Conditions: Congenital Adrenal Hyperplasia
Keywords: Glucocorticoid therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

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

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

1. hydrocortisone only or
2. prednisone or prednisolone, alone or in combination with hydrocortisone
3. dexamethasone only or in combination with any other glucorticoid

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

Arms:
arm 1: Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect. arm 2: Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect.

Interventions: intervention 1: Chronocort® intervention 2: standard glucocorticoid therapy
Intervention descriptions: intervention 1: Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol. intervention 2: Subjects in this arm will continue on their standard hydrocortisone therapy

Protocol document:
Prot_000.pdf: 




Investigational product: 
 CONFIDENTIAL 
Protocol No.: DIUR-005 
Chronocort®  
      
Diurnal Ltd 
 
Page 3 of 91 
Version: Final 7.0 – 23 August 2017 
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 6, 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 
 
 
 
 
 
 
 




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Protocol No.: DIUR-005 
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1. Protocol Synopsis 
PROTOCOL TITLE: 
A Phase III study of efficacy, safety and tolerability of Chronocort® 
compared with standard glucocorticoid replacement therapy in the 
treatment of congenital adrenal hyperplasia (CAH) 
PROTOCOL No: 
DIUR-005 
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 
Parallel arm, randomised, open study 
INCLUSION CRITERIA 
1. Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood with 
documented (at any time) elevated 17-hydroxyprogesterone (17-OHP) and/or androstenedione (A4) 
and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a 
combination of the aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum 
of 6 months. 
2. Male or female subjects aged 18 and above. 
3. Provision of signed written informed consent. 
4. Non-pregnant, non-lactating females who are post menopausal, naturally or surgically sterile, or of 
childbearing potential with a negative urinary pregnancy test and using a medically acceptable method 
of contraception (Note: females presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 
years of age should be considered potentially fertile and therefore, as well as undergoing pregnancy 
testing like all other female subjects, will be expected to be using an acceptable method of 
contraception). 
5. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 
3 months prior to screening, except in subjects who have been diagnosed with hypertension where the 
renin is not being used to monitor fludrocortisone replacement. 
EXCLUSION CRITERIA 
1. Co-morbid condition requiring daily administration of a medication (or consumption of any material) 
that interferes with the metabolism of glucocorticoids. 
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or 
elevated liver function tests (ALT or AST >2 times the ULN). 
3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH. 
4. Subjects with any other significant medical or psychiatric conditions that in the opinion of the 
investigator would preclude participation in the trial. 
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry 
into the study). 
6. Participation in another clinical trial of an investigational or licensed drug or device within the 3 
months prior to inclusion in this study. 
7. Subjects with a history of bilateral adrenalectomy. 
8. Subjects having previously been exposed to Chronocort®. 
9. Subjects who routinely work night shifts and so do not sleep during the usual nighttime hours.  
10. Subjects unable to comply with the requirements of the protocol. 
STUDY DURATION: 
After screening and baseline evaluation, subjects will either be randomised to Chronocort® or continue their 
standard therapy. Treatment will continue for 6 months, during which times the glucocorticoid dose in both 
treatment groups will be titrated according to an agreed algorithm to optimise control of the disease. After 


