chronocort® determined using the 
hydrocortisone equivalent of their previous treatment (immediately prior to the baseline visit).  

Investigational product: 
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All subjects will return to the study centre at 4, 12 and 24 weeks after starting study DIUR-006 for additional 
blood tests and dose titration, if necessary. Visits thereafter will take place at 6-monthly intervals. If there is a 
change of dose, an interim dose titration visit or telephone call will be needed in between the 6-monthly visits. 
All subjects will receive welfare telephone calls at 3 monthly intervals, and unscheduled visits will be arranged 
if necessary. Subjects will be provided with Chronocort® supplies from the study pharmacy at either 3-or 
6-monthly intervals.  
All subjects have the following assessments conducted during the study: 
At all visits: 
• 
AEs recorded, with particular note taken of use of sick day rules and adrenal crises. 
• 
Dose of Chronocort® given, along with compliance assessment. 
• 
Concomitant medications recorded. 
• 
Measurement of 17-OHP and A4 at two time points (the first at 09:00 and the second at 13:00 hours). 
• 
Urine pregnancy test for women of childbearing potential (note: females presenting with 
oligomenorrhoea or amenorrhoea who are aged ≤55 years of age should be considered potentially 
fertile and should therefore undergo pregnancy testing like all other female subjects). 
At baseline, at each 6-monthly visit and at the final visit: 
• 
Physical examination, vital signs, weight, body mass index (BMI) and waist circumference. 
• 
Safety blood tests, serum CTX, osteocalcin, PRA, hsCRP, HbA1c, testosterone, fasting insulin and 
blood glucose levels. 
• 
Quality of life – SF-36®, MAF, EQ-5D™ 
At yearly intervals (except Germany):  
• 
body composition (DEXA) (fat mass, lean mass and total bone density) (to be taken at baseline for 
subjects entering from study DIUR-003).  
At the end of the study subjects will have the option to enter a second long-term study (DIUR-015) to enable 
them to continue to receive open-label Chronocort® until it is commercially available in their region or it is 
decided to stop Chronocort® treatment. Subjects who decide to enter the DIUR-015 study immediately 
following this DIUR-006 study do not require a telephone call 30 days after the end of this study. If there is a 
gap between finishing this DIUR-006 study and entering the DIUR-015 study of greater than 30 days, then the 
30-day telephone call is required. 
Dose Titration Algorithm 
The intention of dose adjustment is to optimise control of CAH according to current standard of care based on 
subject symptoms and the measurement of androgens. As this study is open and uncontrolled, titration will be 
performed by the investigating physician. Dose adjustment will be based on clinical symptoms using the “signs 
and symptoms of adrenal insufficiency questionnaire” and the measurement of 17-OHP and A4. The 17-OHP 
and A4 sample taken at 09:00 will reflect the Chronocort® dose taken at 23:00 hours and the sample taken at 
13:00 will reflect the 07:00 hour Chronocort® dose. Dose adjustments will be considered if the samples show 
out of range values for 17-OHP or A4. If 17-OHP and A4 show inconsistent trends, the A4 parameter will take 
precedence in directing dose adjustment. Confirmation of the dose following the hormone results will be made 
by telephone within two weeks of the visit and will be followed up in writing whether dose titration is needed 
or not. If a dose titration is needed, an interim dose titration visit or telephone call (at the investigator’s 
discretion) will be required to take place approximately 4 weeks after the decision has been communicated to 
the participant. 
The rationale for any dose adjustment will be recorded in the electronic case report form (eCRF). No dose 
adjustments outside of the protocol-defined dose adjustments should be conducted, unless clinical signs and 
symptoms indicate an immediate need. In such cases the Sponsor’s medical monitor must be contacted 
(preferably before any dose changes are implemented). Any such unscheduled dose adjustments should be 
based on clinical symptoms only, with repeated androgen testing discouraged and must be pre-approved by the 
Sponsor’s medical monitor. Stress doses of hydrocortisone will be given for inter-current illnesses as medically 
indicated according to “sick day rules”. Fludrocortisone dose adjustment will be made if medically indicated 
and will be based on blood pressure measurements and laboratory data (goal supine PRA < 1.5 x ULN).  
In subjects who have undetectable androgens at baseline on their regular medication, caution will be taken with 
dose reductions if there is suspicion of the subject having a suppressed hypothalamic-pituitary-adrenal axis. 

Investigational product: 
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Protocol No.: DIUR-006 
Chronocort®  
      
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Version: 20.0 – 16 Jun 2022 
 
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STATISTICAL METHODS:   
A detailed and comprehensive Statistical Analysis Plan (SAP) will be prepared and signed-off before the first 
subject has given informed consent for this extension study. Interim data analyses are expected to be required 
for regulatory review as part of any marketing authorisation applications. No changes to the overall study 
conduct and no changes to the planned formal statistical analyses are anticipated as a result. 
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). Geometric mean and 
coefficient of variation will also be presented for variables which will subsequently be log-transformed during 
the analysis. 
For all analyses using change from baseline, baseline values for this DIUR-006 study will be used for subjects 
entering from study DIUR-003 and for subjects receiving standard therapy in study DIUR-005 or who had a 
gap between completing study DIUR-005 and starting study DIUR-006 during which they received standard 
glucocorticoid therapy. For subjects who received Chronocort® in study DIUR-005 and went straight into this 
DIUR-006 extensions study without a gap, baseline will be the baseline in the DIUR-005 study (i.e. before the 
start of any Chronocort® treatment). 
All efficacy endpoints, including change from baseline, will be summarised at each visit by previous treatment, 
and by study. Exposure to Chronocort® and the incidence of dose titrations will be summarised as efficacy 
variables. All efficacy endpoints will be summarised over time. Disease control will be based on whether 
17-OHP levels are in the optimal range and also whether the A4 levels are in the normal range (both analysed 
separately). A subject will be considered a responder (i.e. disease controlled) if their results are in the optimal 
or normal range, respectively. 
AEs will be coded using the latest version of the MedDRA drug dictionary. Data will be summarised using 
preferred term (PT) and primary system organ class (SOC). Only treatment-emergent AEs, i.e. AEs with an 
onset at or after the first administration of Chronocort® in this study, will be presented in summary tables. 
Where changes in severity are recorded in the eCRF, the most severe incidence of the AE will be reported in 
the tables. Rates will be calculated as the proportion of subjects with at least one AE related to the number of 
subjects treated in each treatment group. Frequency tables will be provided concerning severity and drug 
relationship.  
Summary vital signs changes from baseline will be presented in tabular form using standard summary statistics. 
Absolute and change from baseline in safety laboratory variables will be summarised over time using standard 
summary statistics at each time point. Shift tables from baseline to the maximum and minimum on-treatment 
values will be presented. The 3 x 3 cross tabulations (from low, normal and high to low, normal and high) will 
be presented. Values outside the normal ranges (provided with the laboratory report), will be flagged in the 
subject data listings. 
 
 

Investigational product: 
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Protocol No.: DIUR-006 
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2. List of Abbreviations 
 
17-OHP 
17-hydroxyprogesterone 
A4 
Androstenedione 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CAH 
Congenital adrenal hyperplasia 
CBC 
Complete blood count 
CK 
Creatine kinase 
Cmax 
Maximum concentration  
COVID-19 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
CRA 
Clinical Research Associate 
CRADA 
Cooperative Research and Development Agreement 
CRH 
Corticotropin-releasing hormone 
CRO 
Contract Research Organisation 
CTX 
C-terminal cross-linked telopeptide 
CYP 
Cytochrome P 
DEXA 
Dual energy X-ray absorptiometry 
dL 
Decilitre 
DSMB 
Data Safety Management Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form  
EQ-5D™ 
EQ-5D™ Standardised Health Questionnaire (5-level) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
HbA1c 
Glycated haemoglobin 
Hct 
Haematocrit 
HDL 
High density lipoprotein 
HDPE 
High density polyethylene 
hsCRP 
High sensitivity c-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 

Investigational product: 
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Diurnal Ltd 
 
Version: 20.0 – 16 Jun 2022 
 
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IPI 
Identifiable private information 
IRB 
Institutional Review Board 
IRHC 
Immediate release hydrocortisone  
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
MAF 
Multidimensional Assessment of Fatigue 
MCH 
Mean cell haemoglobin 
MCHC 
Mean cell haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
NF 
National Formulary 
NIH 
National Institutes of Health 
PK 
Pharmacokinetics 
PP 
Polypropylene 
PRA 
Plasma renin activity 
PT 
Preferred term 
PV 
Pharmacovigilance 
QoL 
Quality of life 
RBC 
Red blood cell count 
RDW 
Red cell distribution width 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Standard deviation score 
SDV 
Source data verification 
SF-36® 
Medical Outcome Short Form Health Survey Form 36 (Subject Questionnaire) 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tmax 
Time taken to reach Cmax 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
The term ‘feeder study’ refers to the study the subject was in prior to entering this extension 
study: the feeder studies are DIUR-003 and DIUR-005. 
 
 
 
 
 
 
 

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3. 
Table of Contents 
1. 
Protocol Synopsis ............................................................................................................. 5 
2. 
List of Abbreviations ....................................................................................................... 9 
3. 
Table of Contents ........................................................................................................... 11 
4. 
Investigators and Administrative Structure ................................................................ 14 
5. 
Introduction .................................................................................................................... 16 
5.1 
Overview ............................................................................................................................. 16 
5.2 
Overview of Congenital Adrenal Hyperplasia ................................................................ 16 
5.3 
Overview of Chronocort®.................................................................................................. 17 
5.4  
Rationale for the use of Chronocort® in the treatment of CAH .................................... 17 
5.5 
Overview of Chronocort® clinical studies ........................................................................ 18 
5.6 
Proposed study ................................................................................................................... 20 
5.7 
Benefit/Risk Assessment.................................................................................................... 20 
6. 
Study Objectives............................................................................................................. 21 
6.1 
Primary Objective ............................................................................................................. 21 
6.2 
Secondary Objectives ........................................................................................................ 21 
7. 
Study Endpoints ............................................................................................................. 22 
7.1 
Primary Endpoint .............................................................................................................. 22 
7.2 
Secondary Endpoints ......................................................................................................... 22 
8. 
Study Design ................................................................................................................... 23 
8.1 
Dose Titration Algorithm .................................................................................................. 24 
9. 
Subject Population ......................................................................................................... 25 
9.1 
Number of Subjects and Subject Selection ...................................................................... 25 
9.2 
Inclusion Criteria ............................................................................................................... 25 
9.3 
Exclusion Criteria .............................................................................................................. 26 
10. Study Medication and Administration ........................................................................ 26 
10.1 
Randomisation and Blinding ............................................................................................ 26 
10.2 
Description and Handling of IMPs .................................................................................. 26 
10.2.1 
Chronocort® Formulation ............................................................................................ 26 
10.2.2 
Packaging and Labelling ............................................................................................. 27 
10.2.3 
Storage ........................................................................................................................ 27 
10.2.4 
Accountability and Compliance .................................................................................. 27 
10.3 
Dosage and Administration .............................................................................................. 28 
10.4 
Dose Adjustments .............................................................................................................. 28 
10.5 
Other Study Medications (Non-Investigational Medicinal Products) .......................... 29 
10.6 
Permitted Concomitant Medications/Treatments .......................................................... 29 
11 Study Procedures ........................................................................................................... 29 
11.1 
Visit Schedule ..................................................................................................................... 32 
11.1.1 
Screening Visit (Visit 0) ............................................................................................. 32 
11.1.2 
Baseline Visit (Visit 1) – Day 0 .................................................................................. 32 
11.1.3 
Week 4 (Visit 2) (± 3 Days) ........................................................................................ 34 
11.1.4 
Telephone call (within 2 weeks of Visit 2) ................................................................. 34 
11.1.5 
Week 12 (Visit 3) (± 3 Days) ...................................................................................... 35 
11.1.6 
Telephone call (within 2 weeks of Visit 3) ................................................................. 35 
11.1.7 
Week 24 and then every 6-months (± 2 Weeks) ......................................................... 36 
11.1.8 
Telephone call (within 2 weeks of previous visit) ...................................................... 37 
11.1.9 
Week 18 (± 3 Days) and then 3-monthly between the 6-monthly visits (± 2 Weeks) 37 
11.1.10 
Final visit or early withdrawal visit ............................................................................ 37 

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11.1.11 
Telephone call (30 days after the final visit)............................................................... 38 
11.1.12 
Unscheduled Visits or telephone calls ........................................................................ 39 
11.2 
Study Assessments ............................................................................................................. 39 
11.3 
Sick Day Rules ................................................................................................................... 40 
11.4 
Early Withdrawal from Treatment ................................................................................. 40 
11.5 
Criteria for Withdrawal of Study Treatment ................................................................. 41 
11.6 
Replacement of Withdrawn Subjects............................................................................... 41 
11.7 
Pregnancy ........................................................................................................................... 41 
11.8 
Study Duration and Completion of the Study ................................................................. 42 
11.9 
Overdose ............................................................................................................................. 43 
11.10 Subject Diaries ................................................................................................................... 43 
11.11 COVID-19 Procedures ...................................................................................................... 43 
12 Adverse Events and Toxicity Management ................................................................. 43 
12.1 
Adverse Event Definition .................................................................................................. 43 
12.2 
Adverse Event Collection .................................................................................................. 43 
12.3 
Reporting of Adverse Events ............................................................................................ 44 
12.3.1 
Diagnoses vs. signs/symptoms.................................................................................... 44 
12.3.2 
Laboratory values ....................................................................................................... 44 
12.3.3 
Pre-existing conditions ............................................................................................... 44 
12.3.4 
Pre-planned surgeries or procedures ........................................................................... 44 
12.3.5 
Insufficient clinical response (lack of efficacy) .......................................................... 44 
12.3.6 
Overdose ..................................................................................................................... 44 
12.4 
Assessment of Adverse Event Severity ............................................................................ 44 
12.5 
Assessment of Adverse Event Causality/Relatedness ..................................................... 45 
12.6 
Assessment of Adverse Event Expectedness.................................................................... 45 
12.7 
Serious Adverse Event Definitions ................................................................................... 45 
12.8 
Suspected Unexpected Serious Adverse Reaction .......................................................... 46 
12.9 
Serious Adverse Event Reporting .................................................................................... 46 
12.10 Serious Adverse Event Expedited Reporting .................................................................. 48 
12.10.1 
Standards for Expedited Reporting ............................................................................. 48 
12.10.2 
Expedited Reporting Guideline for Other Observations ............................................. 48 
12.11 Sponsor’s Responsibilities ................................................................................................. 49 
12.12 Procedures for Reporting Pregnancy Exposure and Birth Events ............................... 49 
12.13 Data Safety Management Board ...................................................................................... 49 
13 Statistical Considerations .............................................................................................. 49 
13.1 
Conventions and Methods................................................................................................. 50 
13.1.1 
Summary Tables, Listings and Figures ....................................................................... 50 
13.1.2 
Hypothesis Testing and Confidence Intervals ............................................................ 50 
13.1.3 
Missing Outcome Data ............................................................................................... 50 
13.2 
Analysis Sets ....................................................................................................................... 50 
13.3 
Endpoints............................................................................................................................ 51 
13.3.1 
Primary Endpoint ......................................................................................................... 51 
13.3.2 
Secondary Endpoints .................................................................................................... 51 
13.4 
Analysis of the Conduct of the Study ............................................................................... 52 
13.5 
Demographic and other baseline characteristics ............................................................ 52 
13.6 
Efficacy and Safety Analyses ............................................................................................ 52 
13.6.1 
Safety .......................................................................................................................... 52 
13.6.2 
Efficacy ....................................................................................................................... 53 
13.6.3 
SDS ............................................................................................................................. 53 
13.7 
Power and Sample Size Considerations ........................................................................... 54 
13.8 
Data Review Meeting......................................................................................................... 54 
13.9 
Deviations from the Planned Statistical Analysis ........................................................... 54 
14 Responsibilities ............................................................................................................... 54 

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14.1 
Investigator Responsibilities ............................................................................................. 54 
14.2 
Ethical Conduct of the Study ............................................................................................ 55 
14.3 
Ethics Committee and Institutional Review Board approval ........................................ 55 
14.4 
Informed Consent .............................................................................................................. 56 
14.5 
Subject Data Protection .................................................................................................... 56 
14.6 
Case Report Forms and QoL questionnaires .................................................................. 56 
14.7 
Data Management ............................................................................................................. 57 
14.8 
Drug Reconciliation ........................................................................................................... 57 
14.9 
Inspections .......................................................................................................................... 57 
14.10 Protocol Compliance ......................................................................................................... 57 
14.11 Sponsor Responsibilities.................................................................................................... 58 
14.11.1 
Indemnity and Compensation ..................................................................................... 58 
14.11.2 
Protocol Modifications ............................................................................................... 58 
14.12 Study Monitoring ............................................................................................................... 58 
14.13 Publication Policy .............................................................................................................. 59 
14.14 Clinical Study Report ........................................................................................................ 59 
14.15 Data Retention and Availability ....................................................................................... 59 
14.16 Study Termination ............................................................................................................. 60 
15. References ....................................................................................................................... 61 
Appendix 1 – Standard Safety Haematology and Clinical Chemistry Parameters ......... 63 
Appendix 2 - Expected Adverse Events ............................................................................... 64 
Appendix 3 - Sick Day Rules ................................................................................................. 66 
Appendix 4 - Adrenal Insufficiency Checklist..................................................................... 68 
Appendix 5 - SF-36®............................................................................................................... 69 
Appendix 6 - MAF ................................................................................................................. 75 
Appendix 7 - EQ-5D Health Questionnaire ......................................................................... 78 
Appendix 8 - Labelling of IMP and Rescue Medication .................................................... 81 
Appendix 9 - Protocol Amendment History ........................................................................ 85 
 
 

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4. 
Investigators and Administrative Structure 
 
Co-ordinating Principal 
Investigator 
 
 
 
 
 
 
   
 
 
 
 
 
 
Medical Expert (Sponsor) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Project Manager (Sponsor) 
 
 
 
 
 
 
 
 
 
Statistical Consultants 
 
 
 
 
 
 
 
   
 
 
Contract Research Organisation/ 
Monitors 
 
 
 
 
 
 
Central Laboratory 
 
 
 
  
 
 
 
 

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Safety Reporting 
  
 
  
 
 
 
 
  
 
 

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5. 
Introduction 
5.1 
Overview 
Congenital adrenal hyperplasia (CAH), generally due to 21-hydroxylase deficiency, is a disease 
of the adrenal cortex characterised by cortisol deficiency with or without aldosterone 
deficiency, and androgen excess. The severe or classic form occurs in 1 in 15,000 births 
worldwide (Merke 2005; Pang 1993; Therrell 2001), while the mild non-classic form is a 
common cause of hyperandrogenism (New 2006). The discovery of glucocorticoid therapy as 
a treatment for CAH occurred in the 1950s resulting in subjects with classic CAH surviving. 
However, existing glucocorticoid treatment remains suboptimal and many unresolved clinical 
problems exist (Han 2014).  
 
The glucocorticoid therapies currently used often fail to normalise the growth and development 
of children with CAH. Also adults may experience iatrogenic Cushing’s syndrome, 
hyperandrogenism, infertility or the development of metabolic syndrome (Arlt 2010). 
Chronocort®, a newly-developed modified release oral formulation of hydrocortisone, is 
designed to mimic the normal serum levels of the endogenous cortisol circadian rhythm, 
offering the prospect of an improved treatment outcome. Phase II and III studies have been 
carried out to evaluate whether a twice a day dosing regimen of Chronocort® given at night and 
in the morning (which can more closely normalise cortisol levels) will improve control of 
adrenal androgen production (as measured by 17-hydroxyprogesterone [17-OHP] and 
androstenedione [A4]). This study is a long-term extension study for subjects who were 
included in studies DIUR-003 and DIUR-005 to obtain long-term safety data and to continue 
to monitor long-term efficacy.  
5.2 
Overview of Congenital Adrenal Hyperplasia  
The adrenal cortex secretes the stress hormone cortisol, a glucocorticoid steroid that regulates 
energy balance and many intracellular processes. Cortisol synthesis is stimulated by 
adrenocorticotrophic hormone (ACTH), which increases the synthesis of the cytochrome P 
(CYP) enzymes that are involved in the synthesis of cortisol. ACTH secretion by the pituitary, 
in turn, is increased by hypothalamic secretion of corticotropin-releasing hormone (CRH), 
which is partly regulated by the central ‘zeitgeber’, or clock. Both ACTH and CRH secretion 
are inhibited by hypercortisolism. The adrenal cortex also secretes aldosterone, a 
mineralocorticoid steroid hormone that regulates sodium, potassium and water balance. 
 
The pathophysiology of 21-hydroxylase deficiency-related adrenal hyperplasia is closely 
linked to the degree of enzyme deficiency. In the most severe form, concomitant aldosterone 
deficiency leads to salt loss and dehydration. In CAH, the defect in cortisol biosynthesis leads 
to a compensatory increase in ACTH and hypothalamic CRH due to a lack of the usual negative 
feedback by cortisol. Conventional glucocorticoid and mineralocorticoid replacement doses 
fail to replicate the close temporal relationship between CRH, ACTH and subsequent cortisol 
pulses (Krieger 1971; Ross 2005). Supraphysiologic doses of glucocorticoid are often 
necessary to adequately suppress excess adrenal androgen and oestrogen production (Cutler 
1990; Merke 2001). Thus subjects with treated CAH are often poorly controlled on current 
standard therapy.  
 