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Protocol No.: DIUR-005 
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Page 6 of 91 
Version: Final 7.0 – 23 August 2017 
completion of the 6-month study period, all subjects may then enter a period of open-label treatment with 
Chronocort® as part of an open-label extension study (to be conducted under a separate protocol). 
NUMBER OF SUBJECTS: 
A sample size of 102 subjects provides greater than 95% power and 2-sided alpha 5% to demonstrate a fall in 
the logarithm of the mean daily unsigned standard deviation score of 17-OHP relative to the standard 
glucocorticoid replacement therapy group. It is assumed that (i) the mean fall in the Chronocort® group will be 
the same (0.78) as that observed in the phase II study (DIUR-003) (ii) the mean fall in the standard therapy 
group will be 0.2 (approximately 25% of the Chronocort® phase II study fall) and (iii) the standard deviation 
of the fall (0.681) is that seen in the phase II study. The study is powered to ensure that there can be a reasonable 
description of the comparison of Chronocort® with a variety of standard therapies. 120 subjects will be 
randomised to this study which will account for an inevaluability rate of 15%. Individual sites should not recruit 
more than 25 subjects without first consulting the sponsor. 
TEST PRODUCT, DOSE AND 
MODE OF ADMINISTRATION: 
Chronocort® will be provided as 5mg, 10mg and 20mg capsules for 
oral administration. The starting dose for each subject will be based 
on the subject’s previous glucocorticoid therapy dose and then dose 
titrated to effect. The morning dose of Chronocort® (approximately 
1/3rd of the total daily dose) should be taken at 07:00 hours on an 
empty stomach at least 1 hour before a meal and the evening dose 
(approximately 2/3rd of the total daily dose) should be taken at 23:00 
hours at least 2 hours after the last meal of the day.  
REFERENCE THERAPY, DOSE 
AND MODE OF 
ADMINISTRATION: 
Continuing previous oral glucocorticoid therapy titrated to effect. 
OBJECTIVES: 
Primary Objectives: 
To demonstrate the superior efficacy of Chronocort® compared with standard glucocorticoid replacement 
therapy in the treatment of CAH based on 17-OHP. 
Secondary Objectives: 
In adult subjects with CAH:  
 
To assess the safety and tolerability of Chronocort® treatment in adult subjects with CAH over a 
6-month period. 
 
To assess the efficacy of Chronocort® with regard to the effect on A4 over the 6-month treatment 
period. 
 
To assess the impact of Chronocort® on body composition (using dual energy X-ray absorbtimetry 
[DEXA]) – fat mass, lean mass and total bone density – at selected sites. 
Exploratory Objectives: 
 
To assess the efficacy of Chronocort® with regard to the effect on testosterone levels over the 6-month 
treatment period. 
 
To assess the impact of Chronocort® on cardiovascular (CV) risk (evaluated using high-sensitivity 
C-reactive protein [hsCRP]). 
 
To assess the impact of Chronocort® on bone markers of serum C-terminal cross-linked telopeptide 
(CTX) and osteocalcin (after fasting). 
 
To assess changes from baseline in glucose and insulin in the morning (after fasting) 
 
To assess changes from baseline in glycated haemoglobin (HbA1c) and PRA in the morning. 
 
To assess the impact of Chronocort® on quality of life (QoL) using SF-36®, Multidimensional 
Assessment of Fatigue (MAF), and EQ-5D™. 
 
To assess subject compliance in subjects treated with Chronocort® over a 6-month period. 
ENDPOINTS: 
Primary Endpoint:  
The primary efficacy endpoint is the change from baseline to 24 weeks of the mean of the 24-hour standard 
deviation score (SDS) profile for 17-OHP. The SDS profile is calculated as the SDS of log-transformed 
17-OHP concentration unsigned. 