Conventional medical treatment of CAH is often a difficult balancing act between the 
undesirable states of hypercortisolism and hyperandrogenism (Han 2014). Subjects with CAH 
are at risk of developing a number of clinical manifestations, such as obesity in children 

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(Cornean 1998), insulin resistance (Azziz 1994; Moran 2000; New 1993; Speiser 1985), and 
polycystic ovaries, which may contribute to infertility in women with CAH. Oligomenorrhoea 
or amenorrhoea may be present in adolescence (Barnes 1994; Deneux 2001). The development 
of ectopic adrenal tissue or adrenal rest tissue is also associated with CAH. 
5.3 
Overview of Chronocort® 
The active ingredient of Chronocort® is hydrocortisone. The safety profile of hydrocortisone is 
well characterised in humans and there is extensive clinical experience with the use of 
hydrocortisone in subjects with CAH. The excipients (inactive ingredients) used in the 
Chronocort® formulation under investigation are also well-characterised and are approved for 
use in humans at the proposed levels. The Chronocort® formulation has been manufactured and 
is supplied in accordance with current Good Manufacturing Practice (GMP).  
 
Chronocort® is a patented oral modified release formulation of hydrocortisone which is 
intended to mimic, or closely match, the serum levels of endogenous cortisol, thereby 
improving the treatment of subjects with CAH. The rationale for Chronocort® is based on the 
belief that the delivery of a physiological cortisol profile will offer significant clinical benefits 
over current treatment. Formulations of immediate release hydrocortisone (IRHC) and other 
glucocorticoids used in the treatment of CAH are recognised to be unsatisfactory due to issues 
with: 
 
• 
suboptimal disease control  
• 
risk of glucocorticoid over-treatment 
• 
inconvenient dosing regimens 
• 
complex and inconsistent protocols for monitoring therapy 
• 
poor subject compliance 
 
Mimicry of the physiological cortisol profile is achieved by a delayed release and sustained 
absorption profile, such that when the dosage form is administered at night time (approximately 
23:00 hours) there is a period of absence of drug release followed by a period of sustained 
absorption, to yield an elevation in serum cortisol concentration according to the normal 
circadian profile, with peak concentration occurring in the morning (approximately 06:00-
08:00 hours) (Whitaker 2014; Mallappa 2015). 
5.4  
Rationale for the use of Chronocort® in the treatment of CAH 
Subjects with classic CAH receive replacement glucocorticoid and mineralocorticoid. Many 
different regimens of glucocorticoid are advocated. Hormone levels are monitored prior to 
morning dose of medication, aiming for mildly elevated morning 17-OHP levels and normal 
renin levels (Joint LWPES/ESPE CAH Working Group 2002; Merke 2005; Speiser 2003). 
Physical features and clinical symptoms are monitored for evidence of excessive (e.g. obesity, 
striae, and decreased linear growth in children) or insufficient (e.g. hirsutism, amenorrhoea or 
virilisation in women, fatigue, and increased linear growth, early puberty, advanced bone 
maturation in children) treatment. It is often quite difficult to reduce excess androgen without 
giving excess glucocorticoid because current therapies cannot replace the normal circadian 
rhythm of cortisol.  
 
Chronocort® is a newly-developed formulation of hydrocortisone that allows for slow 
absorption after oral administration when given at 23:00 hours (20 mg) and 07:00 hours 
(10 mg), so that cortisol levels peak in the early morning (Whitaker 2014). The compound has 

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the unique potential to provide the best possible physiologic replacement of cortisol and 
promises to ameliorate many of the unresolved medical issues surrounding the management of 
subjects with CAH (Mallappa 2015).  
5.5 
Overview of Chronocort® clinical studies  
One Phase I study has been completed to assess the pharmacokinetics (PK) of Chronocort® 
(study DIUR-002) (Whitaker 2014). Study DIUR-002 fully characterised the PK performance 
and dose proportionality of Chronocort®. The target PK criteria, commensurate with the 
endogenous circadian profile for cortisol, were as follows: mean maximum concentration 
(Cmax) >300 nmol/L (>10.8 mcg/dL) for the 20 mg dose, time taken to reach Cmax (Tmax) 
approximately 6-8 hours post-dosing to prime waking, mean cortisol level >100 nmol/L 
(>3.6 mcg/dL) up to 16:00 hours, mean cortisol level <100 nmol/L (>3.6 mcg/dL) after 22:00 
hours, and relative bioavailability >80%. In study DIUR-002, all assessment criteria were met.  
 
Study DIUR-003 (Phase II pilot study) was conducted in 16 subjects at a single site, the 
 (Mallappa 
2015). DIUR-003 evaluated the PK profile of cortisol following short-term twice-daily 
administration of Chronocort® (20 mg at night and 10 mg in morning) in subjects with CAH 
and this was compared with data from healthy volunteers in the Phase I study. It also examined 
the effects of both short-term and long-term treatment with Chronocort® on key disease-related 
biochemical markers and other indices of efficacy/PK. The study evaluated 16 subjects with 
CAH over a 6-month period. All subjects started the study on 30 mg daily (given as 10 mg at 
07:00 and 20 mg at 23:00), with dose titration then taking place within 2 weeks, following 
investigator review of biochemical and clinical parameters.  
  
The PK profile of Chronocort® after 20 mg at 23:00 and 10 mg at 07:00 in subjects with CAH 
was similar to that seen in the Phase I clinical study (DIUR-002). The PK profile was 
characterised by an overnight rise in cortisol levels reaching a maximal concentration 
approximately 8 hours post-dosing, consistent with the physiological endogenous profile of 
cortisol reported in normal individuals. The variation in Cmax and area under the curve (AUC) 
was similar to that seen in physiological cortisol levels in healthy volunteers.  
 
This physiological replacement of cortisol with Chronocort® improved the control of disease-
related biomarker androgens in subjects (control compared to baseline standard therapy). This 
was achieved with a similar dose of glucocorticoid; the mean hydrocortisone dose equivalent 
on standard therapy was 28 mg and on Chronocort® was 26 mg. On standard therapy at 
baseline, the majority of subjects had uncontrolled androgen levels, with most having high 
levels of 17-OHP and A4. Following 6-months titration with Chronocort®, the majority of 
subjects had 17-OHP and A4 levels in the normal or optimal range (see Figure 1). 
 
 
 

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Figure 1: 
17-OHP levels (mean ± standard error of the mean) during standard therapy at 
baseline and after the first administration of Chronocort® (Day 1) and 
following 6 months of continued Chronocort® treatment 
 
 
 
There were no safety issues reported in DIUR-002. There were no serious adverse events 
(SAEs) and no events leading to withdrawal from study DIUR-003. Two groups of adverse 
events (AEs) were considered sufficiently remarkable to warrant examination at the time: 5 
subjects had treatment-emergent anaemia and 3 subjects had median nerve entrapment (carpal 
tunnel) syndrome. The anaemia cases were all consistent with acute low level red cell reduction 
attributable to blood loss secondary to the blood draws related to the study. The aetiology of 
the carpal tunnel syndrome was not clear, although thought most likely to be due to increased 
fluid retention. All events were mild and their relationship to the investigational medicinal 
product (IMP) was uncertain. All subjects recovered and the findings were not considered to 
alter the risk/benefit analysis or to raise cause for concern. 
 
Study DIUR-004 was an open-label, randomised, single dose, 3-period, crossover study in 18 
healthy male volunteers that was designed to assess the impact of food on the PK of 
Chronocort®. The study also evaluated the relative bioavailability of Chronocort® and 
immediate release hydrocortisone in the fasted state to support dosing in clinical practice. The 
results of this study showed that whilst extent of absorption of Chronocort® is unaffected, Tmax 
is delayed by approximately 2 hours, and Cmax is reduced by approximately 20% after food. 
Thus it is recommended that the morning dose of Chronocort® is taken on an empty stomach 
at least 1 hour before a meal and the evening dose should be taken at least 2 hours after the last 
meal of the day. From a safety perspective, one subject had mild AEs of epigastric pain and 
shortness of breath that were considered not related to the study drug (both were considered 
related to dexamethasone administration). Both events commenced together more than 4 days 
after dosing and lasted 11 days. The subject was withdrawn from the study as a result of these 
events. A second subject reported an AE of headache, but this occurred 14 days pre-dose and 
lasted 1.5 hours and there was no causal relationship with the study drug. 
 

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Study DIUR-005 was an open-label, randomised, parallel arm, Phase III study that was 
designed to evaluate the efficacy, safety and tolerability of Chronocort® compared with 
standard glucocorticoid replacement therapy in the treatment of subjects with CAH. This study 
has just completed and the results have been reported. The primary endpoint of the study 
(change from baseline to Week 24 of the natural logarithm of the mean of the 24-hour standard 
deviation score [SDS] profile for the natural logarithm of 17-OHP) was not met. However, 
secondary and post-hoc analyses were consistent in showing improved control of 17-OHP with 
Chronocort® treatment. In addition, a reduced incidence of adrenal crises, fewer occurrences 
of the use of sick day rules for AEs, and an increased incidence of therapeutic benefits (fatigue 
reduction, improvement of hirsutes, menstrual benefits) were reported following Chronocort® 
treatment. 
5.6 
Proposed study   
The proposed study aims to build on the results of studies DIUR-003 and DIUR-005 and 
evaluate the long-term safety of Chronocort® and also its long-term efficacy in improving 
control of serum androgen levels (using 17-OHP and A4 as markers). 
5.7 
Benefit/Risk Assessment 
The subjects in this study have classic CAH. As such, they have an absolute requirement for 
lifelong glucocorticoid replacement therapy. It is proposed that the formulation of 
hydrocortisone being evaluated in this study, Chronocort®, has characteristics that may 
improve the outcome in patients with CAH. 
 
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 mimic the physiological circadian profile of 
cortisol. It is hypothesised that this will provide improved CAH disease control. Results of 
clinical trials using Chronocort® have demonstrated that cortisol levels on Chronocort® 
approximated physiologic cortisol rhythm over 24 hours, and  improved control of  androgens 
in subjects with CAH when compared to baseline conventional glucocorticoid therapy.  
 
The risks associated with this study include those associated with blood sampling and general 
involvement with clinical trials. The investigators in this trial are all highly experienced both 
in clinical trials and in the management of patients with CAH, and so these risks are therefore 
negligible. In addition, to minimise the risk of anaemia associated with the withdrawal of 
multiple blood samples for laboratory testing (as seen in a previous study), the planned blood 
volume to be drawn at each visit has been limited to a maximum of 49 mL. The other risks then 
relate to the potential under- or over-treatment of subjects with glucocorticoids as seen in day-
to-day clinical practice. These risks apply to both conventional treatment and Chronocort®. The 
patients will be informed of the potential for under-treatment (as occurs when there is an 
intercurrent illness) and are taught to manage this with supplemental steroids (emergency pack 
for sick day rules) and to seek medical assistance. It is also possible that the new formulation 
of Chronocort® might fail to release properly in the gut with resultant low levels of cortisol. If 
this were to occur once, the associated risk would be low, as a subsequent dose would be given 
either 8 or 16 hours later with little consequence.  It would be hazardous if this occurred 
repeatedly.  However, the formulation technology used is commonly used for other 
pharmaceuticals, and the studies so far in healthy subjects and subjects with CAH do not 
suggest that this happens. If this were to occur, then sick day rules would come into force as 
the subjects would become unwell. Such episodes would also be identified as AEs, which 

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would come to the notice of the independent Data Safety Management Board (DSMB). The 
DSMB will meet on a regular basis during the study to review the safety data and will operate 
in accordance with a predefined charter. 
 
Over-treatment with hydrocortisone is unfortunately common in this condition as physicians 
try to control the androgen levels.  Regular assessment of the subjects (both biochemically and 
clinically) in the study will identify over-treatment and correct it through a reduction in dose.  
 
Thus the potential risks of the study are minimised and mitigated through investigator 
oversight, use of sick day rules by the individual patients when needed, and specific study 
activities (titration of dose, and identification of AEs). All subjects will be given the relevant 
information about the the risks and potential benefits of the study and all subjects have to sign 
a consent form prior to inclusion in the study that meets all the requirements of GCP and 
national regulations.  
 
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 
subject will have received at entry into the Chronocort® studies. However, the delivery of 
hydrocortisone with Chronocort® has been demonstrated to produce a cortisol profile more 
similar to the endogenous cortisol profile than current immediate-release hydrocortisone 
formulations and this is expected to result in improved disease control in patients with CAH. 
For subjects in the study, the potential benefits exceed the potential risks. 
6. 
Study Objectives 
6.1 
Primary Objective 
To evaluate the safety and tolerability of Chronocort® over time, as assessed by signs and 
symptoms of adrenal insufficiency or over-treatment, use of sick day rules, adrenal crisis, AEs, 
laboratory measures and clinical observation. 
6.2 
Secondary Objectives 
The long-term efficacy of Chronocort® will be assessed over time by the measurement of: 
1. Total daily dose of Chronocort®  in mg/day of hydrocortisone and by body surface 
area (BSA) during the study and the incidence of dose titrations 
2. 17-OHP and A4, measured at two time points (at 09:00 and 13:00 hours) for: 
a. Disease control at each visit as assessed by both 17-OHP and A4 levels in 
the optimal and normal range, respectively, at both time points and by the 
proportion of dose given at night.  
b. 17-OHP and A4 SDS 
c. Change in absolute values compared to pre-Chronocort® baseline values  
3. Changes compared to pre-Chronocort® baseline in:  
a. Bone turnover markers  -  serum C-terminal cross-linked telopeptide 
(CTX), osteocalcin 
b. Testosterone (total) 
c. Fasting insulin and blood glucose levels, and glycated haemoglobin 
(HbA1c) 
d. High sensitivity c-reactive protein (hsCRP) and plasma renin activity 
(PRA) 
e. Body composition (dual energy X-ray absorptiometry [DEXA])(fat mass, 

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lean mass and total bone density) (except in Germany) 
f. Quality of life – SF-36®, Multidimensional Assessment of Fatigue (MAF), 
EQ-5D™  
7. 
Study Endpoints 
7.1 
Primary Endpoint 
The primary endpoint is the safety of Chronocort® over time, assessed using but not limited to 
the following endpoints: 
 
1. 
Signs and symptoms of adrenal insufficiency or over-treatment throughout the study. 
2. 
Use of sick day rules throughout the study. 
3. 
Occurrence of adrenal crises throughout the study. 
4. 
Occurrence of AEs throughout the study. 
5. 
Change from pre-Chronocort® baseline in safety laboratory assessments at each visit 
throughout the study.  
6. 
Change from pre-Chronocort® baseline in vital signs, weight, body mass index (BMI), 
and waist circumference at each visit throughout the study. 
7.2 
Secondary Endpoints 
To assess the long-term efficacy of Chronocort®, the following secondary endpoints will be 
assessed: 
 
1. 
Total daily dose of Chronocort® in mg/day of hydrocortisone and by BSA 
2. 
Disease control throughout the study as assessed by both 17-OHP and A4 levels in the 
optimal and normal range, respectively, at 09:00 and at 13:00, and by the proportion of 
dose given at night 
3. 
Change from pre-Chronocort® baseline at each visit in SDS of 17-OHP and A4 at 09:00, 
13:00 and the mean of the two timepoints. Pre-Chronocort® baseline means prior to the 
first dose of continuous Chronocort® which is: 
o 
The reassessed baseline under DIUR-006 for subjects entering from study 
DIUR-003 and those subjects from DIUR-005 who had a gap between 
completing study DIUR-005 and starting study DIUR-006, 
o 
Visit 4 (Week 24) from the feeder study for subjects who received standard 
glucocorticoid replacement therapy in study DIUR-005 and immediately 
entered DIUR-006, 
o 
Prior to the first  Chronocort® dose in study DIUR-005 for subjects who received 
Chronocort® in study DIUR-005 (i.e. DIUR-005 baseline visit) and immediately 
entered DIUR-006. 
4. 
Change from pre-Chronocort® baseline at each visit in the absolute values of 17-OHP 
and A4 at 09:00 and 13:00 
5. 
Change from pre-Chronocort® baseline at each visit in: 
a. 
Bone turnover markers  -  CTX, osteocalcin 
b. 
Testosterone (total) 
c. 
Fasting insulin and blood glucose levels, and HbA1c 
d. 
hsCRP and PRA 

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e. 
Body composition (DEXA)(fat mass, lean mass and total bone density) (except 
in Germany) 
f. 
Quality of life – SF-36®, MAF, EQ-5D™ 
6. 
Incidence of dose titrations 
8. 
Study Design 
 
Subjects completing study DIUR-005 and those who have already completed study DIUR-003 
will be offered the opportunity either to continue Chronocort® therapy or to switch from their 
current glucocorticoid therapy to Chronocort® in this open-label study.  
The intention is that subjects will transition straight from study DIUR-005 into DIUR-006 
without a gap. However, during the conduct of the study, logistical issues arose precluding this 
for some subjects and so the protocol has been amended to allow these subjects who have been 
unable to transition immediately into DIUR-006 to be able to participate in the study 
(incorporated into Protocol version 7.0). However, all subjects must be enrolled by 31 October 
2018, with no subjects allowed to enter the study after this date. In general, subjects who 
complete study DIUR-005 should not have an interruption in treatment; if this does occur prior 
approval should be sought from the Sponsor before entering them into study DIUR-006. 
All subjects will have a screening visit prior to the baseline assessment to allow DIUR-006 
procedures to be fully explained and informed consent to be given by the subject. For subjects 
from DIUR-003 and any subjects from DIUR-005 who had a gap between completing study 
DIUR-005 and starting study DIUR-006 during which they received standard glucocorticoid 
therapy, this screening visit will include safety blood tests. Any subjects not meeting the 
inclusion/exclusion criteria following these blood tests will be not be entered into the study. 
All subjects will then return for the baseline visit. For subjects entering from study DIUR-003 
and any subjects from DIUR-005 who had a gap between completing study DIUR-005 and 
starting study DIUR-006 during which they received standard glucocorticoid therapy, the full 
set of baseline assessments will be completed, including 2 blood samples (one at 09:00 and one 
at 13:00 hours) for 17-OHP and A4 (note: baseline DEXA scan only needed for subjects 
entering from study DIUR-003). For subjects entering immediately from study DIUR-005, test 
results from their last visit in the feeder study (V4) will be used for this baseline assessment, 
with the 09:00 and 13:00 hour results taken from the 24-hour hormone profiles conducted at 
the visit. Any subjects not meeting the inclusion/exclusion criteria following these blood tests 
will be withdrawn from this study. 
Once the baseline assessments are completed, the subjects will be given sufficient Chronocort® 
to use until the next visit at Week 4. Subjects entering immediately from study DIUR-005 who 
were previously on Chronocort®  will continue on the same dose of Chronocort® as they were 
receiving at the end of the feeder study. Subjects from study DIUR-005 on standard therapy, 
subjects from DIUR-005 who had a gap between completing study DIUR-005 and starting 
study DIUR-006 during which they received standard glucocorticoid therapy, and subjects 
from study DIUR-003 will have their initial dose of Chronocort® determined using the 
hydrocortisone equivalent of their previous treatment (immediately prior to the baseline visit). 
All subjects will return to the study centre at 4, 12 and 24 weeks after starting study DIUR-006 
for additional blood tests and dose titration, if necessary. Visits thereafter will take place at 
6-monthly intervals. If there is a change of dose, a dose titration interim visit or telephone call 
will be needed in between the 6-monthly visits. 

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All subjects will receive welfare telephone calls at 3 monthly intervals, and unscheduled visits 
will be arranged if necessary. Subjects will be provided with Chronocort® supplies from the 
study pharmacy at either 3- or 6-monthly intervals.  
At the end of the study subjects will have the option to enter a second long-term study 
(DIUR-015) to enable them to continue to receive open-label Chronocort® until it is 
commercially available in their region or it is decided to stop Chronocort® treatment. Subjects 
who decide to enter the DIUR-015 study immediately following this DIUR-006 study do not 
require a telephone call 30 days after the end of this study. If there is a gap between finishing 
this DIUR-006 study and entering the DIUR-015 study of greater than 30 days, then the 30-day 
telephone call is required. 
All subjects have the following assessments conducted during the study (see Table 1): 
At all visits:  
• AEs recorded, with particular note taken of use of sick day rules and adrenal crises. 
• Dose of Chronocort® given, along with compliance assessment. 
• Concomitant medications recorded. 
• Measurement of 17-OHP and A4 at two time points (the first at 09:00 and the second 
at 13:00 hours). 
• Urine pregnancy test for women of childbearing potential (note: females presenting 
with oligomenorrhoea or amenorrhoea who are aged ≤55 years of age should be 
considered potentially fertile and should therefore undergo pregnancy testing like all 
other female subjects). 
At baseline, at each 6-monthly visit and at the final visit:  
• Physical examination, vital signs, weight, BMI and waist circumference. 
• Safety blood tests, serum CTX, osteocalcin, PRA, hsCRP, HbA1c, testosterone, fasting 
insulin and blood glucose levels. 
• Quality of life – SF-36®, MAF, EQ-5D™ 
At yearly intervals (except Germany):  
• Body composition (DEXA) (fat mass, lean mass and total bone density) (also taken at 
baseline for subjects entering from study DIUR-003) (note: subjects with a gap between 
completing study DIUR-005 and starting study DIUR-006 do not require an additional 
DEXA scan at the time they enter study DIUR-006).  
8.1 
Dose Titration Algorithm 
The intention of dose adjustment is to optimise control of CAH according to current standard 
of care based on subject symptoms and the measurement of androgens. As this study is open 
and uncontrolled, titration will be performed by the investigating physician. Dose adjustment 
will be based on clinical symptoms using the “signs and symptoms of adrenal insufficiency 
questionnaire” and the measurement of 17-OHP and A4. The 17-OHP and A4 sample taken at 
09:00 will reflect the Chronocort® dose taken at 23:00 hours and the sample taken at 13:00 will 
reflect the 07:00 hour Chronocort® dose. Dose adjustments will be considered if the samples 
show out of range values for 17-OHP or A4. If 17-OHP and A4 show inconsistent trends, the 
A4 parameter will take precedence in directing dose adjustment. Confirmation of the dose 
following the hormone results will be made by telephone within two weeks of the visit and will 
be followed up in writing whether dose titration is needed or not. If a dose titration is needed, 
an interim dose titration visit or telephone call (at the investigator’s discretion) will be required 

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to take place approximately 4 weeks after the decision has been communicated to the 
participant. 
The rationale for any dose adjustment will be recorded in the electronic case report form 
(eCRF). No dose adjustments outside of the protocol-defined dose adjustments should be 
conducted, unless clinical signs and symptoms indicate an immediate need. In such cases the 
Sponsor’s medical monitor must be contacted (preferably before any dose changes are 
implemented). Any such unscheduled dose adjustments should be based on clinical symptoms 
only, with repeated androgen testing discouraged and must be pre-approved by the Sponsor’s 
medical monitor. Stress doses of hydrocortisone will be given for inter-current illnesses as 
medically indicated according to “sick day rules”. Fludrocortisone dose adjustment will be 
made if medically indicated and will be based on blood pressure measurements and laboratory 
data (goal supine PRA < 1.5 x upper limit of normal [ULN]).  
In subjects who have undetectable androgens at baseline on their regular medication, caution 
will be taken with dose reductions if there is suspicion of the subject having a suppressed 
hypothalamic-pituitary-adrenal axis. 
 
The study design is shown graphically in Figure 2. 
 
Figure 2: 
Overview of DIUR-006 Study Schema 
 
9. 
Subject Population 
9.1 
Number of Subjects and Subject Selection 
All eligible subjects from study DIUR-003 (16 subjects) and DIUR-005 (122 subjects) may 
enter this study, giving a maximum of 138 subjects. The study centres in this study will be the 
same centres that recruited the subject into the initial study. 
9.2 
Inclusion Criteria 
1. Subjects with CAH who have successfully completed the DIUR-003 or DIUR-005 
clinical trials with the current formulation of Chronocort®. 

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2. Provision of signed written informed consent. 
9.3 
Exclusion Criteria 
1. Co-morbid condition requiring daily administration of a medication (or use of any 
medications/supplements) that interferes with the metabolism of glucocorticoids. 
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the 
ULN or elevated liver function tests (alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST] >2 times ULN]). 
3. Females who are pregnant or lactating. 
4. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other 
than CAH. 
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months 
prior to entry into the study). 
6. Subjects with a history of bilateral adrenalectomy. 
7. Participation in another clinical trial of an investigational or licensed drug or device 
within the 3 months prior to inclusion in this study, except for another clinical trial with 
the current formulation of Chronocort®. 
8. Subjects unable to comply with the requirements of the protocol.  
9. Subjects who routinely work night shifts and so do not sleep during the usual nighttime 
hours. 
10. 
Study Medication and Administration 
10.1 
Randomisation and Blinding 
This is an open-label, non-comparative study so no randomisation or blinding will occur. 
Subjects will retain the three-digit site number and the three-digit subject number used in the 
feeder study (i.e., the number used for that subject in DIUR-003 and DIUR-005), but 600 will 
be added to the study number. Thus subject D005/001/001 in study DIUR-005 will become 
D605/001/001 in study DIUR-006 and subject D003/001/001 in study DIUR-003 will become 
D603/001/001 in study DIUR-006. 
10.2 
Description and Handling of IMPs 
The IMP for this study is Chronocort® (Hydrocortisone Modified Release Capsule). In this 
study Chronocort® will be supplied in three unit dose strengths of 5 mg, 10 mg and 20 mg per 
capsule.  
 
Diurnal will supply the study sites with adequate bulk study medication of Chronocort® in 
batches over the study period.  
10.2.1 Chronocort® Formulation  
Chronocort® is a modified-release formulation of hydrocortisone for oral administration. 
Chronocort® is available for this study in dose strengths of 5 mg, 10 mg and 20 mg 
hydrocortisone. The 5 mg formulation will be presented in white opaque body/blue opaque cap 
size 1 hard gelatin capsules, printed with either 'CHRONOCORT 5mg' or 'CHC 5mg' on the 
capsule body. The 10 mg formulation will be presented in white opaque body/green opaque 
cap size 1 hard gelatin capsules, printed with either 'CHRONOCORT 10mg' or 'CHC 10mg' on 
the capsule body. The 20mg formulation will be presented in white opaque body/orange opaque 

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cap size 0 hard gelatin capsules, printed with either 'CHRONOCORT 20mg' or 'CHC 20mg' on 
the capsule body. 
 
All excipients used in Chronocort® modified release capsules are standard materials normally 
used in pharmaceutical drug products, are the subject of United States Pharmacopeia/National 
Formulary (NF) and/or European Pharmacopeia Monographs, and have been used in 
pharmaceutical products worldwide over many years. 
10.2.2 Packaging and Labelling 
Chronocort® capsules are contained within either a PVC/PE/PVdC blister pack sealed with 
aluminium lidding foil or a high-density polyethylene (HDPE) bottle sealed with a 
polypropylene (PP) lid. Each blister pack contains 10 capsules of the same dose strength. Each 
bottle contains 50 capsules of the same dose strength. The Sponsor will supply Chronocort® to 
the pharmacy at the study site as clinical packs containing 100 capsules of each dose strength, 
i.e. 10 x 10-count blisters (100-count pack) or 2 x 50-count bottles.   
 
A treatment pack for each subject will be assembled by the pharmacy using the required 
number of clinical packs according to the individual subject prescription. Subjects will receive 
treatment packs at baseline, Week 4, Week 12, Week 18 and then either 3- or 6-monthly 
thereafter. At each visit the subjects will return the used packs and any unused medication to 
the pharmacy for compliance accountability. At baseline and Week 4, two weeks extra 
medication will be included in each treatment pack to allow for dose adjustments and overage. 
If the subject collects their medication at 3-monthly intervals, a total of  100 days of 
Chronocort® will be supplied to each subject or if a 6-monthly supply schedule is used, a total 
of  200 days of Chronocort® will be supplied to each subject. The three dose strengths will be 
identifiable by the unique colour hard gelatin capsule and product/dose identifier printed on 
the capsule. 
 
Chronocort® will be labelled as shown in Appendix 8.  
10.2.3 Storage 
Chronocort® will be securely stored in the study site pharmacy at a temperature not exceeding 
25°C. Subjects dispensed with Chronocort® will be advised to store it securely in a cool (room 
temperature) and dry place out of the reach of children.  
10.2.4 Accountability and Compliance 
The study team or pharmacist will review the returned packs and count the number of used and 
unused capsules at each visit. This information will be entered in the eCRF so compliance can 
be calculated against the treatment prescriptions. All used and unused packs will be stored in a 
secure location  and made available for review by the Clinical Research Associate (CRA) as 
outlined in Section 14.8. Following the Sponsor’s approval, all remaining Chronocort® will 
either be returned to the supplier or destroyed on site unless otherwise instructed.  
Accountability must also be performed at each visit for the safety pack (see Section 10.5), 
which should be used in conjunction with the site's “sick day rules”. Any use of the medications 
in the safety pack should be recorded in the eCRF, along with the reason for use. If the safety 
pack is unused then it should be given back to the subject intact. If the safety pack has been 
used then the medication used will be replaced and the pack re-sealed and prescribed to the 
subject for the next study period. 

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10.3 
Dosage and Administration  
For subjects entering from DIUR-003, subjects receiving standard therapy in study DIUR-005, 
and subjects from DIUR-005 who had a gap between completing study DIUR-005 and starting 
study DIUR-006 during which they received standard glucocorticoid therapy, the initial dose 
of Chronocort® will be determined using the hydrocortisone equivalent of the subject’s 
previous treatment (immediately prior to the baseline visit). Subjects from study DIUR-005 
who are on Chronocort® at the end of DIUR-005 and enter study DIUR-006 immediately will 
start study DIUR-006 on the same dose as they completed study DIUR-005.  
Approximately 2/3rds of the daily dose will be given in the evening, with the remainder given 
in the morning. All morning doses of Chronocort® in this study should be taken at 
approximately 07:00 hours on an empty stomach at least 1 hour before a meal and all the 
evening doses should be taken at approximately 23:00 hours at least 2 hours after the last meal 
of the day. Subjects will be asked to self-administer the dose of Chronocort® with a small drink 
of water. 
10.4 
Dose Adjustments 
The intention of dose adjustment is to optimise control of CAH according to current standard 
of care based on subject symptoms and the measurement of androgen levels. Stress doses of 
hydrocortisone will be given for intercurrent illnesses as medically indicated according to “sick 
day rules” (see Appendix 3 for an example). All dose adjustments must be recorded in the 
subject notes and the eCRF.  
 
• Dose adjustment will be based on clinical symptoms using the “signs and symptoms of 
adrenal insufficiency questionnaire” (Appendix 4) and the measurement of the 17-OHP 
and A4 levels at two time points at 09:00 and 13:00 hours. The adrenal insufficiency 
questionnaire should only be used to determine if symptoms of under or over 
replacement of glucocorticoids have occurred over the last 4 weeks – it should not be 
used to record AEs due to other causes. 
• Dose adjustments will be made by the investigator according to the instructions 
provided in Section 8 under the heading “Dose Titration Algorithm” 
• Dose adjustment will be made within 2 weeks after the visits at which 17-OHP and A4 
levels are assessed. Subjects will be contacted by telephone to tell them of the outcome 
of the dose adjustment process – either to tell them of the new dose, or of no change in 
dose. This will be followed in writing (whether there is a change in dose or not) 
repeating the instruction of the phone call. If a dose titration is needed, an interim dose 
titration visit or telephone call (at the investigator’s discretion) will be required to take 
place approximately 4 weeks after the decision has been communicated to the 
participant. 
• No dose adjustments outside of the protocol-defined dose adjustments should be 
conducted, unless clinical signs and symptoms indicate an immediate need. In such 
cases the Sponsor’s medical monitor must be contacted (preferably before any dose 
changes are implemented). Any such unscheduled dose adjustments should be based on 
clinical symptoms only, with repeated androgen testing discouraged and must be 
pre-approved by the Sponsor’s medical monitor. Any such dose changes must be 
recorded in the eCRF.  
 
Fludrocortisone dose adjustment will be made if medically indicated and will be based on blood 
pressure measurements and laboratory data (goal supine PRA < 1.5 x ULN).  

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In subjects who have undetectable androgens at baseline on their regular medication, caution 
will be taken with dose reductions if there is suspicion of the subject having a suppressed 
hypothalamic-pituitary-adrenal axis. 
10.5 
Other Study Medications (Non-Investigational Medicinal Products) 
Stress doses to be used when the “sick day rules” are implemented will be supplied by the study 
site as part of a safety pack, which will typically include (according to local practice): 
 
• A supply of oral hydrocortisone that would allow dosage of up to 20 mg three times 
daily  
• 2 vials of hydrocortisone for injection plus syringes and needles 
• The site’s standard information guidance regarding “sick day rules” (routinely given to 
any subject receiving hydrocortisone replacement therapy) 
 
Any use of the safety pack medication must be recorded in the eCRF, along with the reason for 
use. 
 
Diurnal will also provide appropriate labels for the safety pack that can be used to label the 
drugs dispensed to subjects (See Appendix 8).  
 
Subjects will continue to take Chronocort® twice daily when taking stress doses. Any 
additional doses of hydrocortisone needed should only be taken from the safety pack and 
should not be taken from the study medication packs. Further safety pack supplies can be 
obtained from the study site if required. 
10.6 
Permitted Concomitant Medications/Treatments 
The subjects must be instructed that no additional medication is allowed without the prior 
consent of the investigator. Any medication considered necessary for the subject’s safety and 
well-being may be given at the discretion of the investigator. Medication for sick days does not 
require authorisation but any use of the safety pack medication must be recorded in the eCRF. 
All concomitant medications and treatments will be recorded in the subject’s eCRF. 
 
If a participant has received the severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2/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 “sick day rules” (see Appendix 3 - Sick 
Day Rules). If a stress dose is taken within 5 days of a scheduled visit, then the visit should be 
delayed until the participant has had a 5-day period without use of any stress doses. 
11 
Study Procedures 
 
The study procedures to be conducted for each subject enrolled in the study are summarised in 
Table 1. Written informed consent must be taken prior to any study related procedures. 

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Table 1:  Schedule of Study Assessments  
 
Screening 
Visit (V0) 
-14 days 
Baseline 
Visit (V1) 
Day 017 
Week  
4 (V2) 
±3 days17 
Week  
12 (V3) 
±3 days 
Week 18 ±3 days 
then every 3 
months 
±2 weeks 
Week 24 (V4) then 
every 6 months1 
±2 weeks 
Final 
Visit18 
 
Follow-up 
telephone 
call19 
Informed consent form2 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demography/medical history/current medical status3 
 
X 
 
 
 
 
 
 
Previous/concomitant medication4 
 
X5 
X 
X 
 
X 
X 
 
Physical examination 
 
X5 
 
 
 
X 
X 
 
Weight, BMI, waist circumference 
 
X5 
 
 
 
X 
X 
 
Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
 
X5 
 
 
 
X 
X 
 
Blood samples for 17-OHP and A4 testing6 
 
X7 
X 
X 
 
X 
X 
 
Glucocorticoid/Chronocort dose recorded (mg/day) 
 
X8 
X 
X 
 
X 
X 
 
Dose titration 
 
X9 
X9 
 
X9 
 
 
Study medication dispensed 
 
X 
X 
X 
X16 
X 
 
 
Compliance assessment 
 
X 
X 
 
X 
X 
 
Serum CTX, osteocalcin, hsCRP, HbA1c, testosterone 
 
X5 
 
 
 
X 
X 
 
Fasting insulin and glucose 
 
X5 
 
 
 
X 
X 
 
PRA10 
 
X5 
 
 
 
X 
X 
 
DEXA11 
 
X5 
 
 
 
X11 
 
 
QoL (MAF, SF-36®, EQ-5D™) 
 
X5 
 
 
 
X 
X 
 
AEs and SAEs12 
X 
X 
X 
X 
X 
X 
X 
X 
Signs and symptoms of adrenal insufficiency, incidence of adrenal crisis and 
implementation of sick day rules 
 
 
X 
X 
 
X 
X 
 
Safety blood tests 
X13 
X5 
 
 
 
X 
X 
 
Urine pregnancy test (females)14 
X13 
X5 
X 
X 
 
X 
X 
 
Genotyping 
X15 
 
 
 
 
 
 
 
Interim telephone calls 
 
 
X 
X 
X 
X 
 
 
1 After the initial visits at 4, 12 and 24 weeks, subjects will have a visit every 6 months. If the Chronocort® dose is changed at any point after the Week 24 visit, the subject should have an interim dose titration visit 
(which will include the assessments noted for Week 4) or an interim dose titration telephone call to check on the well-being of the subject (the telephone call includes all Week 4 assessments apart from blood sampling 
for 17-OHP and A4, and the urine pregnancy test). The subject will then continue with visits every 6 months. 
2 The informed consent form must be given to the subject at least 24 hours prior to the screening visit so they have sufficient time to review before being asked to sign. 
3 For subjects from study DIUR-005 only, demography and medical history can be obtained from the start of the DIUR-005 feeder study, with any changes that occurred during or after the feeder study and prior to entry 
into this DIUR-006 study being noted. 
4 Previous medication recorded in the 4 weeks prior to entry into DIUR-006. 
5 New information collected in subjects entering from study DIUR-003 and in subjects who have a gap between completing study DIUR-005 and starting study DIUR-006 during which they received standard glucocorticoid 
therapy (with the exception of DEXA scan - see Note 11). In subjects entering immediately from study DIUR-005 this information can be taken from the last visit of the feeder study.  
6 Two samples taken: the first at 09:00 and the second at 13:00 hours. 
7 In study DIUR-005 the results from the last endocrine profile can be used (V4) if the subject has entered study DIUR-006 immediately following completing study DIUR-005. If there is a gap between DIUR-005 and 
DIUR-006 then new samples must be taken at this baseline visit. 
8 At baseline, details of the last glucocorticoid dose taken prior to attending the visit will be recorded, including details of the drug(s), dose and time of administration. The initial dose of Chronocort will then be determined 
as follows: in DIUR-003 it will be determined using the hydrocortisone equivalent of the subject's previous treatment (immediately prior to the baseline visit); for subjects on Chronocort® in DIUR-005 the same dose of 

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      Page 31 of 96 
 
Chronocort® will be used; and for subjects on standard therapy in DIUR-005 and for subjects who have a gap between completing study DIUR-005 and starting study DIUR-006 during which they received standard 
glucocorticoid therapy, the initial dose will be determined using the hydrocortisone equivalent of their previous treatment (immediately prior to the baseline visit). 
9 Dose adjusted based on 17-OHP and A4 measurements taken at each visit and clinical symptoms assessed using the signs and symptoms of adrenal insufficiency questionnaire. Where 17-OHP and A4 show inconsistent 
trends, the A4 parameter will take precedence in directing dose adjustment. The subject will be notified whether a dose adjustment is needed or not by telephone within two weeks of the visit and this will be followed up 
in writing. 
10 Blood sample taken for PRA after the subject has been supine for 30 minutes. 
11 To be conducted at baseline only for subjects entering from study DIUR-003 and then annually in all subjects (except in Germany) (note: subjects with a gap between completing study DIUR-005 and starting study 
DIUR-006 do not require an additional DEXA scan at the time they enter study DIUR-006). 
12 AEs and SAEs will be recorded from the time of informed consent in this study until 30 days after the last dose of Chronocort® or until the subject starts receiving Chronocort® in the second long-term extension study 
(DIUR-015) if this is less than 30 days after the end of dosing in this DIUR-006 study. Any AEs or SAEs experienced after this 30-day period should only be reported if the Investigator suspects a causal relationship to 
Chronocort® and treatment with Chronocort® has stopped. 
13 Only in subjects from study DIUR-003 and any subjects from DIUR-005 who had a gap between completing study DIUR-005 and starting study DIUR-006 during which they received standard glucocorticoid therapy. 
14 Females presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 years of age should be considered potentially fertile and should therefore undergo pregnancy testing like all other female subjects. 
15 A blood sample for genotyping will be obtained, if necessary, from subjects entering from study DIUR-003, but if previous genotyping has been performed the patient will be asked for their permission for this 
information to be taken from their medical records and recorded in the eCRF and recorded in the eCRF. 
16 3-monthly drug supplies can be issued at this visit if necessary, or the site can issue 6 months’ supply at the 6-monthly site visits. 
17 Baseline and Week 4 visits are repeated for subjects who re-enter the study post-pregnancy (see Section  11.7 for details). 
18 If the end of study visit is within 3 months after a scheduled 6-monthly visit then only minimal safety assessments (AE and SAE collection only) will be performed. 
19 At the end of the study subjects will have the option to enter a second long-term study (DIUR-015). Subjects who decide to enter the DIUR-015 study immediately following this DIUR-006 study do not require this 
telephone call. If there is a gap between finishing this DIUR-006 study and entering the DIUR-015 study of greater than 30 days, then this 30-day telephone call is required.

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11.1 
Visit Schedule  
A window of +/- 3 days is allowed around each visit up to and including the Week 18 visit. 
After Week 18, a visit window of  +/- 2 weeks is allowed around each visit. If a visit is delayed 
e.g. due to sick day rules, the visit schedule will continue as scheduled i.e. the original timings 
will not be adjusted based on the delayed visit date. 
 
If a participant has received the COVID-19 vaccine then the next visit must be scheduled at 
least 5 days post-vaccine. 
11.1.1 Screening Visit (Visit 0) 
• At least 24 hours prior to the screening visit subjects must be given the informed 
consent document to review (this can be sent to subjects by email). At this screening 
visit any questions they have about the study will be answered and the subject will then 
be asked to sign the consent form. 
• All inclusion and exclusion criteria will be checked. 
• For subjects entering from study DIUR-003 and any subjects from DIUR-005 who had 
a gap between completing study DIUR-005 and starting study DIUR-006 during which 
they received standard glucocorticoid therapy, safety blood tests and a urine pregnancy 
test will be done to confirm eligibility criteria. A blood sample for genotyping will also 
be obtained, if necessary, from subjects entering from study DIUR-003, but if previous 
genotyping has been performed the patient will be asked for their permission for this 
information to be taken from their medical records and recorded in the eCRF. 
 