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Secondary Endpoints: 
1. The change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4 (calculated in the 
same way as the primary endpoint). 
2. The presentation of 17-OHP and A4 by individual baseline treatment strata in the study will be presented 
in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks). 
3. 17-OHP and A4 levels at 09:00 as a responder analysis (i.e. the number of subjects achieving results in 
the optimal range). 
4. Changes relative to standard glucocorticoid replacement therapy in body composition (DEXA) (fat mass, 
lean mass and total bone density) to be measured at all sites except Germany. 
Exploratory Endpoints: 
1. Partial area under the curve (AUC) of 17-OHP at 15:00-23:00, 23:00-07:00, and 07:00-15:00 (all refer to 
actual clock time of sampling). 
2. The primary endpoint measure will also be presented for the profiles measured at 4 and 12 weeks for the 
purposes of titration. 
3. Changes relative to standard treatment in the following: 
a. 
Bone markers – serum CTX and osteocalcin (after fasting) 
b. hsCRP 
c. 
Assessment of glucose and insulin in the morning (after fasting) 
d. Assessment of HbA1c, total testosterone, and PRA in the morning 
e. 
QoL using SF-36®, MAF, and EQ-5D™ 
4. Use of glucocorticoids at beginning and end of the study will be presented both as individual 
glucocorticoids used, and as calculated hydrocortisone equivalents using accepted conversion constants 
for the calculations. 
Safety Endpoints: 
1. Routine haematology, biochemistry, physical examination, vital signs, urinalysis, electrocardiogram 
(ECG). 
2. Clinical adverse events (AEs) – particular note of use of sick day rules and Addisonian crises. Under or 
over-replacement with glucocorticoids will be considered in the efficacy endpoints. 
3. Changes relative to the standard treatment in weight, body mass index (BMI), waist circumference, and 
blood pressure (BP). 
METHODOLOGY: 
As part of the baseline assessment, subjects will be admitted overnight for a 24-hour endocrine profile whilst 
on their standard therapy. Subjects will attend the study site in the morning and have a profile taken: 17-OHP 
and A4 at 15:00, 17:00, 19:00, 21:00, 23:00, 01:00, 03:00, 05:00, 07:00, 09:00, 11:00, 13:00 and 15:00. 
Baseline bloods will be taken on the second morning and will include: safety measurements, all secondary 
endpoints to be measured – PRA, fasting osteocalcin and CTX, DEXA scan for body composition (except 
Germany) (DEXA scan may be performed at other times up to 2 weeks before baseline if scheduling proves 
difficult), insulin and glucose, HbA1c, QoL, height, weight (BMI to be calculated) and waist circumference. 
After these measurements have been taken, the subject will be randomised to Chronocort® or to continue on 
their standard care. Randomisation will be stratified by baseline treatment: 
1. hydrocortisone only or 
2. prednisone or prednisolone, alone or in combination with hydrocortisone  
3. dexamethasone only or in combination with any other glucorticoid 
The initial dose setting at the start of the Chronocort® treatment will be based on hydrocortisone dose 
equivalent of baseline therapy in accordance with standard clinical practice. Further dose refinement/titration 
will be conducted in both treatment groups as necessary after 4 weeks and 12 weeks using a standardised 
titration algorithm after the subject has been re-admitted for further 24-hour profiles, to include 17-OHP and 
A4. Safety endpoints and PRA will also be measured at the 07:00 morning sample at each profile. 
At 6 months, all the baseline tests will be repeated (including the 24-hour profile). All subjects may then 
continue on Chronocort®, whatever their randomised treatment, as part of an open-label extension study (to 
be conducted under a separate protocol). 
Blinding:  The decision to change doses in both treatment groups will be made by an independent blinded 
physician  but the actual change in dose will be made by the local investigator looking after the subject. 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 is currently recommended to clinical practice.  
Stress doses of hydrocortisone will be given for intercurrent illnesses as medically indicated according to 
“sick day rules”. Fludrocortisone dose adjustment will be allowed if medically indicated and will be based on 


Investigational product: 
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Protocol No.: DIUR-005 
Chronocort®  
      
Diurnal Ltd 
 
Page 8 of 91 
Version: Final 7.0 – 23 August 2017 
BP measurements and laboratory data (goal supine PRA above the lower limit and <1.5 times ULN). 
o 
Dose changes in both treatment groups will be under the direction of an independent blinded 
physician and will be made following an inpatient assessment of symptoms and androgen levels. 
o 
Dose adjustment will be based on clinical symptoms using the “signs and symptoms of adrenal 
insufficiency questionnaire” and the measurement of the 17-OHP and A4 profiles. 
o 
The 5 samples taken between 01:00 and 09:00 will reflect the glucocorticoid dose taken in the 
evening or last thing at night on standard or Chronocort® therapy and the 5 samples taken between 
11:00 and 19:00 will reflect the morning glucocorticoid dose on standard or Chronocort® therapy. 
Dose adjustments will be considered if 3 or more of the 5 sample times show out of range values for 
17-OHP or A4. 
For subjects continuing on standard therapy the local investigator can change the daytime and evening doses 
of the standard therapy (within the limits set by the independent blinded physician) but the timing and the 
drugs used must not be changed. Dose adjustment will use the lowest dose adjustment available with the 
specific therapy, so generally for hydrocortisone this will be 5mg, for prednisolone 1mg and dexamethasone 
0.25mg.  
Where 17-OHP and A4 show inconsistent trends the A4 parameter will take precedence in directing dose 
adjustment. 
If required, dose adjustments will be made within 2 weeks of the week 4 and week 12 visits when 
biochemical results are reviewed. 
 