The subject will then be asked to attend Visit 1 in a maximum of 2 weeks’ time (for subjects 
in study DIUR-005 who are entering immediately into this extension study this can be Day 2 
of Visit 4 of the DIUR-005 study). During the time between the screening visit and Visit 1, the 
subject will continue to take the medication they are currently receiving i.e. standard treatment 
for subjects in study DIUR-003 and for those subjects in DIUR-005 who have had a gap 
between completing study DIUR-005 and entering this extension study, and study medication 
for subjects in study DIUR-005 who are entering study the extension study immediately.  
11.1.2 Baseline Visit (Visit 1) – Day 0 
If the subject has been receiving their normal glucocorticoid medication for the previous 5 days 
(i.e. sick days rules have not been applied in the preceding 5 days) they will attend the clinic 
on the morning of Visit 1 (this will also be Visit 4 of the DIUR-005 study for subjects who are 
entering study the extension study immediately, so some test results will be included in both 
studies). If sick day rules have been applied in the previous 5 days then this visit should be 
postponed until the subject has been receiving their normal medication for 5 days. Subjects 
from study DIUR-003 and subjects in DIUR-005 who have had a gap between completing 
study DIUR-005 and entering this extension study must attend this visit after fasting from 21:00 
hours the previous evening. Subjects entering immediately from study DIUR-005 will be 
admitted for Visit 4 of the DIUR-005 study and so will be fasting overnight as part of this 
Visit  4.  
 
The following assessments will be conducted at this visit: 
• Check of inclusion/exclusion criteria. 

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• Demographic data, medical history and any current medical conditions will be recorded 
in the eCRF.  For subjects from study DIUR-005 only, demography and medical history 
can be obtained from the start of the DIUR-005 feeder study, with any changes that 
occurred during or after the feeder study and prior to entry into this DIUR-006 study 
being noted.  
For subjects entering immediately from study DIUR-005, the following test results can be 
obtained from the data collected at Visit 4. However, if these are not available or the subject 
enters from study DIUR-003 or has a gap between completing study DIUR-005 and starting 
study DIUR-006 during which they received standard glucocorticoid therapy, the following 
assessments must be completed: 
• Previous medications taken within the last 4 weeks and any current concomitant 
medications will be recorded. CAH medication will be recorded separately from other 
concomitant medications. 
• Record the last glucocorticoid dose taken prior to attending for this visit, with details 
of the drug(s), dose and time of administration being recorded in the eCRF.  
• A physical examination will be conducted and weight, BMI, and waist circumference 
recorded. 
• Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be 
recorded. 
• Blood samples will be taken for PRA after the subject has been supine for 30 minutes. 
• Blood samples taken for serum CTX, osteocalcin, hsCRP, HbA1c, testosterone, fasting 
insulin and glucose, and safety laboratory tests. 
• Blood sample taken for 17-OHP and A4 at 09:00 and 13:00 hours.  
• Urine sample will be taken for a urine pregnancy test in females of childbearing 
potential (note: females presenting with oligomenorrhoea or amenorrhoea who are aged 
≤55 years of age should be considered potentially fertile and should therefore undergo 
pregnancy testing like all other female subjects). 
• DEXA scan to be taken at baseline for subjects entering from study DIUR-003 (except 
in Germany) (note: subjects with a gap between completing study DIUR-005 and 
starting study DIUR-006 do not require an additional DEXA scan at the time they enter 
study DIUR-006). 
• Completion of the following questionnaires: MAF, SF-36® and EQ-5D™ 
• Chronocort® supplies issued, with the starting dose for subjects currently on 
Chronocort® in study DIUR-005 being based on the dose being taken at the end of the 
feeder study. For subjects from study DIUR-003 and for subjects receiving standard 
therapy in study DIUR-005, the Chronocort® starting dose will be based on the 
hydrocortisone dose equivalent, with the hydrocortisone dose calculated as prednisone 
and prednisolone dose multiplied by 5 and dexamethasone dose multiplied by 80 (up to 
a maximum starting dose of Chronocort® 30mg, split as 20mg at night and 10mg in the 
morning).   
 
Once all the above assessments have been completed, the subject will be allowed home. 

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11.1.3 Week 4 (Visit 2) (± 3 Days) 
If the subject has been receiving their Chronocort® medication for the previous 5 days (i.e. sick 
days rules have not been applied in the preceding 5 days) they will attend the clinic on the 
morning of Visit 2. If sick day rules have been applied in the previous 5 days then Visit 2 
should be postponed until the subject has been receiving their normal medication for 5 days.  
The subject will be asked to return all packs of study medication, including any unused 
medication, and the number of capsules used and unused will be counted and recorded in the 
eCRF so compliance can be calculated. The safety pack should also be returned and checked, 
with any rescue medication use being recorded. Subjects will then be dispensed with new study 
medication for the next treatment period. If the safety pack has been used then the medication 
used will be recorded for drug accountability purposes, replaced, and the pack re-sealed and 
prescribed to the subject for the next study period. 
The following assessments will be carried out and recorded at this visit: 
• Subjects will be asked about any AEs and concomitant medications changes since the 
last visit. 
• Signs and symptoms of adrenal insufficiency (see checklist in Appendix 4) and any 
occurrences of adrenal crises or implementation of sick day rules. 
• Record the time and dose of the last Chronocort® dose taken prior to attending this visit 
(this should be the 07:00 hours dose on the morning of this visit). 
• Blood samples will be taken at 09:00 and 13:00 hours for testing of 17-OHP and A4 
level. 
• Urine sample will be taken for a urine pregnancy test in females of childbearing 
potential (note: females presenting with oligomenorrhoea or amenorrhoea who are aged 
≤55 years of age should be considered potentially fertile and should therefore undergo 
pregnancy testing like all other female subjects). 
 
Once all the above assessments have been completed, the subject will be allowed home. 
Subjects will be asked to attend the clinic in 8 weeks’ time. 
11.1.4 Telephone call (within 2 weeks of Visit 2) 
Following the assessment of the 17-OHP and A4 levels and the clinical evaluation using the 
adrenal insufficiency checklist conducted at the previous visit, a decision will be made by the 
investigator whether to adjust the dose for the subject. This assessment must be made within 
2 weeks of the visit. All subjects will be contacted by telephone, whether or not a dose 
adjustment is needed. The subject will receive clear written instructions of the dose they will 
be taking until the next study visit (even if there is no adjustment to be made) following the 
telephone call. Subjects will be asked about any AEs at this call and any AEs reported will be 
recorded in the eCRF. 
 
If a dose titration is needed, an interim dose titration visit or telephone call (at the investigator’s 
discretion) will be required to take place approximately 4 weeks after the decision has been 
communicated to the participant. The same assessments as noted for the Week 4 visit will be 
performed at the interim dose titration visit. If an interim dose titration telephone call is used 
instead, blood sampling for 17-OHP and A4 and the urine pregnancy test will not be performed 
but all other Week 4 assessments will be performed. 

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11.1.5 Week 12 (Visit 3) (± 3 Days) 
If the subject has been receiving their Chronocort® medication for the previous 5 days (i.e. sick 
days rules have not been applied in the preceding 5 days) they will attend the clinic on the 
morning of Visit 3. If sick day rules have been applied in the previous 5 days then Visit 3 
should be postponed until the subject has been receiving their normal medication for 5 days.  
The subject will be asked to return all packs of study medication, including any unused 
medication, and the number of capsules used and unused will be counted and recorded in the 
eCRF so compliance can be calculated. The safety pack should also be returned and checked, 
with any rescue medication use being recorded. Subjects will then be dispensed with new study 
medication for the next treatment period. If the safety pack has been used then the medication 
used will be recorded for drug accountability purposes, replaced, and the pack re-sealed and 
prescribed to the subject for the next study period. 
The following assessments will be carried out and recorded at this visit: 
• Subjects will be asked about any AEs and concomitant medications changes since the 
last visit. 
• Signs and symptoms of adrenal insufficiency (see checklist in Appendix 4) and any 
occurrences of adrenal crises or implementation of sick day rules. 
• Record the time and dose of the last Chronocort® dose taken prior to attending this visit 
(this should be the 07:00 hours dose on the morning of this visit). 
• Blood samples will be taken at 09:00 and 13:00 hours for testing of 17-OHP and A4 
level.  
• Urine sample will be taken for a urine pregnancy test in females of childbearing 
potential (note: females presenting with oligomenorrhoea or amenorrhoea who are aged 
≤55 years of age should be considered potentially fertile and should therefore undergo 
pregnancy testing like all other female subjects). 
 
Once all the above assessments have been completed, the subject will be allowed home. 
Subjects will be asked to attend the clinic in 12 weeks’ time. 
11.1.6 Telephone call (within 2 weeks of Visit 3) 
Following the assessment of the 17-OHP and A4 levels and the clinical evaluation using the 
adrenal insufficiency checklist conducted at the previous visit, a decision will be made by the 
investigator whether to adjust the dose for the subject. This assessment must be made within 
2 weeks of the visit. All subjects will be contacted by telephone, whether or not a dose 
adjustment is needed. The subject will receive clear written instructions of the dose they will 
be taking until the next study visit (even if there is no adjustment to be made) following the 
telephone call. Subjects will be asked about any AEs at this call and any AEs reported will be 
recorded in the eCRF. 
 
If a dose titration is needed, an interim dose titration visit or telephone call (at the investigator’s 
discretion) will be required to take place approximately 4 weeks after the decision has been 
communicated to the participant. The same assessments as noted for the Week 4 visit will be 
performed at the interim dose titration visit. If an interim dose titration telephone call is used 
instead, blood sampling for 17-OHP and A4 and the urine pregnancy test will not be performed 
but all other Week 4 assessments will be performed. 

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11.1.7 Week 24 and then every 6-months (± 2 Weeks) 
Subjects will have a visit at 24 weeks and then every 6 months afterwards until the final visit 
or early withdrawal from the study, as long as their Chronocort® dose remains stable. Interim 
welfare telephone calls and supply of medication (if necessary) will be conducted on a 
3-monthly basis (see Section 11.1.8). At Week 24 and then at each 6-monthly visit, the 
assessments listed below will be conducted. However, if the investigator thinks that the 
Chronocort® dose needs to be changed at any point after the Week 24 visit, then the subject 
should undergo an interim dose titration visit or telephone call approximately 4 weeks after the 
dose has been changed to check on the well-being of the subject. The same assessments as 
noted for the Week 4 visit will be performed at the interim dose titration visit. If an interim 
dose titration telephone call is used instead, blood sampling for 17-OHP and A4 and the urine 
pregnancy test will not be performed but all other Week 4 assessments will be performed. 
 
The subject should then continue with the 6-monthly visit schedule as determined before this 
visit (i.e. the original timings will be maintained with this extra interim dose itration visit or 
telephone call added in between). 
 
If the subject has been receiving their Chronocort® medication for the previous 5 days (i.e. sick 
days rules have not been applied in the preceding 5 days) they will attend the clinic on the 
morning of the visit. If sick day rules have been applied in the previous 5 days then the visit 
should be postponed until the subject has been receiving their normal medication for 5 days. 
Subjects must attend this visit after fasting from 21:00 hours the previous evening. 
 
At each visit, the subject will be asked to return all packs of study medication, including any 
unused medication, and the number of capsules used and unused will be counted and recorded 
in the eCRF so compliance can be calculated. The safety pack should also be returned and 
checked, with any rescue medication use being recorded. Subjects will then be dispensed with 
new study medication for the next treatment period. If the safety pack has been used then the 
medication used will be recorded for drug accountability purposes, replaced, and the pack 
re-sealed and prescribed to the subject for the next study period. 
 
The following assessments will be carried out and recorded at this visit: 
 
• Subjects will be asked about any AEs and concomitant medications changes since the 
last visit. 
• Signs and symptoms of adrenal insufficiency (see checklist in Appendix 4) and any 
occurrences of adrenal crises or implementation of sick day rules. 
• Urine sample will be taken for a urine pregnancy test in females of childbearing 
potential (note: females presenting with oligomenorrhoea or amenorrhoea who are aged 
≤55 years of age should be considered potentially fertile and should therefore undergo 
pregnancy testing like all other female subjects). 
• A physical examination will be conducted and weight, BMI, and waist circumference 
recorded. 
• Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be 
recorded. 
• Record the time and dose of the last dose of Chronocort® taken prior to attending for 
this visit. 
• Blood samples taken for serum CTX, osteocalcin, hsCRP, HbA1c, testosterone, fasting 

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insulin and glucose, and safety laboratory tests. 
• Blood sample taken for PRA after the subject has been supine for 30 minutes. 
• Blood samples will be taken at 09:00 and 13:00 hours for testing of 17-OHP and A4 
level.  
• DEXA scan conducted annually (except in Germany). 
• Completion of the following questionnaires: MAF, SF-36® and EQ-5D™. 
 
Once all the above assessments have been completed, the subject will be allowed home.  
11.1.8 Telephone call (within 2 weeks of previous visit) 
Following the assessment of the 17-OHP and A4 levels and the clinical evaluation using the 
adrenal insufficiency checklist conducted at the previous visit, a decision will be made by the 
investigator whether to adjust the dose for the subject. This assessment must be made within 
2 weeks of the visit. All subjects will be contacted by telephone, whether or not a dose 
adjustment is needed. The subject will receive clear written instructions of the dose they will 
be taking until the next study visit (even if there is no adjustment to be made) following the 
telephone call. Subjects will be asked about any AEs at this call and any AEs reported will be 
recorded in the eCRF. 
 
If a dose titration is needed, an interim dose titration visit or telephone call (at the investigator’s 
discretion) will be required to take place approximately 4 weeks after the decision has been 
communicated to the participant. The same assessments as noted for the Week 4 visit will be 
performed at the interim dose titration visit. If an interim dose titration telephone call is used 
instead, blood sampling for 17-OHP and A4 and the urine pregnancy test will not be performed 
but all other Week 4 assessments will be performed. 
11.1.9 Week 18 (± 3 Days) and then 3-monthly between the 6-monthly visits (± 2 Weeks) 
In between the 6-monthly visits, telephone calls only (i.e. not a formal study visit) will be made 
at approximately 3 months to check on the welfare of the subjects. Any Aes spontaneously 
reported by the subjects at these calls will be recorded in the eCRF. Subjects may either return 
to the site pharmacy every 3 months between the 6-monthly site visits to collect new supplies 
of Chronocort® or the site may issue 6 month’s supply of Chronocort® at each 6-monthly site 
visit. Subjects will be asked to return all packs of study medication, including any unused 
medication, at these visits for drug accountability purposes. The safety pack should also be 
returned and checked, with any rescue medication use being recorded. Subjects will then be 
dispensed with new study medication for the next treatment period. If the safety pack has been 
used then the medication used will be recorded for drug accountability purposes, replaced, and 
the pack re-sealed and prescribed to the subject for the next study period. 
11.1.10  Final visit or early withdrawal visit  
If the subject has been receiving their Chronocort® medication for the previous 5 days (i.e. sick 
days rules have not been applied in the preceding 5 days) they will attend the clinic on the 
morning of the visit. If sick day rules have been applied in the previous 5 days then the visit 
should be postponed until the subject has been receiving their normal medication for 5 days. 
Subjects must attend this visit after fasting from 21:00 hours the previous evening. 
 
If the end of study visit is within 3 months after a scheduled 6-monthly visit then only minimal 
safety assessments (AE and SAE collection only) will be performed. 

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The subject will be asked to return all packs of study medication, including any unused 
medication, and the number of capsules used and unused will be counted and recorded in the 
eCRF so compliance can be calculated. The safety pack should also be returned and checked, 
with any rescue medication use being recorded.  
 
The following assessments will be carried out and recorded at this visit: 
 
• Subjects will be asked about any AEs and concomitant medications changes since the 
last visit. 
• Signs and symptoms of adrenal insufficiency (see checklist in Appendix 4) and any 
occurrences of adrenal crises or implementation of sick day rules. 
• Urine sample will be taken for a urine pregnancy test in females of childbearing 
potential (note: females presenting with oligomenorrhoea or amenorrhoea who are aged 
≤55 years of age should be considered potentially fertile and should therefore undergo 
pregnancy testing like all other female subjects). 
• A physical examination will be conducted and weight, BMI, and waist circumference 
recorded. 
• Vital signs (blood pressure, heart rate, respiratory rate and body temperature) will be 
recorded. 
• Record the time and dose of the last dose of Chronocort® taken prior to attending for 
this visit. 
• Blood samples taken for serum CTX, osteocalcin, hsCRP, HbA1c, testosterone, fasting 
insulin and glucose, and safety laboratory tests. 
• Blood sample taken for PRA after the subject has been supine for 30 minutes. 
• Blood samples will be taken at 09:00 and 13:00 hours for testing of 17-OHP and A4 
level.  
• Completion of the following questionnaires: MAF, SF-36® and EQ-5D™ 
 
Once all the above assessments have been completed, the subject will be discharged. If the 
subject discontinues from the study early then as many of the above assessments as possible 
should be completed. The investigator must ensure that continuing therapy for CAH is given 
according to best practice using either commercially available Chronocort® (assuming a 
successful licensing application) or standard therapy. 
11.1.11  Telephone call (30 days after the final visit) 
At the end of the study subjects will have the option to enter a second long-term study 
(DIUR-015) to enable them to continue to receive open-label Chronocort® until it is 
commercially available in their region or it is decided to stop Chronocort® treatment. Subjects 
who decide to enter the DIUR-015 study immediately following this DIUR-006 study do not 
require a telephone call 30 days after the end of this study. If there is a gap between finishing 
this DIUR-006 study and entering the DIUR-015 study of greater than 30 days, then the 30-day 
telephone call is required.  
If this call is required, subjects will be asked about any AEs at this call and any AEs reported 
will be recorded in the eCRF. Any AEs experienced after this 30-day period should only be 
reported if the Investigator suspects a causal relationship to Chronocort® and treatment with 
Chronocort® has stopped. Any ongoing AEs at this point will be followed to resolution or 
stabilisation if resolution is not expected.  

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11.1.12  Unscheduled Visits or telephone calls 
If any unscheduled visits are 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 (note that the local laboratory 
normal reference ranges will then be needed). Additional telephone calls may also be required 
in between visits to maintain contact with the subject and to ensure AEs and use of any sick 
day rules are being noted. Any information collected in such calls must be recorded in the 
eCRF. 
11.2 
Study Assessments 
• Vital signs 
o Blood pressure, heart rate, respiratory rate and body temperature will be 
measured according to normal clinical practice at the investigational sites and 
the results recorded in the eCRF.  
 
• Blood samples  
Will be taken by suitably qualified study personnel for: 
o routine safety laboratory tests (see Appendix 1).  
o measurement of serum CTX, osteocalcin, hsCRP, HbA1c, testosterone, fasting 
insulin and glucose. The fasting samples should be taken as soon as possible 
after the subject arrives for the visit before any food is consumed. 
o measurement of PRA after the subject has been supine for 30 minutes 
o blood samples will be taken at 09:00 and 13:00 hours for testing of 17-OHP and 
A4 levels.  
o A blood sample for genotyping will be obtained, if necessary, from subjects 
entering from study DIUR-003, but if previous genotyping has been performed 
the patient will be asked for their permission for this information to be taken 
from their medical records and recorded in the eCRF. 
 
To minimise the risk of anaemia associated with the withdrawal of multiple blood samples for 
laboratory testing, the planned blood volume to be drawn at each visit will be limited to a 
maximum of 49 mL. The date and time of collection of all blood samples will be recorded in 
the subject’s eCRF. Copies of laboratory accreditation certificates and reference ranges will be 
provided prior to the analysis of the first subject sample. 
 
All laboratory analyses will be carried out by the central laboratory 
 
. If laboratory 
results are needed urgently for safety reasons during the study, these can be processed at the 
local laboratory but the results must be recorded in the eCRF. 
 
• Urinalysis 
A pregnancy test in females of childbearing potential will be done locally at the site 
using a dipstick test (note: females presenting with oligomenorrhoea or amenorrhoea 
who are aged ≤55 years of age should be considered potentially fertile and should 
therefore undergo pregnancy testing like all other female subjects). 
 

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• DEXA scans (except Germany) 
To be performed at baseline for subjects entering from study DIUR-003 and then 
annually for all subjects (except in Germany) (note: subjects with a gap between 
completing study DIUR-005 and starting study DIUR-006 do not require an additional 
DEXA scan at the time they enter study DIUR-006). The DEXA scans will be 
performed according to the site’s standard clinical procedures.  
 
• Quality of life questionnaires (QoL)  
QOL questionnaires (MAF, SF-36® and EQ-5D™) will be administered and completed 
in a quiet environment.  
 
• Waist circumference, height and weight 
Waist circumference, height and weight will be measured according to each site’s 
normal clinical practice and the result recorded in the eCRF. The subject’s BMI will be 
calculated automatically.  
 
• Physical examination 
A full physical examination to assess the subject’s general appearance and overall 
health will be carried out at the baseline visit, every 6 months throughout the study, and 
at the last visit in the study. Significant findings that are present prior to the start of 
study drug must be included in the relevant medical history/current medical status 
section of the eCRF and significant findings made after the start of study drug which 
meet the definition of an AE must be recorded as AEs in the eCRF.  
11.3 
Sick Day Rules  
All subjects will be educated regarding “sick day rules”. “Sick day rules,” a written guideline 
regarding what to do during any illness, will be given to the subjects (as is done for all CAH 
subjects). Where sites have a standard set of “sick day rules” these will be supplied to subjects 
at that site routinely along with an emergency pack of medication (see Appendix 3 for an 
example of sick day rules that can be used for this study if a site choses to do so). Use of sick 
day rules will be recorded in eCRF, including both duration, dose of steroid and use of 
injection. Sick day rules from each site will be collected prior to the beginning of recruitment 
and placed on file by the Sponsor. 
11.4 
Early Withdrawal from Treatment  
If a subject withdraws or is withdrawn prior to the last scheduled visit, all efforts should be 
made to perform the end of study assessments. Additional follow-up by telephone may be 
required to obtain information regarding follow-up of AEs (both non-serious and serious) 
ongoing at the time of study discontinuation.  
 
The date the subject withdraws/is withdrawn from the study and the reason(s) for 
discontinuation will be recorded on the subject’s eCRF.  

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11.5 
Criteria for Withdrawal of Study Treatment 
Subjects may withdraw from the study at any time without stating a reason and without 
prejudice to further treatment. The investigator may withdraw a subject from the study and 
discontinue study treatment and assessments at any time. Events that will result in 
discontinuation of treatment include:  
 
1. Inability to tolerate Chronocort® secondary to perceived or observed side effects. 
2. Pregnancy (not due to safety reasons but because pregnancy may interfere with the 
study endpoints) – see Section 11.7 Pregnancy for further details on withdrawal due 
to pregnancy.  
3. Any other changes to clinical signs or changes in laboratory values, physical status or 
AEs that could compromise the subject’s status if they were to continue with the study 
or if the investigator feels that it is not in the best interests of the subject. 
 
The Sponsor reserves the right to request the withdrawal of a subject due to protocol violations, 
administrative or other reasons, or in the event of emergence of adverse risk data on the product. 
 
If a subject withdraws from the study prior to study completion, the reason for withdrawal 
should be sought and recorded on the eCRF. AEs should be followed up until resolution.  
11.6 
Replacement of Withdrawn Subjects 
There will be no replacement of withdrawn subjects. 
11.7 
Pregnancy  
Female subjects who are pregnant or lactating will not be allowed to enter the study. However, 
no specific contraception requirements are required by the protocol during the study since this 
is a long-term study and subjects all need to be on continuous hydrocortisone treatment for 
their underlying condition, and therefore the risks of pregnancy whilst receiving Chronocort® 
are perceived to be no greater than the risks of pregnancy on standard hydrocortisone treatment. 
If Chronocort® leads to improved hormonal control, this may be more likely to confer an 
advantage in subjects who want to become pregnant. If a subject is sexually active, the 
investigator will provide counselling on contraception and pregnancy, where appropriate, on 
an individual basis. Urine pregnancy tests will be conducted at each visit to monitor for 
pregnancy cases. 
 
Since hydrocortisone is a well-established product, no pre-clinical reproductive toxiciology 
studies have been conducted or are planned with Chronocort®. However, information from the 
Summary of Product Characteristics (SmPC) of hydrocortisone should be noted 
(http://www.medicines.org.uk/emc/medicine/27652).  
 
If a subject becomes pregnant during the study they should be withdrawn – not due to safety 
reasons but because pregnancy may interfere with the study endpoints. However, subjects who 
withdraw from the study due to pregnancy can re-enter the study, if they choose to do so, at 
least 6 weeks 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). Subjects who chose 
to re-enter the study will retain the same subject number. 

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As soon as the pregnancy is confirmed, the Investigator will conduct as many of the evaluations 
included in the early withdrawal visit as possible (Section 11.1.10) and the subject 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 subject from Chronocort onto standard of care 
therapy in line with the “DIUR-006 Participant Pregnancy: Advice to Investigators” document 
circulated to all Investigators in January 2020. AEs will be collected for 30 days after the early 
withdrawal visit and a follow-up telephone call will be conducted at 30 days, as detailed in 
Section 11.1.11. No other data will be collected while the subject is off study due to the 
pregnancy unless the Investigator considers any AEs are related to Chronocort 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
If the subject decides to re-enter the study after the pregnancy, 2 post-pregnancy visits must be 
conducted: 
• Post-pregnancy baseline visit, comprising the following:  
o Re-consent for re-entry into the study.  
o Review of the inclusion/exclusion criteria to ensure the subject is still eligible 
for the study. 
o The tests detailed for the basline visit will be conducted (Section 11.1.2) to 
establish a new second post-pregnancy baseline (note: the androgen results will 
reflect the standard of care treatment only so the results will not be used to 
inform dose titration decisions) 
o The Chronocort dose used after re-entry should be determined using the 
hydrocortisone equivalent of the subject’s standard of care dose at the end of 
the pregnancy/breast-feeding period. The first dose of Chronocort after re-entry 
should be taken in the evening of the first dosing day. 
• Post-pregnancy Week 4 Visit (Section 11.1.3) and subsequent telephone call 
(Section 11.1.4) 
 
On completion of the Post-pregnancy Week 4 Visit, subjects will attend their following study 
visits based on the schedule determined by their original baseline date (i.e. not using the new 
post-pregnancy baseline date).  
 
Further details on data collection during pregnancy are provided in Section 12.12.  
11.8 
Study Duration and Completion of the Study 
The length of the study will be 5.5 years from the date of the first subject entering the study, 
so subjects will be treated for a maximum of 5.5 years. The end of the study will be the final 
telephone call (30 days after the last visit) of the last subject or the date the last subject enters 
the DIUR-015 extension study, which ever is the latest. All subjects must be enrolled by 31 
October 2018, with no subjects allowed to enter the study after this date. 

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11.9 
Overdose 
In the event of an overdose, the subject should immediately contact the Investigator or Study 
Nurse for advice. There is no antidote available for Chronocort®. 
11.10 Subject Diaries 
Subjects will be provided with an ad hoc diary in which they will be asked to record any use 
of sick day medications and to record any AEs that occur between study visits. 
11.11 COVID-19 Procedures 
Appropriate measures have been put in place to enable the study to continue during the 
COVID-19 restrictions. Therefore, if necessary, visits can be performed remotely (via 
telephone or video call) and IMP shipments can be made directly to the subject’s home. Safety 
and endocrine blood sampling can also be performed locally if required (which could include 
nurses/phlebotomists performing home visits or subjects attending local doctor/general 
practitioner’s office, local endocrinologist’s office and local patient centres or clinics) for 
scheduled 6-monthly visits and dose titrations, to maintain patient safety and consideration of 
local environmental factors. If local laboratories are used, then normal ranges and certification 
of the local laboratories will be required. However, prior to implementation of any of these 
measures Sponsor approval must be obtained.  
12 Adverse Events and Toxicity Management 
12.1 
Adverse Event Definition 
An AE is defined as (21CFR312.32):  “Any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.”  An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. This includes any newly occurring event 
or previous condition that has increased in severity or frequency since the administration of 
study drug.  
12.2 
Adverse Event Collection  
AEs will be collected for all subjects from the time of consent up to 30 days after the last visit 
or the early withdrawal visit. Any AEs experienced after this 30-day period should only be 
reported if the Investigator suspects a causal relationship to Chronocort®. Any ongoing AEs at 
this point will be followed to resolution or stabilisation if resolution is not expected. Only 
treatment emergent AEs (i.e. those that started or worsened during Chronocort® treatment in 
this study) will be included in the main safety analysis: other AEs will be listed. 
 
Details of any AEs, signs, and symptoms will be collected, including details of onset, 
resolution, frequency, severity, seriousness, relationship to the drug, effect on the study drug, 
treatments administered, and outcome. All AEs will be followed, whenever possible, until they 
return to the baseline conditions or become stable with no further changes expected. In the 
event of any abnormalities considered to be clinically significant by the investigating physician, 
subjects will be followed up with appropriate medical management until values are considered 
to be clinically acceptable. Referral or collaborative care will be organised if required.  

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12.3 
Reporting of Adverse Events 
Individual AEs should be evaluated by the investigator and recorded in the eCRF. AEs must 
be reported regardless of whether the investigator thinks the AEs are related to the study 
treatment. 
12.3.1 Diagnoses vs. signs/symptoms 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values if not constituting AEs themselves) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded as the AE(s). 
12.3.2 Laboratory values  
Changes in laboratory values may be considered AEs if they are judged to be clinically 
significant (i.e., if some action or intervention is required or if the investigator judges the 
change to be beyond the range of normal physiological fluctuation). If abnormal laboratory 
values are the result of pathology for which there is an overall diagnosis (e.g., increased 
creatinine in renal failure), the diagnosis only should be reported as an AE. 
12.3.3 Pre-existing conditions 
Pre-existing conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should NOT be recorded as AEs. However, if the subject 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE. Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of….”). 
12.3.4 Pre-planned surgeries or procedures 
Pre-planned procedures (surgeries or therapies) that were scheduled prior to the start of AE 
event collection are not considered AEs. However, if a pre-planned procedure is performed 
early (e.g., as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured as an AE. 
12.3.5 Insufficient clinical response (lack of efficacy) 
Insufficient clinical response, efficacy, or pharmacological action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. 
12.3.6 Overdose 
Cases of drug overdose without manifested side effects are NOT considered AEs. 
12.4 
Assessment of Adverse Event Severity 
The following guidelines for rating severity of AEs should be used: 
 
Mild: 
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no loss of time 
from normal activities; symptoms would not require medication or a medical evaluation; signs 
and symptoms may be transient, disappearing during continued treatment with study 
medication.  

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Moderate: 
Discomfort enough to cause interference with usual activities; the study medication may have 
been interrupted.  
 
Severe: 
Incapacitating with inability to do work or do usual activities; signs and symptoms may be of 
systemic nature or require medical evaluation; the study drug may have been stopped, and 
treatment for the event may be required.  
 
The term “severe” is often used to describe the intensity of a specific event, as in mild, 
moderate, or severe myocardial infarction; the event itself, however, may be of relatively minor 
medical significance, such as severe headache. This is not the same as serious, which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to 
a subject’s life or functioning. 
12.5 
Assessment of Adverse Event Causality/Relatedness 
All AEs will be assigned one of the following assessments of causality: 
 
• Not related 
• Related to Chronocort®  
• Related to sick day medication 
• Related to an interaction between Chronocort® and sick day medication 
• Related to either Chronocort® or sick day medication 
• Related to study medication from previous Chronocort® study 
 
All AEs judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to Chronocort®, or are due to an interaction with Chronocort®, qualify as adverse 
drug reactions (ADRs).  
 
Appendix 2 provides a comprehensive list of events that are anticipated to occur in the targeted 
study entry population of subjects with CAH undergoing hydrocortisone replacement therapy. 
During the course of the trial, if aggregate analyses indicate that the events are occurring more 
frequently than anticipated, the sponsor will notify Regulatory Authorities expeditiously as 
appropriate. 
12.6 
Assessment of Adverse Event Expectedness 
An AE is considered “unexpected” if it is not listed in the Reference Safety Information (RSI) 
in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed.  
 
The concept of expectedness does not refer to what may occur in the course of the treated 
disease such as in the case of disease progression and/or lack of drug effect. 
12.7 
Serious Adverse Event Definitions 
An AE is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes (21CFR312.32): 
 

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• Death. 
• Is life-threatening. Life-threatening, in the definition of serious, refers to an event in 
which the subject 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. 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered serious when, based upon appropriate medical 
judgment, they may jeopardise the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
12.8 
Suspected Unexpected Serious Adverse Reaction 
The definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) includes a 
suspected causal relationship with administration of the test preparation (thus, a causality 
assessment of unrelated is not a SUSAR). 
12.9 
Serious Adverse Event Reporting  
As with all AEs, the investigator is responsible for the collection of SAE data. All SAEs should 
be recorded on the SAE form and the eCRF. Any SAE that occurs between informed consent 
being signed and 30 days after the last dose of the study treatments (or until the first dose of 
Chronocort® in the second extension study DIUR-015 for subjects who do not need the 30-day 
telephone call) must be reported promptly to the sponsor or designee not later than 24 hours 
after the study site becomes aware of its occurrence, using the SAE form provided. Any SAEs 
experienced after the 30-day reporting period should only be reported if the Investigator 
suspects a causal relationship to Chronocort® and treatment with Chronocort® has stopped. All 
SAEs should be monitored until they are resolved or stabilised.  
 
The initial report shall be promptly followed by detailed, written reports using the SAE report 
form provided. The initial and follow-up reports shall identify the trial subjects by unique code 
numbers assigned to the subject. The investigator shall supply the sponsor and the Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB) with any additional requested 
information. 
 
The report must be made by telephone, facsimile, or email to the following contacts at the 
following numbers: 
 
SAEs must be notified immediately (and within 24 hours) by telephone or email to the 
sponsor’s responsible Medical Monitor, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. This should be done even if the required information is incomplete or if 
the investigator is awaiting laboratory or diagnostic reports. This should be followed by a 
written report within 3 working days. 
 

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The SAE form requires the following information (at a minimum): 
 
• Subject ID (case number, gender, date of birth, initials [unless date of birth and initials 
are not allowed to be collected according to local law]) 
• Trial no. 
• Study therapy (dose, route, form regime, start date, end date) 
• Concomitant medication (including dose, route, form, regime, start date where 
available) 
• Nature of SAE (overall diagnosis where available or alternatively signs and symptoms) 
• Severity of SAE 
• Date and time of occurrence 
• Any associated factors (concomitant disease or medication) 
• Proposed relationship to study therapy 
• Outcome  
• Identification of the reporter 
• Action in relation to study (withdrawn, suspended, none). 
 
Investigators may be asked for additional information for any report of an SAE. An SAE form 
indicated as a follow-up report with attached documents (if necessary) should be forwarded to 
the sponsor/designee as soon as the additional information is available. The sponsor will submit 
to the Regulatory Authority(ies) all safety updates and periodic reports, as required by 
applicable regulatory requirement(s). 
 
Some of the AEs likely to occur in subjects with CAH, are of special interest, and whilst they 
may not be defined as SAEs, they will be reported in the same manner in order to capture the 
data in real time, together with additional data, if this should be required. However these events 
will not be reported to the Regulatory Authorities unless they are defined as SAEs. These 
events will include, but not be limited to, Addisonian crisis and events causing implementation 
of ‘sick day rules’.  
 
Addisonian or adrenal crisis is defined as follows (based on Allolio 2015): 
 
• (A): Major impairment of general health with at least two of the following 
signs/symptoms: 
Hypotension (systolic blood pressure <100 mmHg) 
Nausea or vomiting 
Severe fatigue 
Fever 
Somnolence 
Hyponatraemia (<132 mmol/L) or hyperkalaemia (as judged by characteristic 
electrocardiogram [ECG] changes) 
Hypoglycaemia 
• (B): Parenteral glucocorticoid (hydrocortisone) administration followed by clinical 
improvement: 
Grade 1: outpatient care only 
Grade 2: hospital care (general ward) 
Grade 3: admission to intensive care unit 

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Grade 4: death from adrenal crisis (with or without parenteral glucocorticoid 
administration) 
 
In addition, some events may occur that represent an improvement in the subject’s condition 
e.g. restoration of menses. These events are of special interest and should be recorded as AEs 
of special interest, clearly stating that the event is an improvement in the condition, and these 
events will be coded as ‘Unexpected Therapeutic Effect’. Whilst these events are not SAEs, 
they should be reported in the same manner as SAEs in order to capture the data in real time, 
together with additional data, if this should be required. However these events will not be 
reported to the regulatory authorities as SAEs.  
12.10 Serious Adverse Event Expedited Reporting 
The sponsor or designee will expedite the reporting to the appropriate Regulatory 
Authority(ies) of all ADRs that are both serious and unexpected. Such expedited reports should 
comply with the applicable regulatory requirement(s) (i.e., 21CFR312.32).  
12.10.1 
Standards for Expedited Reporting 
For each SAE/SUSAR, the investigator and sponsor (or designee) will independently assess 
whether there is a reasonable possibility that the event may have been caused by the study drug 
(“drug-related”). If the SAE is assessed to be both drug-related and unexpected, the sponsor or 
designee will report it to the appropriate Regulatory Authorities and notify investigators as 
required by applicable local regulations. The sponsor or designee will report SAEs to the US 
FDA as required by 21 CFR 312.32, and EU Competent Authorities as per EU requirements.  
 
SUSARs are required to be reported within 7 calendar days for life threatening events and those 
resulting in death, or 15 calendar days for all others. These timeframes begin with the first 
notification of the SUSAR to the sponsor/designee.  
 
All events qualifying as SAEs and SUSARs will be reported by the Pharmacovigilance (PV) 
Contract Research Organisation (CRO), as necessary, to Regulatory Authorities and IEC/IRB 
(the latter may be through the local investigator, as required by local regulations). The PV CRO 
for this study is Bionical-Emas up to the end of March 2022, then Pharmalex from April 2022 
onwards. 
12.10.2 
Expedited Reporting Guideline for Other Observations 
Other safety issues that might be considered for expedited reporting when they could materially 
alter the current benefit-risk assessment of the IMP (sufficient to consider changes in the 
administration or in the overall conduct of the trial) include, for example: 
 
• An increase in the rate of occurrence of an expected serious ADRs, which is judged to 
be clinically important 
• Post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported by the investigator to the sponsor 
• New event relating to the conduct of the trial or the development of the IMP likely to 
affect the safety of the subjects, such as a SAE which could be associated with the trial 
procedures and which could modify the conduct of the trial 

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12.11 Sponsor’s Responsibilities  
The sponsor is responsible for the ongoing safety evaluation of the IMP. The PV CRO is 
responsible for ensuring that expedited reports are made to the Regulatory Authority(ies) and 
all applicable investigators of all ADRs that are both serious and unexpected, of findings that 
could adversely affect the health of subjects, impact on the conduct of the trial or alter the 
competent authority’s authorisation to continue the trial.  
 
Such expedited reports should comply with the applicable regulatory requirements (e.g., 
21CFR312.32). The sponsor should submit to the Regulatory Authority all safety updates and 
periodic reports, as required by applicable regulatory requirements.  
 
The PV CRO is responsible for arranging structures and written standard operating procedures 
to ensure that the necessary quality standards are observed in every step of the case 
documentation, data collection, validation, evaluation, archiving and reporting. The PV CRO 
will assign a case number to be used in all future correspondence regarding the event and will 
forward the case to Diurnal Ltd within one working day.  
 
All events qualifying as SUSARs will be reported by the PV CRO, as necessary, to Regulatory 
Authorities and ethics committees/IRB (the latter may be through the local investigator, as 
required by local regulations). 
12.12 Procedures for Reporting Pregnancy Exposure and Birth Events 
Should a female subject become pregnant or be suspected of being pregnant while participating 
in this study they must be withdrawn from the study immediately (not due to safety reasons but 
because pregnancy may interfere with the study endpoints) (see Section 11.7). The event must 
be reported to the sponsor immediately upon receipt of information by the study staff using the 
pregnancy form. While the pregnancy itself is not considered to be an AE or SAE, any 
pregnancy complications should be recorded as AEs or SAEs (if applicable). Any pregnancy 
will be followed through delivery for the observation of any SAEs. Fatalities and spontaneous 
abortions must be reported as SAEs. 
12.13 Data Safety Management Board 
An independent DSMB will meet on a regular basis during the study in order to review safety 
data. The DSMB will operate in accordance with a charter. 
13 Statistical Considerations 
 
A detailed and comprehensive statistical analysis plan (SAP) will be prepared and signed-off 
before the first subject has given informed consent for this extension study. Minor changes to 
the statistical methods set out in this protocol need not be recorded as a protocol amendment 
but must be documented in the SAP and in the study report.  
 
Interim data analyses are expected to be required for regulatory review as part of any marketing 
authorisation applications. No changes to the overall study conduct and no changes to the 
planned formal statistical analyses are anticipated as a result. 
 

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The statistical analysis will be undertaken by 
 The statistical analysis and report will 
conform to the relevant ICH requirements, including but not limited to those set out in ICH 
documents E3 and E9. SAS version 9.2 or later will be used for the analysis.  
13.1 
Conventions and Methods 
13.1.1 Summary Tables, Listings and Figures 
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). Geometric mean and coefficient of variation will also be presented for variables 
which will subsequently be log-transformed during the analysis. 
 
Summary tables and figures will be supported by full subject listings. 
 
Data will be summarised according to time since first dose of Chronocort® treatment (which 
may have been in the feeder study for study DIUR-005). Time slotting will be described in the 
SAP. 
 
Safety and efficacy parameters will be explored based on previous treatment in the feeder study 
and by previous standard therapy. Exploratory analyses will also be undertaken to assess the 
relationship between disease control and the proportion of daily dose given at night. Further 
details will be provided in the SAP. 
 
For subjects who re-enter the study post-pregnancy, data collected during the post-pregnancy 
phase will be listed only. Only data up to the time of first study withdrawal will be included in 
summary tables and figures. Individual subject profiles will be created to support discussion of 
data from this small subset of subjects in the clinical study report. 
 