All subjects (whether or not there has been a titration) will receive a telephone call one week after 
any dose adjustments to enquire as to whether there have been any AEs, and reinforce any other 
protocol requirements. 
 
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.The rationale for 
any dose adjustment, by both the independent blinded physician and also any changes made by the 
local investigator, will be recorded in the electronic case report form (eCRF). 
 
In subjects who have undetectable androgens at baseline on their regular medication, caution will be 
taken over dose reduction so as to avoid the risk of suppressed pituitary-adrenal axis occurring in 
these subjects. 
STATISTICAL METHODS:   
The Statistical Analysis Plan (SAP) must be finalised before any subject is randomised into the trial.  
Efficacy: The primary efficacy endpoint is the change from baseline to 24 weeks in the primary efficacy 
variable (natural logarithm of the mean over the 24-hour SDS profile for 17-OHP). The primary efficacy 
endpoint will be compared between treatment groups within a Normal linear analysis of covariance 
(ANCOVA) model with baseline treatment category and baseline SDS as covariates. Exploratory analyses will 
investigate the sensitivity of the results to the transformation of the endpoint and to the form of the model. 
Secondary endpoints will also be analysed as a change from pre-randomisation baseline to end-of-study. To 
ensure that the treatment effect of Chronocort® is not all as a result of non-hydrocortisone based regimes being 
different in achieving control, the effect of Chronocort® within baseline treatment subgroups will be presented.  
Safety: Summary vital signs change from baseline data will be presented in tabular form, by dose level across 
time, with N, mean, standard deviation (SD), median, quartiles, minimum and maximum as appropriate.  
Summary ECG (heart rate, PR interval, QRS width, QT interval and QTC interval) change from baseline data 
will be presented in tabular form, by dose level across time, with N, n, mean, SD, median, minimum and 
maximum as appropriate.  
AEs will be coded using the latest version of the MedDRA drug dictionary. Data will be summarised using 
preferred term and primary system organ class. Only treatment-emergent AEs, being events with an onset at 
or after the first administration of study drug, 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.  
 
 


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Protocol No.: DIUR-005 
Chronocort®  
      
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Page 9 of 91 
Version: Final 7.0 – 23 August 2017 
Absolute and change from baseline laboratory variables (haematology, biochemistry) will be summarised by 
treatment group (N, n, mean, SD, median, quartiles, minimum and maximum) at each time point. Shift tables 
from pre-dose to each time point for laboratory variables (haematology, biochemistry) will be presented. The 
3 x 3 cross tabulations (from low, normal and high to low, normal and high) will be presented by treatment 
group. Urinalysis variables will be listed by subject and time point. Values outside the normal ranges (provided 
with the laboratory report) will be flagged in the subject data listings. 
 
 


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Protocol No.: DIUR-005 
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2. List of Abbreviations 
 
17-OHP 
17-hydroxyprogesterone 
A4 
Androstenedione 
AE 
Adverse event 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAH 
Congenital adrenal hyperplasia 
CBC 
Complete blood count 
CK 
Creatine kinase 
Cmax 
The maximum concentration achieved after a single dose 
CRA 
Clinical Research Associate 
CRADA 
Cooperative Research and Development Agreement 
eCRF 
Electronic case report form  
CRH 
Corticotropin-releasing hormone 
CRO 
Contract Research Organisation 
CTX 
C-terminal cross-linked telopeptide 
CV 
Cardiovascular 
CYP 
Cytochrome P 
DEXA 
Dual Energy X-ray Absorptiometry 
dL 
Decilitre 
DSMB 
Data Safety Management Board 
ECG 
Electrocardiogram 
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 
HR 
Heart rate 
hsCRP 
High sensitivity c-reactive protein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 