Disruptions due to the COVID-19 pandemic will be summarised by feeder study and previous 
treatment. The summary will include an overview of study visit or study medication disruptions 
due to the COVID-19 pandemic, as well as including whether the scheduled visit was delayed 
or scheduled assessments were not done. Detailed listings of study visit disruptions and study 
medication disruptions will be produced. 
13.1.2 Hypothesis Testing and Confidence Intervals 
Since all subjects participating in this trial will be receiving Chronocort®, there will be no 
formal treatment comparisons. Summaries over time will be produced for safety and efficacy 
parameters. 
13.1.3 Missing Outcome Data 
Blood samples for analysis of 17-OHP and A4 values are to be taken at 09:00 and 13:00, with 
a window of +/- 1 hour allowed. Missing 17-OHP and A4 values (including those considered 
missing due to being taken outside the permitted time window) will not be imputed. In 
calculating the mean of the 09:00 and 13:00 SDS, if one value is missing, then only the 
non-missing value will be used. If both values are missing, the mean value will be missing. 
13.2 
Analysis Sets 
The full analysis set comprises all subjects who entered the study and who subsequently 

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received at least one dose of Chronocort®. Subjects in the full analysis set will be analysed 
according to the actual treatment received. 
 
The interim analysis set is a subset of the full analysis set. In addition to entering the study and 
receiving at least one dose of Chronocort®, subjects must also have completed the Week 24 
(Visit 4) assessment or discontinued early from treatment and withdrawn from the study 
(Interim Analysis 1). For subsequent interim analyses, a data cut-off date will be defined for 
each interim analysis set. At the time of interim analyses, all primary, secondary and 
exploratory endpoints will be summarised using the interim analysis set. Subjects in the interim 
analysis set will be analysed according to the actual treatment received. 
13.3 
Endpoints 
13.3.1 Primary Endpoint 
The primary objective of summarising the safety of Chronocort® over time will be assessed 
using but not limited to the following endpoints: 
 
1. Signs and symptoms of adrenal insufficiency or over-treatment throughout the study. 
2. Use of sick day rules throughout the study. 
3. Occurrence of adrenal crises throughout the study. 
4. Occurrence of AEs throughout the study. 
5. Change from pre-Chronocort® baseline in safety laboratory assessments at each visit 
throughout the study.  
6. Change from pre-Chronocort® baseline in vital signs, weight, BMI, and waist 
circumference at each visit throughout the study. 
13.3.2 Secondary Endpoints 
To assess the long-term efficacy of Chronocort®, the following secondary endpoints will be 
assessed: 
 
1. Total daily dose of Chronocort® in mg/day of hydrocortisone and by BSA 
2. Disease control throughout the study as assessed by 17-OHP levels in the optimal range 
at 09:00 and again at 13:00, and by the proportion of dose given at night 
3. Disease control throughout the study as assessed by A4 levels in the normal range at 
09:00 and again at 13:00, and by the proportion of dose given at night 
4. Change from pre-Chronocort® baseline at each visit in SDS of 17-OHP and A4 at 09:00, 
13:00 and the mean of the two timepoints. 
5. Change from pre-Chronocort® baseline at each visit in the absolute values of 17-OHP 
and A4 at 09:00 and 13:00 
6. Change from pre-Chronocort® baseline at each visit in: 
a. Bone turnover markers  -  CTX, osteocalcin 
b. Testosterone (total) – analysed separately by males and females 
c. Fasting insulin and blood glucose levels, and HbA1c 
d. hsCRP and PRA 
e. Body composition (DEXA)(fat mass, lean mass and total bone density) 
(except in Germany) 
f. Quality of life – SF-36®, MAF, EQ-5D™ 
7. Incidence of dose titrations 

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13.4 
Analysis of the Conduct of the Study 
Data concerning the conduct of the study (subject disposition/withdrawals, compliance, study 
termination/duration) will be listed and summarised descriptively. Details will be described in 
the SAP. 
13.5 
Demographic and other baseline characteristics 
Demographic and other baseline characteristics for all enrolled subjects will be listed and 
summarised.  
 
Baseline values are defined as pre-Chronocort® values: 
 
• for subjects entering from study DIUR-003, baseline values are defined as those taken 
at Visit 1 of this DIUR-006 study 
• for subjects entering immediately from study DIUR-005 who received comparator 
treatment, baseline values are defined as those taken at the last visit in the feeder study 
i.e. V4 (week 24) in study DIUR-005 
• for subjects entering immediately from study DIUR-005 who received Chronocort®, 
baseline values are defined as the pre-Chronocort® values recorded at Visit 1 in study 
DIUR-005 
• for subjects who delayed entering study DIUR-005 and received standard 
glucocorticoid therapy in the gap between the DIUR-005 and DIUR-006 studies,  
baseline values are defined as those taken at Visit 1 of this DIUR-006 study. 
 
13.6 
Efficacy and Safety Analyses 
13.6.1 Safety 
Signs and symptoms of adrenal insufficiency or over-treatment will be summarised over time. 
A listing of all signs and symptoms of adrenal insufficiency will be produced, flagging any 
significant findings as well as a listing of significant findings related to under/over replacement 
of steroid.  
 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). Data will be summarised using preferred term (PT) and primary system organ 
class (SOC). Only treatment-emergent AEs, i.e. AEs with an onset at or after the first 
administration of Chronocort®in this study and up to 30 days after the end of the study or the 
early withdrawal visit, will be presented in summary tables. Where changes in severity are 
recorded in the eCRF, the most severe incidence of the AE will be reported in the tables. 
Frequency tables will be provided concerning severity and drug relationship.  
 
Each site will have a set of sick day rules where certain AEs will result in emergency 
hydrocortisone being taken. All AEs leading to use of “sick day rules” will be summarised 
(frequency and percentage of subjects) by SOC and PT. Use of sick day medication will be 
summarised. 
 
All AEs leading to adrenal crises will be summarised (frequency and percentage of subjects) 
by SOC and PT.  
 

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All AEs of unexpected therapeutic benefit will be summarised (frequency and percentage of 
subjects) by PT, lower level term, and treatment group. There will be a separate listing showing 
details of all AEs of unexpected therapeutic benefit. 
 
Absolute and change from baseline in safety laboratory variables will be summarised over time. 
Shift tables from baseline to the maximum and minimum on-treatment values will be presented. 
The 3 x 3 cross tabulations (from low, normal and high to low, normal and high) will be 
presented. Values outside the normal ranges will be flagged in the subject data listings. 
 
Changes from baseline in vital signs data, weight, BMI, and waist circumference will be 
summarised over time. Abnormal findings in the physical examination will be tabulated by 
body system showing the frequency and percentage of subjects with an abnormal finding. 
13.6.2 Efficacy 
The total daily dose of Chronocort® in mg/day of hydrocortisone and by BSA will be 
summarised over time.  
 
Disease control will be based on whether 17-OHP levels are in the optimal range and also 
whether the A4 levels are in the normal range (both analysed separately). A subject will be 
considered a responder (i.e. disease controlled) if their 09:00 results are in the optimal range 
for 17-OHP and then separately if their 09:00 results for A4 are in the normal range. The 
number and percentage of subjects achieving results in the optimal range will be presented at 
each visit and by the proportion of dose given at night. This will be repeated for the 13:00 
values. 
 
DEXA scans will be performed at baseline for subjects entering from study DIUR-003 and 
then annually for all subjects, except in Germany. Summary statistics will be produced for the 
absolute values and change from pre-Chronocort® baseline for fat mass, lean mass, total bone 
density, T scores and Z scores at each visit. Due to the length of the study, it is possible that 
there will be changes in the DEXA scanners used at some sites. Therefore, the above summary 
tables will be repeated excluding data collected after a scanner change and an analysis of 
variance (ANOVA) model will be created to explore whether there is any statistically 
significant difference in the DEXA results before and any scanner changes. 
13.6.3 SDS 
The SDS is defined as the absolute (unsigned) number of standard deviations above or below 
the average of the lower and upper limit of normal. For each of the 17-OHP and A4 
concentrations at each visit at each time point (09:00, 13:00), the natural logarithm will be 
taken and the SDS will be calculated by counting the number of standard deviations which are 
above or below the mean of the log transformed range. Further details will be provided in the 
SAP. The mean and standard deviation values to be used for these calculations will be 
pre-specified. Change from baseline at each visit in these values will be summarised over time. 
 
In addition to presenting change from baseline SDS at 09:00 and 13:00 separately, an arithmetic 
mean of the SDS at the two timepoints will be calculated and summarised over time. Change 
from baseline at each visit in the absolute values of 17-OHP and A4 at 09:00 and 13:00 will 
also be summarised over time. 
 

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All other efficacy endpoints (change from baseline in bone turnover markers, testosterone, 
fasting insulin, blood glucose levels, HbA1c, hsCRP, PRA, DEXA, QoL questionaires) will be 
summarised over time. 
 
Exposure to Chronocort® (time since first dose) and the incidence of dose titrations will be 
summarised.  
13.7 
Power and Sample Size Considerations 
Since this is an open label extension study to gather long term safety and efficacy data on 
Chronocort®, no formal power or sample size calculations have been performed.  All eligible 
subjects from study DIUR-003 (16 subjects) and DIUR-005 (122 subjects) may enter this 
study, giving a maximum of 138 subjects. Subjects from study DIUR-003 can be enrolled at 
any time (since this study has been completed), but subjects from study DIUR-005 will be 
enrolled when they complete Visit 4 of study DIUR-005. However, in some cases there may 
be a delay between a subject completing study DIUR-005 and starting study DIUR-006 during 
which the subject receives standard glucocorticoid therapy. In this case the subject should be 
entered into study DIUR-006 as soon as possible. All subjects must be enrolled by 31 October 
2018, with no subjects allowed to enter the study after this date. 
13.8 
Data Review Meeting 
The sponsor will convene a Data Review Meeting after the data has been cleaned and before 
the database is locked and the 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 may include, but will not be limited to: 
• a review of missing data and of outliers 
• a review of the distribution of the efficacy variables, considering any 
implications for the proposed method of statistical analysis 
• revisions to SAP in light of any Data Review Meeting findings  
13.9 
Deviations from the Planned Statistical Analysis 
All deviations from the planned statistical analysis will be documented in the clinical study 
report. 
14 Responsibilities 
14.1 
Investigator Responsibilities 
The investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and make changes only after notifying 
the sponsor, except to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Inform any subjects enrolled in the study that the drug is being used for investigational 
purposes.  
4. 
Ensure that the requirements relating to obtaining informed consent and IEC/IRB review 
and approval meet EU and US Federal guidelines, as stated in 21 CFR, parts 50 and 56. 
5. 
Report to the sponsor any AEs that occur during the course of the study, in accordance 
with ICH guidelines and 21 CFR 312.64 (US sites only).  

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6. 
Have read and understood the Investigator’s Brochure, including potential risks and side 
effects of the drug. 
7. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
8. 
Maintain adequate and accurate records (in accordance with 21 CFR 312.62 for US sites) 
and to make those records available for inspection with the sponsor, their designated 
representative, the FDA or any agency authorised by law. 
9. 
Ensure that an IEC/IRB that complies with the requirements of ICH Good Clinical 
Practice (GCP) guidelines and local law (and 21 CFR 56 in the US) will be responsible 
for initial and continuing review and approval of the clinical study. 
10. Report promptly to the IEC/IRB and the sponsor all changes in the research activity and 
all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
11. The investigator should not implement any deviation from or changes in the protocol 
without agreement by the sponsor and prior review and documented approval/favourable 
opinion from the IEC/IRB of an amendment, except where necessary to eliminate an 
immediate hazard to trial subjects, or when the change involves only logistical or 
administrative aspects of the trial (e.g., change in monitor, change of telephone numbers 
etc.). The investigator, or person designated by the investigator, should document and 
explain any deviation from the approved protocol. If the investigator implements a 
deviation from the protocol to eliminate an immediate hazard without prior IEC/IRB 
approval/favourable opinion, the implemented deviation or change, the reasons for it, 
and, if appropriate, the proposed protocol amendment should be submitted as soon as 
possible to the IRB/IEC for review and approval/favourable opinion, to the sponsor for 
agreement and, if required, to the regulatory authorities. 
12. Comply with all other requirements regarding the obligations of the clinical investigators 
and all other pertinent requirements listed in in ICH GCP and 21 CFR 312 (US sites). 
14.2 
Ethical Conduct of the Study 
The trial will be conducted in accordance with this protocol, the principles that have their 
origins in the Declaration of Helsinki, as well as ICH GCP and applicable regulatory 
requirements, including the US Code of Federal Regulations on Protection of Human Rights 
(21 CFR 50) for US sites. All essential documents will be archived for a minimum of 5 years 
after completion of the study. Note in Sweden all essential documents will be archived for a 
minimum of 10 years.  
14.3 
Ethics Committee and Institutional Review Board approval 
The final study protocol and subject informed consent form will be reviewed and approved by 
each of the participating institution’s IEC/IRB prior to the initiation of subject recruitment. 
Any changes to the protocol will be formally documented in protocol amendments and 
approved by the IEC/IRB prior to implementation, except in the case of changes made to 
protect subject safety, which will be implemented immediately. In addition, progress reports 
will be submitted to the IEC/IRB by the investigator as indicated by IRB/IEC guidelines. 
 
Each IRB/IEC must meet the FDA/EMEA, ICH, and any additional national requirements for 
composition, documentation, and operational procedures. The investigator shall provide the 
Sponsor with the IRB/IEC written notification of approval along with the membership list 
and/or statement that the IRB/IEC operates in accordance with GCP.  

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14.4 
Informed Consent 
The principles of informed consent as laid down in the Declaration of Helsinki, in the current 
requirements of GCP published by the ICH, and in local regulation, whichever affords the 
greater subject protection, will be implemented before any protocol-specified procedures or 
interventions are carried out.  
 
A signed and dated informed consent form (ICF) shall be obtained from each subject prior to 
entering the study. The investigator is responsible for obtaining written informed consent from 
the subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol specific screening procedures or any study 
medications are administered. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the IEC/IRB. Subjects will also be asked to 
consent to allow the sponsor, sponsor representative or external regulatory auditor to review 
their medical records to confirm compliance with GCP. All information sheets and consent 
forms will be provided in local language. 
 
The acquisition of informed consent(s) should be documented in the subject’s medical record 
and the ICF should be signed and personally dated by the subject or the subject’s legally 
acceptable representative and by the person who conducted the informed consent discussion 
(not necessarily by the investigator). The original signed ICF will be retained with the medical 
records at each site, a copy retained in the Investigator Site File and a further copy of the signed 
consent will be provided to the subject prior to participation in the trial. 
14.5 
Subject Data Protection 
The ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data legislation. All data computer processed by 
Diurnal Ltd. Will be identified by subject number/study code. The ICF will also explain that 
for data verification purposes, authorised representatives of Diurnal Ltd., a Regulatory 
Authority, and/or an IEC/IRB may require direct access to parts of the hospital or practice 
records relevant to the study, including subjects’ medical history. 
 
Extra precautions are taken to preserve confidentiality and prevent genetic information being 
linked to the identity of the subject. This involves coding of the samples and data. For coded 
samples this will mean that there is segregation of the databases containing coded genotypic 
and clinical information with protection of confidentiality achieved by limited access. 
14.6 
Case Report Forms and QoL questionnaires 
All data will be collected using an eCRFs, which will automatically enter the data into a 
validated computerised clinical data management system.  
 
Each subject will complete the QoL Questionnaires during the clinic visits. The answers to the 
questionnaires will then be transcribed into the eCRF by the study site staff. 
 
Laboratory data received electronically from the central laboratory will be merged with the 
database and not entered from the eCRF.  
 

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Analysis of the data will only be performed after all queries have been resolved using 
appropriate software for analysis. 
14.7 
Data Management 
Data management will be undertaken by 
 who will: 
• Generate the database to include data collected in the eCRF, the QoL questionnaires 
and the laboratory data in accordance with the CRO’s standard operating procedures.  
• Complete efficacy and endpoint reporting. 
• Generate safety data listings to include AEs coded using the latest version of the 
MedDRA coding dictionary. These will be produced on an ongoing basis for review by 
the DSMB. 
14.8 
Drug Reconciliation 
The CRA will perform drug reconciliation of supplies received on site, used, and destroyed or 
returned. The medication provided for this study is for use only as directed in the protocol. It 
is the investigator/institution’s responsibility to establish a system for handling study 
treatments, including IMPs, so as to ensure that: 
 
• Deliveries of such products from Diurnal Ltd are correctly received by a responsible 
person 
• Such deliveries are recorded 
• Study treatments are handled and stored safely and properly as stated on the label 
• Study treatments are only dispensed to study subjects in accordance with the protocol 
• Any unused products are either returned for destruction or destroyed on site in liaison 
with the CRA and following approval from the sponsor of the destruction procedure 
 
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock. Records of usage should include the identification of the person 
to whom the study treatment was dispensed and the quantity and date of dispensing. This record 
is in addition to any drug accountability information recorded on the eCRF. Any discrepancies 
must be accounted for on the appropriate forms. Certificates of delivery and return must be 
signed, preferably by the investigational pharmacist, and copies retained in the Investigator 
Site File. 
 
All unused medication should be either returned for destruction or destroyed on site following 
appropriate drug accountability procedures.  
14.9 
Inspections 
The sponsor or sponsor representative or external regulatory agency may at any time during or 
after completion of the study conduct a GCP audit. Notice will be given to the site in advance 
of a planned GCP audit. 
14.10 Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in the protocol. 

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14.11 Sponsor Responsibilities 
14.11.1 
Indemnity and Compensation 
Diurnal Ltd agrees to abide by the compensation requirements described in the current ABPI 
Guidelines for medical experiments. Terms for the provision of indemnity and for the provision 
and maintenance of insurance will be documented in contracts between Diurnal Ltd and the 
relevant parties. 
14.11.2 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to subjects in the study, 
may be made only by Diurnal Ltd in conjunction with Principal Coordinating Investigator. All 
protocol modifications, except when the change involves only logistical or administrative 
aspects of the trial (e.g., change in monitor, change of telephone numbers etc.). must be 
submitted to the IEC/IRB in accordance with local requirements. Approval by the sponsor, 
Regulatory Authorities, and IEC/IRB must be obtained before changes can be implemented. 
 
If a deviation from the protocol is implemented to eliminate an immediate hazard without prior 
IEC/IRB approval/favourable opinion, the implemented deviation or change, the reasons for it, 
and, if appropriate, the proposed protocol amendment should be submitted as soon as possible 
to the IRB/IEC for review and approval/favourable opinion, and, if required, to the regulatory 
authorities. 
14.12 Study Monitoring 
The CRO will be responsible for the monitoring of the study. A risk-based monitoring approach 
will be used for monitoring the study sites with details included in the Monitoring Plan. Remote 
monitoring may also be conducted, if required. 
 
 
 
 with reasonable advance notice and at 
reasonable times, the site will permit the sponsor or its designee(s) to monitor the conduct of 
the research, as well as to audit source documents containing raw data.  
 
The information in original documents and records (e. g. patient files, laboratory results, QoL 
questionnaires, etc.) are defined as source data, as detailed for each site in their source data 
agreement and will be reviewed by the monitor for source data verification (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. If 
remote monitoring is being conducted, SDV against the source documents will be conducted 
using remote access to the subject’s electronic medical records or using scanned documents, if 
either are permitted. All subject identifiers must be redacted prior to scanning (further details 
are provided in the Monitoring Contingency Plan). 
 
At all sites the study monitor will review the progress of the study on a regular basis (using a 
risk-based monitoring approach), with reasonable advance notice and at reasonable times to 
ensure adequate and accurate data collections. Monitoring site visits to review eCRFs, subject 
case notes, administrative documentation including the Investigator Site File and frequent 
telephone communications with site will be performed throughout the study. At each study 

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monitoring visit the investigator will make available all records pertaining to the study. To 
allow sufficient time to assemble documentation for the study monitor, monitoring visits will 
be confirmed in advance of planned visits. 
 
All key communications between the sponsor, designated study representative, and 
investigators should be documented and retained within the Trial Master File (TMF).  
14.13 Publication Policy 
This section details the collaboration contractual terms relating to the data ownership and 
publication policy for Diurnal Ltd and the participating investigators stemming from the data 
generated from this study. 
 
The study results will be published irrespective of the study outcome. The sponsor and 
Principal Coordinating Investigator will jointly arrange for the preparation of one or more 
manuscripts. The sponsor’s and investigator’s comments on the proposed publication(s) shall 
be considered in good faith by the authors. Publication of the results will not include company 
confidential information without the permission of the sponsor. 
 
The sponsor may announce summary data in order to comply with Financial and other 
Regulatory Authorities, whilst ensuring that release of such data will not compromise the 
investigator’s ability to publish the data in appropriate scientific forms. Announcements made 
prior to the first scientific publication of the data will be reviewed and approved by the Principal 
Coordinating Investigator. 
 
Data from individual study sites (unless the only site of a study, or a circumscribed sub-study) 
will not be published separately unless exceptional circumstances prevail. 
14.14 Clinical Study Report 
The results of the study will be presented in an integrated clinical study report according to 
GCP and ICH-E3 guidance.  
14.15 Data Retention and Availability 
The investigator is required to maintain all study documentation, including regulatory 
documents, copies of eCRFs, signed ICFs, and records for the receipt and disposition of study 
medications, for a period of two years following approval date of a New Drug Application or 
a Marketing Authorisation Application for the drug, or until 15 years after completion of the 
study, whichever is later. 
 
During the study, the investigator must make study data accessible to the sponsor, IEC/IRBs, 
and appropriate Regulatory Authorities. A file for each subject must be maintained that 
includes the signed ICF and copies of all source documentation related to that subject. The 
investigator must ensure the availability of source documents from which the information on 
the eCRF was derived. 
 
At the end of the study, archiving will be authorised by the Sponsor following submission of 
the end of study report. The trial documents the sponsor will be responsible for archiving and 
the trial documents the CRO will be responsible for archiving will be documented in a separate 

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agreement. All essential documents will be archived for a minimum of 5 years after completion 
of trial. Destruction of essential documents will require authorisation from the sponsor. 
14.16 Study Termination 
The study may be terminated prior to completion at the request of the sponsor, the investigator, 
the IEC/IRB or Regulatory Authority or by mutual agreement. Conditions that may warrant 
early termination include, but are not limited to, insufficient adherence to the protocol 
requirement, the discovery of a significant, unexpected and unacceptable risk to the subjects, 
attainment of study objectives, or at the discretion of the sponsor. Procedures for terminating 
the study will be agreed upon by both the sponsor and the investigator. 

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15. 
References 
 
Allolio B. Adrenal crisis. Eur J Endocrinol. 2015;172:R115–R124. 
 
Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: 
a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. 
 
Azziz R, Dewailly D, Owerbach D. Clinical review 56: Nonclassic adrenal hyperplasia: current 
concepts. J Clin Endocrinol Metab. 1994;78(4):810-815.  
 
Barnes RB, Rosenfield RL, Ehrmann DA, et al. Ovarian hyperandrogynism as a result of 
congenital adrenal virilizing disorders: evidence for perinatal masculinization of 
neuroendocrine function in women. J Clin Endocrinol Metab. 1994;79(5):1328-1333.  
 
Cornean RE, Hindmarsh PC, Brook CG. Obesity in 21-hydroxylase deficient patients. Arch 
Dis Child. 1998;78(3):261-263.  
 
Cutler GB Jr, Laue L. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N 
Engl J Med. 1990;323(26):1806-1813.  
 
Deneux C, Tardy V, Dib A, et al. Phenotype-genotype correlation in 56 women with 
nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin  
Endocrinol Metab. 2001;86(1):207-213.  
 
Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital 
adrenal hyperplasia. Nat Rev Endocrinol. 2014;10(2):115-124. 
 
Joint LWPES/ESPE CAH Working Group 2002. Consensus Statement on 21-Hydroxylase 
Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society 
for Paediatric Endocrinology. J Clin  Endocrinol Metab. 2002;87(9):4048-4053.  
 
Krieger DT, Allen W, Rizzo F, Krieger HP. Characterization of the normal temporal pattern of 
plasma corticosteroid levels. J Clin Endocrinol Metab. 1971;32(2):266-284.  
 
Mallappa A, Sinaii N, Kumar P, et al. A Phase 2 Study of Chronocort(R), a Modified-release 
Formulation of Hydrocortisone, in the Treatment of Adults with Classic Congenital Adrenal 
Hyperplasia. J Clin Endocrinol Metab. 2015;100(3):1137-1145. 
 
Merke DP, Cutler GB Jr. New ideas for medical treatment of congenital adrenal hyperplasia. 
Endocrinol Metab Clin North Am. 2001;30(1):121-135. 
 
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-2136.  
 
Moran C, Azziz R, Carmina E, et al. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia 
is a progressive disorder: a multicenter study. Am J Obstet Gynecol. 2000;183(6):1468-1474. 
 
New MI. Nonclassical congenital adrenal hyperplasia and the polycystic ovarian syndrome. 
Ann NY Acad Sci. 1993;687:193-205.  
 

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New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin 
Endocrinol Metab. 2006;91(11):4205-4214.  
 
Pang S, Clark A, Neto EC, 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);105-139. 
 
Ross RJ, Rostami-Hodjegan A. Timing and type of glucocorticoid replacement in adult 
congenital adrenal hyperplasia. Horm Res. 2005;64(Suppl 2):67-70.  
 
Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21 
hydroxylase deficiency. Am J Hum Genet. 1985;37(4):650-667.  
 
Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349(8):776-788.  
 
Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin 
North Am. 2001;30(1):15-30.  
 
Whitaker MJ, Debono M, Huatan H, et al. An oral multiparticulate, modified-release, 
hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin 
Endocrinol (Oxf). 2014;80(4):554-561. 
 
 
 
 
 
 
 
 

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Appendix 1 – Standard Safety Haematology and Clinical Chemistry 
Parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry  
 
Sodium, potassium, chloride, total CO2, creatinine, glucose, blood urea nitrogen (BUN), 
albumin, total calcium, total magnesium, inorganic phosphorus, alkaline phosphatase, 
ALT/GPT, AST/GOT, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total 
protein, total creatine kinase (CK), uric acid, total cholesterol, high density lipoprotein 
(HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides. 
 
 
Haematology 
 
Complete blood count (CBC): 
Red blood cell count (RBC), red cell distribution width (RDW), haemoglobin (Hb), 
haematocrit (Hct), mean corpuscular volume (MCV), mean cell haemoglobin (MCH), mean 
cell haemoglobin concentration (MCHC) platelet count, white blood cell count (WBC), 
WBC differential count (% and  absolute). 
 
 

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Appendix 2 - Expected Adverse Events 
 
The active ingredient of Chronocort® is hydrocortisone. The safety profile of hydrocortisone is 
well characterised in humans and there is extensive clinical experience with the use of 
hydrocortisone in subjects with CAH. The excipients used in the Chronocort® formulation are 
also well-characterised and approved for use in humans at the proposed levels. The risks of 
Chronocort® are, therefore, expected to be no greater than the risks of an equivalent dose of 
cortisol.  
 
: The active ingredient of Chronocort® is 
hydrocortisone. The safety profile of hydrocortisone is well characterized in humans and there 
is extensive clinical experience with the use of hydrocortisone in subjects with CAH. The 
excipients used in the Chronocort® formulation are also well-characterized and approved for 
use in humans at the proposed levels. The risks of Chronocort® are, therefore, expected to be 
no greater than the risks of an equivalent dose of cortisol. However, until the safety, efficacy 
and tolerability of this formulation in the treatment of individuals with CAH has been 
proven, the risk is considered to be greater than minimal rsk with the prospect of direct 
benefit in indidivual subjects. 
 
The following is reproduced from section 4.8 of a generic hydrocortisone SmPC:  
 
The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal 
suppression correlates with the relative potency of the drug, dosage, timing of administration 
and the duration of treatment. The following side effects may be associated with the long-term 
systemic use of corticosteroids: 
 
Gastrointestinal: 
Dyspepsia, peptic ulceration with perforation and haemorrhage, abnormal distension, 
oesophageal ulceration, candidiasis, acute pancreatitis. 
 
Musculoskeletal: 
Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, 
tendon rupture. 
 
Fluid and electrolyte disturbance: 
Sodium and water retention, hypertension, potassium loss, hypokalaemic alkalosis. 
 
Dermatological: 
Impaired healing, skin atrophy, bruising, striae, acne, telangiectasia. 
 
Endocrine/metabolic: 
Suppression of the hypothalamo-pituitary-adrenal axis, growth suppression in infancy, 
childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, 
hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for 
antidiabetic therapy, negative protein and calcium balance, and increased appetite. 
 

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Neuropsychiatric: 
Euphoria, psychological dependence, depression, insomnia and aggravation of schizophrenia. 
Increased intracranial pressure with papilloedema in children (pseudotumour cerebri), usually 
after treatment withdrawal. Aggravation of epilepsy. 
 
Ophthalmic: 
Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, 
corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases. 
 
Cardiovascular: 
Myocardial rupture following recent myocardial infarction. 
 
General: 
Hypersensitivity, including anaphylaxis has been reported. Nausea, malaise, leucocytosis, 
thromboembolism. 
 
Withdrawal symptoms: 
Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute 
renal insufficiency, hypotension and death. A withdrawal syndrome may also occur including 
fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin modules and weight loss. 
 
A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, 
depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, 
delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, 
irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and 
amnesia have been reported. Reactions are common and may occur in both adults and children. 
In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological 
effects have been reported on withdrawal of corticosteroids; the frequency is unknown. 
 
 
In addition, 3 out of 16 subjects in a phase 2 study of Chronocort® had symptoms of carpal 
tunnel syndrome (median nerve compression), which may be related to fluid retention 
secondary to Chronocort® treatment. 
 
 
 

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Appendix 3 - Sick Day Rules 
 
Each site should follow their own sick day 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 10mg Hydrocortisone 
three times a day in addition to the usual daily dose of Chronocort®. 
 
Fever greater than or equal to 101°F (38.3°C)/ more severe illness: take 20mg Hydrocortisone 
three times a day in addition to the usual daily dose of Chronocort®.  
 
Vomiting: If you vomit, wait one half-hour and then take 20mg of hydrocortisone for sick day 
rules from your packet provided. If you vomit the Chronocort® dose do not take another dose 
of Chronocort® 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 - 2mL 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 behaviour, 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 4 - 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 5 - SF-36® 
 
 

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Appendix 6 - MAF 
 
 
 
 
 
 

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Appendix 7 – EQ-5D Health Questionnaire 
 
 
 

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Appendix 8 – Labelling of IMP and Rescue Medication 
 
Examples of the label text are provided below. 
 
EU Primary (Blister) label (version number: DIUR-006.IMP.EU.01.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., 
 
PI: 
 
CRO: 
 
 
Dose instruction: The morning dose of Chronocort® should be taken on an empty stomach at 
least 1 hour before a meal and the evening dose should be taken at least 2 hours after the last 
meal of the day 
Batch No.: XXXX 
Protocol No.: DIUR-006       
Subject No.: YY 
EudraCT No. 2015-005448-32 
Keep out of reach of children 
 
EU Secondary label (version number: DIUR-006.IMP.EU.02.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Quantity: 100 capsules 
Batch No.: XXXX 
Storage: Store at no more than 25°C 
Expiry: MM/YYYY 
Protocol No.: DIUR-006         
Subject No.: YY  
 
Pack No.: YY 
Directions for use: For oral administration. The morning dose of Chronocort® should be taken 
on an empty stomach at least 1 hour before a meal and the evening dose should be taken at 
least 2 hours after the last meal of the day 
For clinical trial use only 
Investigator: 
 
Sponsor: Diurnal Ltd., 
  
CRO: 
 
 
EudraCT No. 2015-005448-32 
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
 
 
 
 

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EU Primary (Bottle) label (version number: DIUR-006.IMPBOT.EU.01.003) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., 
 
PI: 
 
Dose instruction: The morning dose of Chronocort® should be taken on an empty stomach at 
least 1 hour before a meal and the evening dose should be taken at least 2 hours after the last 
meal of the day 
Quantity: 50 capsules 
Batch No.: XXXX 
Expiry: MM/YYYY 
Protocol No.: DIUR-006       
Subject No.: YY 
Bottle/Pack No.: XX/YYYY 
EudraCT No. 2015-005448-32 
Keep out of reach of children 
 
EU Secondary label (version number: DIUR-006.IMPBOT.EU.02.003) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Quantity: 100 capsules 
Batch No.: XXXX 
Storage: Store at no more than 25°C 
Expiry: MM/YYYY 
Protocol No.: DIUR-006         
Subject No.: YY 
Pack No.: YY 
Directions for use: For oral administration. The morning dose of Chronocort® should be taken 
on an empty stomach at least 1 hour before a meal and the evening dose should be taken at 
least 2 hours after the last meal of the day 
For clinical trial use only 
Investigator: 
 
Sponsor: Diurnal Ltd.,
  
EudraCT No. 2015-005448-32 
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
 
EU safety pack label (version number: DIUR-006.SAFE.EU.02.003) 
 
Protocol No.: DIUR-006         
Subject No.: YY  
 
Contents: YY 
Sponsor: Diurnal Ltd., 
 
PI: 
 
EudraCT-No. 2015-005448-32 

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US Primary (Blister) label (version number: DIUR-006.IMP.US.01.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., 
 
PI: 
 
CRO: 
 
 
Dose instruction: The morning dose of Chronocort® should be taken on an empty stomach at 
least 1 hour before a meal and the evening dose should be taken at least 2 hours after the last 
meal of the day 
Batch No.: XXXX 
Protocol No.: DIUR-006         
Subject No.: YY 
IND No.: 076485 
Keep out of reach of children 
CAUTION: New Drug Limited by Federal (or United States Law) for Investigational Use 
 
US Secondary label (version number: DIUR-006.IMP.US.02.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Quantity: 100 capsules 
Batch No.: XXXX 
Storage: Store at no more than 25°C 
Expiry: MM/YYYY 
Protocol No.: DIUR-006    
Subject No.: YY 
Pack No.: YY      
IND No.: 076485 
Directions for use: For oral administration. The morning dose of Chronocort® should be taken 
on an empty stomach at least 1 hour before a meal and the evening dose should be taken at 
least 2 hours after the last meal of the day 
Investigator: 
 
Sponsor: Diurnal Ltd., 
  
CRO: 
 
 
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
CAUTION: New Drug Limited by Federal (or United States Law) for Investigational Use 
 
 
 

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US Primary (Bottle) label (version number: DIUR-006.IMPBOT.US.01.003) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., 
 
PI: 
 
Dose instruction: The morning dose of Chronocort® should be taken on an empty stomach at 
least 1 hour before a meal and the evening dose should be taken at least 2 hours after the last 
meal of the day 
Quantity: 50 capsules 
Batch No.: XXXX 
Expiry: MM/YYYY 
Protocol No.: DIUR-006         
Subject No.: YY 
Bottle/Pack No.: XX/YYYY 
IND No.: 076485 
Keep out of reach of children 
CAUTION: New Drug Limited by Federal (or United States Law) for Investigational Use 
 
US Secondary label (version number: DIUR-006.IMPBOT.US.02.003) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Quantity: 100 capsules 
Batch No.: XXXX 
Storage: Store at no more than 25°C 
Expiry: MM/YYYY 
Protocol No.: DIUR-006    
Subject No.: YY 
Pack No.: YY      
IND No.: 076485 
Directions for use: For oral administration. The morning dose of Chronocort® should be taken 
on an empty stomach at least 1 hour before a meal and the evening dose should be taken at 
least 2 hours after the last meal of the day 
Investigator: 
 
Sponsor: Diurnal Ltd., 
  
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
CAUTION: New Drug Limited by Federal (or United States Law) for Investigational Use 
 
US safety pack label (version number: DIUR-006.SAFE.US.02.003) 
 
Protocol No.: DIUR-006      
Subject No.: YY  
 
Contents: YY      
Sponsor: Diurnal Ltd., 
 
PI: 
 
IND No.: 076485 
 

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Appendix 9 – Protocol Amendment History 
 
Protocol Version 1.0 dated 22 December 2015 
Original protocol. 
 
Protocol Version 2.0 dated 20 June 2016 
 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
 to 
. 
 
2) In response to comments from the MHRA, it has been clarified that the assessments at 
Week 18 and then 3-monthly thereafter are not a formal study visits and just comprise 
telephone calls to check on the welfare of the subject. This has been added as a footnote 
to Table 1 and revised text in  Section 11.1.9. 
 
3) The protocol originally stated that subjects would continue in the study until a decision 
was reached concerning a marketing authorisation for Chronocort® in the relevant 
territory. This open-ended study design was not considered acceptable to the MHRA so 
the protocol has been revised to state that the length of the study will be 2.5 years from the 
date of the first subject entering the study, so subjects will be treated for a maximum of 
2.5 years. If after this time point a decision has not been reached concerning a marketing 
authorisation for Chronocort®, a further extension of the study through a protocol 
amendment may be considered. 
 
Protocol Version 3.0 dated 26 July 2016 
 
1) Different clinicians use different conversion factors for dexamethasone to hydrocortisone. 
The protocol states that ‘The initial dose setting at the start of Chronocort® treatment will 
be made on hydrocortisone dose equivalent of baseline therapy, with the hydrocortisone 
dose calculated as dexamethasone dose multiplied by 80’. Investigators and Diurnal have 
been concerned that this may lead to a safety issue that if patients on a higher dose of 
dexamethasone were converted by x80 they would be exposed to excess hydrocortisone, 
therefore a greater mineralocortiocoid effect, and be at risk of being overdosed. Therefore 
the protocol was amended to state that the current conversion rate of x80 should be used 
as per protocol up to a maximum starting dose of Chronocort® 30mg (split 20mg at night 
and 10mg in the morning). The justification for the maximum of 30mg Chronocort® is 
based on the fact this was the starting dose for all patients in the Phase 2 study (DIUR-003) 
(Mallappa 2015) and is in line with recommendations for hydrocortisone dosing in CAH 
(Speiser 2010). If the investigator has any concerns regarding the starting dose in a patient 
then these can be discussed with the Medical Monitor. 
 
2) Subjects entering from study DIUR-005 had to have genotyping conducted at entry to the 
DIUR-005 feeder study or the information could be retrieved from the patient notes if 
genotyping had been done in the past. However, subjects were not required to have 
genotyping at entry into study DIUR-003. As a result, this protocol was amended to either 
obtain a blood sample for genotyping at screening, if necessary, or if previous genotyping 
had been performed the patient was to be asked for their permission for this information 
to be taken from their medical records. 

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3) Subjects who routinely work night shifts and so do not sleep during the usual nighttime 
hours was added to the exclusion criteria.  
 
4) In the synopsis, Section 8 (Study Design) and Section 10.4 (Dose Adjustment) it was stated 
that ‘Dose adjustment will not take place without measurement of androgens at an inpatient 
visit,  unless the local investigator considers it is indicated by the severity of symptoms.’ 
However, this statement was considered confusing and also seemed to mandate the 
measurement of androgens at an unscheduled dose adjustment, which was not the case. 
The text was therefore revised to say ‘No dose adjustments outside of the protocol-defined 
dose adjustments should be conducted, unless clinical signs and symptoms indicate an 
immediate need. In such cases the Sponsor’s medical monitor must be contacted 
(preferably before any dose changes are implemented). Any such unscheduled dose 
adjustments should be based on clinical symptoms only, with repeated androgen testing 
discouraged and must be pre-approved by the Sponsor’s medical monitor.’ 
 
5) In Section 11.2 for DEXA scans, it is stated that a DEXA scan has to be conducted at the 
final visit. This is an error since DEXA scans are required annually and not automatically 
at the final visit.  
 
6)  A follow-up telephone call 30 days after the final visit has been added to collect 
information on any AEs occurring within this 30-day post-treatment period. This change 
has been made to the study schedule in Table 1 and in Section 11.1.11. 
 
7) The maximum planned blood volume to be drawn at each visit has been increased from 
20 mL to 40 mL following a recalculation of the volume of blood needed at each visit. 
 
8) The AE reporting period after the last dose of study medication was extended from 7 days 
to 30 days.  
 
9) Clarified that the statement “If the Chronocort® dose is changed at any point, the subject 
should have an interim visit which includes the assessments noted for Week 4, after which 
they will then continue with visits every 6 months” only applies after the Week 24 visit 
onwards. The text has therefore been revised to the following “If the Chronocort® dose is 
changed at any point after the Week 24 visit, the subject should have an interim visit 
which includes the assessments noted for Week 4, after which they will then continue with 
visits every 6 months.” 
 
10) The term ‘safety analysis set’ used in Section 13.2 to describe the analysis population was 
renamed ‘full analysis set’ to match the statistical analysis plan.  
 
11) The telephone number of 
 was added and the international dialing code was 
added to the fax number. 
 
Protocol Version 4.0 dated 23 September 2016 
 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
 to 
. 

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2) The Chronocort® capsules may now be supplied in either blister packs or bottles. 
Therefore, Section 10.2.2 (Packaging and Labelling) and Appendix 9 (Labelling) were 
updated. 
 
3) For accountability purposes, all used and unused packs of study medication will be stored 
in a secure location. However, this does not have to be in the pharmacy. Section 10.2.4 has 
therefore been amended to correct this. 
 
Protocol Version 5.0 dated 04 November 2016 
 
The following changes were made to the protocol: 
 
1)  Section 11.7 states that subjects who become pregnant during the study may continue to 
receive Chronocort® outside of the study after discussion with the sponsor and if the 
investigator considers this is in the best interest of the subject. However, in Sweden use of 
Chronocort® is not allowed for pregnant women once they are withdrawn from the study 
so it has been added that all subjects who become pregnant in Sweden must be switched 
to standard care. 
 
2) Section 11.7 stated that data would be collected on subjects continuing Chronocort® 
through the pregnancy, although not all the assessments required in this study will be 
performed (e.g. DEXA scans will not be performed). This text was removed and replaced 
with a link to Section 12.12, which describes in more detail the collection of data during 
pregnancy. 
 
3) Protocol Version 3.0 (dated 26 July 2016) extended the AE reporting period at the end of 
the study from 7 days to 30 days. As such the definition of the end of the study in 
Section 11.8 has been revised to say that the end of the study will be the final telephone 
call (30 days after the last visit) of the last subject. Section 12.2 has also been revised to 
state that AEs will be collected for all subjects from the time of consent up to 30 days after 
the last visit, rather than as previously stated up to 30 days after the end of the study.  
 
4). Section 14.2 states that all essential documents will be archived for a minimum of 5 years 
after completion of the study. However, according to Swedish legislation the minimum 
reporting period is 10 years, so this has been added to this section. 
 
5). The responsible statistician was changed from 
 to 
. 
 
Protocol Version 6.0 dated 12 May 2017 (non-substantial amendment for France only) 
 
1) It was noted that the first inclusion criterion was worded slightly differently in the synopsis 
and in the main protocol. The wording in the main protocol was therefore revised to match 
the synopsis and now states "Subjects with CAH who have successfully completed the 
DIUR-003 or DIUR-005 clinical trials with the current formulation of Chronocort®." 
 

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Protocol Version 7.0 dated 21 June 2017 
 
The following changes were made to the protocol: 
 
1)  Due to delays in the supply of study medication for this study, some subjects entering from 
study DIUR-005 had to be treated with standard glucocorticoid therapy for a short period. 
Such subjects will then need to have the safety blood tests and adrenal hormone levels 
assessed at the baseline visit for study DIUR-006 rather than using the results from Visit 4 
of study DIUR-005 i.e. these subjects will be treated in the same way as subjects who are 
entering from study DIUR-003, with the exception that a DEXA scan at the DIUR-006 
baseline visit will not be needed for subjects with a gap between completing study 
DIUR-005 and starting study DIUR-006. In all cases where a gap occurs, the subject 
should be entered into study DIUR-006 as soon as possible. This change has been 
implemented in various sections of the protocol. 
 
2) The sample size in study DIUR-005 was increased from 110 to 120 subjects due to a higher 
level of protocol deviations than originally anticipated. As such, the maximum number of 
subjects eligible to enter this extension study is increased from 126 to 136 subjects. 
 
3) It was noted that the first inclusion criterion was worded slightly differently in the synopsis 
and in the main protocol. The wording in the main protocol was therefore revised to match 
the synopsis and now states "Subjects with CAH who have successfully completed the 
DIUR-003 or DIUR-005 clinical trials with the current formulation of Chronocort®." Note: 
this change was implemented in France in protocol version 6.0. 
 
4) Clarification has been added that female subjects presenting with oligomenorrhoea or 
amenorrhoea who are aged ≤55 years of age should be considered potentially fertile and 
therefore should still undergo pregnancy testing like all other female subjects. 
 
5) 
Some events may occur during the study that represent an improvement in the subject's 
condition e.g. restoration of menses. To ensure sufficient details of such events are 
recorded, Section 12.9 has been updated to state that these events will be reported in the 
same manner as SAEs in order to capture the data in real time, together with additional 
data, if this should be required. However these events will not be reported to the regulatory 
authorities as SAEs.  
 
6) 
After the Week 24 visit, the study visits should occur every 6 months, with interim 
telephones at approximately 3 months in between each visit. However, Week 24 is not a 
full 6 months so the visits do not fall regularly at 6-monthly intervals thereafter. To 
overcome this, the visit windows from Week 18 onwards will be extended to ±2 weeks to 
allow flexibility in scheduling the visits so they can occur at 6-monthly intervals. 
 
7) 
The change added in protocol amendment 4 to allow Chronocort® capsules to be supplied 
in either blister packs or bottles has been removed since Chronocort® capsules will now 
only be supplied in blister packs. 
 
8) The definition of pre-Chronocort® baseline in the synopsis and Section 7.2 was revised to 
match the SAP as following: 
  
Pre-Chronocort® baseline means prior to the first dose of continuous Chronocort® which 

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is: 
o The reassessed baseline under DIUR-006 for subjects entering from study 
DIUR-003 and those subjects from DIUR-005 who had a gap between 
completing study DIUR-005 and starting study DIUR-006, 
o Visit 4 (Week 24) from the feeder study for subjects who received standard 
glucocorticoid replacement therapy in study DIUR-005 and immediately 
entered DIUR-006, 
o Prior to the first  Chronocort® dose in study DIUR-005 for subjects who 
received Chronocort® in study DIUR-005 (i.e. DIUR-005 baseline visit) and 
immediately entered DIUR-006. 
 
9) In the synopsis, it incorrectly stated that summary statistics for vital signs and laboratory 
values would be presented by dose. This analysis by dose is not included in later sections 
of the protocol or the SAP so this has also been removed from the synopsis for consistency. 
 
10) In Section 13.6.1 it was stated that shift tables from baseline to each time point would be 
presented. However, to bring this in line with the SAP this has been changed to state that 
shift tables from baseline to the maximum and minimum on-treatment values will be 
presented. 
 
11) Interim data analyses are expected to be required for regulatory review as part of any 
marketing authorisation applications. However, no changes to the overall study conduct 
and no changes to the planned formal statistical analyses are anticipated as a result. As 
such a statement to this effect was added to the statistical methods section of the synopsis 
and in Section 13. 
 
Protocol Version 8.0 dated 23 August 2017 (administrative local amendment for US only) 
 
Following comments from the IRB, an additional statement has been added in Appendix 2 
(Expected Adverse Events) amending the risk category from 'minimal risk with the prospect of 
direct benefit to individual subjects' to 'greater than minimal risk with the prospect of direct 
benefit to individual subjects'. This is administrative change at the 
 in the 
US only and has arisen due to an error in the NIH IRB classification at the beginning of the 
study (i.e. there is no actual change to the benefit/risk assessment). 
 
Protocol Version 9.0 dated 08 November 2017 
 
The following changes were made to the protocol: 
 
1)  Due to a clerical error, the maximum amount of blood to be drawn at any one study visit 
was incorrectly stated as 40 mL in the protocol, but in fact up to 49 mL was taken for some 
visits as per the laboratory manual. The protocol has therefore been corrected so it is 
consistent with the laboratory manual and describes the maximum allowable amount of 
blood that can be taken at any one visit. 
 
2) Section 11.1.9 has been revised to allow for subjects to be issued with 6 months supply of 
Chronocort® at each visit after Week 18 rather than subjects having to return to the study 
centre to collect new supplies every 3 months. The option to collect supplies from a local 
pharmacy instead has been removed since this was not practical in terms of drug 

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accountability and put adequate control of shipping conditions at risk. This change has 
also been made to Table 1 and at all other relevant places in the protocol. 
3) Section 13.2 (Analysis Sets) has been updated to include an interim analysis set which will 
be used for any interim analyses carried out in this study. 
 
4)  Clarified in the protocol that any use of medication from the safety pack will be recorded 
for drug accountability purposes and any such use should also be recorded on the sick day 
medication page of the eCRF. 
 
5) In Table 1 an 'X' has been added at the Screening Visit for collection of AE and SAEs to 
be consistent with footnote 12 (which states AEs and SAEs are recorded from the time of 
informed consent). Footnote 8 also revised to clarify that dose adjustments also take into 
account clinical symptoms assessed using the signs and symptoms of adrenal insufficiency 
questionnaire. 
 
6) Clarified in Section 11.1.1 and Table 1 that any prior genotyping information collected 
from DIUR-003 subjects will be recorded in the eCRF. 
 
7) Clarified in Section 11.1.2 and in Table 1 that the last glucocorticoid dose taken prior to 
the baseline visit should be recorded, with details of the drug(s), dose and time of 
administration being recorded in the eCRF. 
 
8) Clarified in Section 11.1.2 that the prednisone conversion to Chronocort® of x5 should 
also apply to prednisolone, i.e. prednisone and prednisolone dose multiplied by 5. 
 
9) Clarified in Section 14.12 that all communications between the sponsor, designated study 
representative, and investigators should be documented in the TMF. 
 
10) Clarified in Section 14.15 that the investigator is required to maintain all study 
documentation for two years following the approval date of a Marketing Authorisation 
Application, as well as for a New Drug Application. 
 
11) Some of the dates of the protocol amendments in Appendix 9 were incorrect so these have 
been corrected. 
 
Protocol Version 10.0 dated 21 August 2018 
 
The following changes were made to the protocol: 
 
1) Project Manager changed from 
 to 
. 
 
2) Since a decision concerning a marketing authorisation for Chronocort® has not yet been 
reached, the estimated end of the study has been extended by 1 year. Thus the total length 
of the study will be now be 3.5 years from the date of the first subject entering the study 
i.e. from August 2016 until February 2020.  
 

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3) An end date for enrolment has been added to ensure all patients are enrolled promptly and 
sufficient data are obtained before the end of the study. So it is now specified all subjects 
must be enrolled by 31 October 2018, with no subjects allowed to enter the study after this 
date. 
 
4) Section 5.5 (Overview of Chronocort® clinical studies): description of study DIUR-007 
has been updated to reflect the final design of this study. 
 
5) Section 10.2.1 (Chronocort® formulation) has been revised to state that the Chronocort® 
capsules may be printed with either 'CHRONOCORT 5mg/10mg/20mg' or 'CHC 
5mg/10mg/20mg' on the capsule body. 
 
6) Sections 10.2.2 (Packaging and Labelling) and 10.5 (Other Study Medications [Non-
Investigational Medicinal Products]): Some centres do not allow the pharmacist to write 
the subject numbers on the safety packs (printed labels have to be used) so the sentence 
"The subject number will be written on the study pack by the pharmacist" has been deleted.  
 
7) Section 10.5 (Other Study Medications [Non-Investigational Medicinal Products]): the 
wording of the first bullet point has been revised to make the statement more general, thus 
just stating that a supply of oral hydrocortisone will be provided that would allow dosage 
of up to 20 mg three times daily. 
 
8) Section 11.7 states that subjects who become pregnant during the study may continue to 
receive Chronocort® outside of the study after discussion with the sponsor and if the 
investigator considers this is in the best interest of the subject. Previously it was added that 
in Sweden, the use of Chronocort® is not allowed for pregnant women once they are 
withdrawn from the study, so subjects who become pregnant in Sweden must be switched 
to standard care. The criterion has now been added for the US as well, so subjects who 
become pregnant in Sweden and the US must be switched to standard care. 
 
Protocol Version 11.0 dated 25 January 2019 
 
The IRB at the NIH centre in the US requested details of study DIUR-007 to be removed from 
the protocol since this study is currently suspended. This change is considered an 
administrative change only. A few other minor administrative changes were also made at the 
same time as follows: 
 
1) The Sponsor signatory was changed from 
 to 
. 
 
2) The Project Manager was changed from 
 to 
. 
 
3) The contact details for the Sponsor's Medical Expert were updated. 
 
4) Section 5.5 (Overview of Chronocort® clinical studies) has been revised to remove the 
reference to study DIUR-007, since this study is currently suspended. The paragraph on 
study DIUR-005 has also been revised since this study has now been completed and 
reporting of the results is ongoing. 
 

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Protocol Version 12.0 dated 04 September 2019 
 
The following changes were made to the protocol: 
 
1) The statistician has changed from 
 to 
. 
 
2) The name of the CRO being used has changed its name from 
to 
so this has 
been changed throughout. 
 
3) Synopsis, Section 9.1 (Number of Subjects and Subject Selection) and Section 13.7 
(Power and Sample Size Considerations) - since study DIUR-005 has now finished, the 
actual number of participants enrolled in this study can be added (a total of 122 
participants). As such, the maximum number of subjects potentially eligible to enter this 
extension study is increased from 136 to 138 subjects. 
 
4) Synopsis and Section 11.8 (Study Duration and Completion of the Study) - since a decision 
concerning a marketing authorisation for Chronocort® has not yet been reached, the 
estimated end of the study has been extended until February 2022. Thus the total length of 
the study will be now be approximately 5.5 years from the date of the first subject entering 
the study i.e. from August 2016 until February 2022.  
 
5) Synopsis, Section 8 (Study Design), Section 8.1 (Dose Titration Algorithm), Section 10.4 
(Dose Adjustments), Section 11 (Study Procedures), Section 11.1.4 (Telephone call 
(within 2 weeks of Visit 2)), Section 11.1.6 (Telephone call (within 2 weeks of Visit 3)), 
Section 11.1.7 (Week 24 and then every 6-months (± 2 Weeks)), and Section 11.1.8 
(Telephone call (within 2 weeks of previous visit)) - if the Chronocort® dose is changed at 
any point after the Week 24 visit, the subject was previously required to have an interim 
dose titration visit where the assessments noted for Week 4 were required to be repeated. 
However, this has now been replaced with an option to perform either an interim dose 
titration visit or a telephone call to check on the well-being of the subject. The same 
assessments as noted for the Week 4 visit will be performed at the interim dose titration 
visit. If an interim dose titration telephone call is used instead, blood sampling for 17-OHP 
and A4 and the urine pregnancy test will not be performed but all other Week 4 
assessments will be performed. 
 
6) Synopsis, Section 6.2 (Secondary Objectives), Section 7.2 (Secondary Endpoints), Section 
13.3.2 (Secondary Endpoints) and Section 13.6.2 (Efficacy) - during the interim analyses 
for this study, two additional exploratory analyses were added to the SAP to further 
explore the pattern of Chronocort® dosing (based on the proportion of the dose given at 
night and the dose by body surface area). These new analyses have therefore been added 
to the protocol for consistency with the SAP. 
 
7) Section 5.5 (Overview of Chronocort® clinical studies) - summary of the results from study 
DIUR-005 added. 
 
8) Section 10.2.2 (Packaging and Labelling) and Appendix 8 (Labelling of IMP and Rescue 
Medication) - the Chronocort® capsules may now be supplied in either blister packs or 
bottles so these sections have been updated. In addition, the label text in Appendix 8 has 
been updated to the latest label text.  

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9) Section 12.5 (Assessment of Adverse Event Causality/Relatedness) - a new category of 
"related to study medication from previous Chronocort study" has been added for any AEs 
that might occur in participants who have recently joined the DIUR-006 study from one 
of the feeder studies. 
 
10) Section 12.6 (Assessment of Adverse Event Expectedness) - the definition of 
“unexpected” was updated to reference the RSI in the Investigator's Brochure. 
 
11) Section 13.2 (Analysis Sets) - clarified the different definitions for the 'Interim Analysis 1' 
data set and subsequent interim analysis data sets.  
12) Section 13.3.2 (Secondary Endpoints) - clarified the testosterone will be analysed for 
males and females separately. 
13) Section 14.12 (Study Monitoring) - study monitoring will be moved to a risk-based 
monitoring approach, with full details of this methodology included in the Monitoring 
Plan. 
14) Appendix 2 (Expected Adverse Events) - the reference to the SmPC of hydrocortisone for 
expected AEs has been removed since this is no longer used in the RSI. 
 
15) Some minor administrative and consistency changes have been made throughout the 
protocol.  
 
Protocol Version 13.0 dated 24 October 2019 
 
The following changes were made to the protocol: 
 
1) Section 4 (Investigators and Administrative Structure) and Appendix 8 (Labelling of IMP 
and Rescue Medication) - the CRO has been changed from
 to 
 
 
 
2) Appendix 5 (SF-36®) - the script version of the SF-36® was replaced with the validated 
paper questionnaire. 
 
3) Appendix 8 (Labelling of IMP and Rescue Medication) - the pack number has been added 
to the EU and US primary bottle labels. 
 
Protocol Version 14.0 dated 17 Apr 2020 
 
The following changes were made to the protocol: 
 
1) Section 11 (Study Procedures) - footnote 11 added to DEXA scan assessment to make it 
clear the DEXA scans are only needed once a year 
 
2) Section 11 (Study Procedures) - new footnote 17 added to indicate that Baseline and 
Week 4 visits are repeated for subjects who re-enter the study post-pregnancy. 
 
3) Section 11.7 (Pregnancy) - subjects who become pregnant must still be withdrawn from 
the study, but they are now allowed to re-enter the study 6 weeks after the pregnancy is 
complete (i.e. 6 weeks post-partum regardless of outcome or 6 weeks after abortion or 

Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-006 
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Diurnal Ltd 
 
 
Version: 20.0 – 16 Jun 2022 
 
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termination) or 6 weeks after they have finished lactating and are no longer breast feeding. 
Details of re-entry into the study and of the post-pregnancy visits are also included. 
 
4) Section 4 (Investigators and Administrative Structure), Section 11.7 (Pregnancy), Section 
12.9 (Serious Adverse Event Reporting) and Section 12.10.1 (Standards for Expedited 
Reporting) - updated 
 to 
 and updated email address 
 
 
5) Section 4 (Investigators and Administrative Structure) and Section 12.9 (Serious Adverse 
Event Reporting) - contact details for 
 (Medical Monitor) updated. 
 
6) Appendix 8 (Labelling of IMP and Rescue Medication) - expiry date and bottle number 
added to the example bottle labels to reflect the bottle labels being used. 
 
Protocol Version 15.0 dated 17 Aug 2020 
 
1) 
Section 11.7 (Pregnancy) - clarified that the time period before pregnant subjects can 
re-enter the study is at least 6 weeks.  
 
2) 
Section 11.8 (Study Duration and Completion of the Study) - clarified that the end of the 
study will be the final telephone call (30 days after the last visit) of the last subject, i.e. 
March 2022. 
 
3) 
Section 11.10 (Subject Diaries) - added that subject will be provided with an ad hoc diary 
in which they will be asked to record any use of sick day medications and to record any 
AEs that occur between study visits. 
 
4) 
Section 11.11 (COVID-19 Procedures) - new section added to describe the interim 
measures put in place to enable the study to continue during the COVID-19 restrictions.  
 
5) 
Section 13 (Statistical Considerations) - section updated in line with changes made to the 
SAP (Version 4.0 dated 13 Jul 2020). 
 
6) 
Section 13.1.3 (Missing Outcome Data) - the window around the blood sampling times 
for analysis of 17-OHP and A4 at 09:00 and 13:00 have been increased from half an hour 
to 1 hour. 
 
7) 
Section 14.12 (Study Monitoring) - the option to conduct remote monitoring has been 
added, with SDV conducted using the subject’s electronic medical records or using 
scanned documents, if either are permitted. 
 
Protocol Version 16.0 dated 28 Jun 2021 
 
1) Section 4 (Investigators and Administrative Structure) – address for 
 
 updated. 
 
2) Section 10.6 (Permitted Concomitant Medications/Treatments) - clarification has been 
added for what should happen if a participant receives a COVID-19 vaccine to bring the 

Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
 
Version: 20.0 – 16 Jun 2022 
 
Page 95 of 96 
 
 
protocol in line with the latest MHRA guidance on COVID-19 vaccinations and clinical 
trials. 
 
3) Section 11 (Study Procedures) and Section 11.1.10 (Final Visit or Early Withdrawal Visit) 
– added that if the end of study visit is within 3 months after a scheduled 6-monthly visit 
then only minimal safety assessments (AE and SAE collection only) will be performed. 
 
4) Section 11.1 (Visit Schedule) – added that if a participant has received the COVID-19 
vaccine then the next visit must be scheduled at least 5 days post-vaccine. 
 
5) Section 11.7 (Pregnancy) – added that the first dose of Chronocort after re-entry following 
pregnancy should be taken in the evening of the first dosing day. 
 
6) Section 11.11 (COVID-19 Procedures) – clarified that the specified COVID-19 measures 
can only be implemented after Sponsor approval has been obtained. 
 
7) Appendix 8 (Labelling of IMP and Rescue Medication) – bottle labels updated to reflect 
current labels in use.  
 
Protocol Version 17.0 dated 29 Apr 2022 
 
1) Section 4 (Investigators and Administrative Structure), Section 11.7 (Pregnancy), Section 
12.9 (Serious Adverse Event Reporting) and Section 12.10.1 (Standards for Expedited 
Reporting) – added that SAE and pregnancy reporting will change to 
 from April 
2022 onwards. 
2) Signature page, Section 4 (Investigators and Administrative Structure) – name and contact 
details for 
 statistician updated. 
 
Protocol Version 18.0 dated 25 May 2022 (applicable for USA and France only) 
Protocol signed off but not submitted - voided and protocol amendment 19 implemented 
instead. 
 
Protocol Version 19.0 dated 15 June 2022 (applicable for USA and France only) 
 
1) Synopsis, Section 8 (Study Design), Section 11 (Study Procedures), Section 11.1.11 
(Telephone call (30 days after final visit)) – added that at the end of the study subjects will 
have the option to enter a second long-term study (DIUR-015) to enable them to continue 
to receive open-label Chronocort® until it is commercially available in their region or it is 
decided to stop Chronocort® treatment. Subjects who decide to enter the DIUR-015 study 
immediately following this DIUR-006 study do not require a telephone call 30 days after 
the end of this study. If there is a gap between finishing this DIUR-006 study and entering 
the DIUR-015 study of greater than 30 days, then the 30-day telephone call is required. 
2) Section 11 (Study Procedures), Section 11.1.11 (Telephone call (30 days after final visit)), 
Section 12.9 (Serious Adverse Event Reporting) –  clarified that AEs and SAEs are reported 
until 30 days after the last dose of Chronocort® or until the subject starts receiving 
Chronocort® in the second long-term extension study (DIUR-015) if this is less than 
30 days after the end of dosing in this DIUR-006 study. 
 

Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-006 
Chronocort®  
      
Diurnal Ltd 
 
 
Version: 20.0 – 16 Jun 2022 
 
Page 96 of 96 
 
 
Protocol Version 20.0 dated 16 June 2022 (applicable for USA and France only) 
 
1) 
Section 11.8 (Study Duration and Completion of the Study) – end of study definition 
expanded to include the date the last subject enters the DIUR-015 extension study since 
these subjects won’t have the final telephone call 30 days after the last visit.