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IPI 
Identifiable private information 
IR 
Immediate release 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IWRS 
Interactive Web Response System 
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 
QoL 
Quality of life 
PK 
Pharmacokinetics 
PP 
Polypropylene 
PRA 
Plasma renin activity 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
REC 
Research Ethics Committee 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Standard deviation score 
SF-36® 
Medical Outcome Short Form Health Survey Form 36 (Subject Questionnaire) 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tmax 
Time taken to reach Cmax 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organisation 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No.: DIUR-005 
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3. 
Table of Contents 
1. 
Protocol Synopsis ............................................................................................................. 5 
2. 
List of Abbreviations ..................................................................................................... 10 
3. 
Table of Contents ........................................................................................................... 12 
4. 
Investigators and Administrative Structure ................................................................ 15 
5. 
Introduction .................................................................................................................... 16 
6. 
Study Objectives............................................................................................................. 21 
6.1 
Primary Objectives ............................................................................................................ 21 
6.2 
Secondary Objectives ........................................................................................................ 21 
6.3 
Exploratory Objectives ..................................................................................................... 21 
7. 
Study Endpoints ............................................................................................................. 21 
7.1 
Primary Endpoint .............................................................................................................. 21 
7.2 
Secondary Endpoints ......................................................................................................... 22 
7.3 
Exploratory Endpoints ...................................................................................................... 22 
7.4 
Safety Endpoints ................................................................................................................ 22 
8. 
Study Design ................................................................................................................... 22 
9. 
Subject Population ......................................................................................................... 26 
9.1 
Number of Subjects and Subject Selection ...................................................................... 26 
9.2 
Inclusion Criteria ............................................................................................................... 27 
9.3 
Exclusion Criteria .............................................................................................................. 27 
10. Study Medication and Administration ........................................................................ 28 
10.1 
Randomisation and Blinding ............................................................................................ 28 
10.2 
Description and Handling of IMPs .................................................................................. 28 
10.2.1 
Chronocort® Formulation ............................................................................................ 28 
10.2.2 
Packaging and Labelling ............................................................................................. 28 
10.2.3 
Storage ........................................................................................................................ 29 
10.2.4 
Accountability ............................................................................................................. 29 
10.3 
Dosage and Administration .............................................................................................. 30 
10.4 
Dose Adjustments .............................................................................................................. 30 
10.5 
Other Study Medications (Non-Investigational Medicinal Products) .......................... 31 
10.6 
Permitted Concomitant Medications/Treatments .......................................................... 31 
11 Study Procedures ........................................................................................................... 31 
11.1 
Visit Schedule ..................................................................................................................... 31 
11.1.1 
Visit 0 (Screening Visit) ............................................................................................. 32 
11.1.2 
Visit 1 (Baseline Visit) ............................................................................................... 32 
11.1.3 
Visit 2 (Week 4) .......................................................................................................... 35 
11.1.4 
Telephone call T2.1 .................................................................................................... 36 
11.1.5 
Telephone call T2.2 .................................................................................................... 36 
11.1.6 
Visit 3 (Week 12) ........................................................................................................ 36 
11.1.7 
Telephone call T3.1 .................................................................................................... 37 
11.1.8 
Telephone call T3.2 .................................................................................................... 37 
11.1.9 
Visit 4 (Week 24) or early termination visit ............................................................... 37 
11.1.10 
Telephone call T4 ....................................................................................................... 38 
11.1.11 
Unscheduled Visits or telephone calls ........................................................................ 38 
11.2 
Study Assessments ............................................................................................................. 39 


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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 
Additional Information for the Study Population .......................................................... 41 
11.8 
Completion of the Study.................................................................................................... 42 
11.9 
Subject Payment Schedule ................................................................................................ 42 
11.10 
Overdose......................................................................................................................... 42 
12 Adverse Events and Toxicity Management ................................................................. 42 
12.1 
Adverse Event Definition .................................................................................................. 42 
12.2 
Adverse Event Collection .................................................................................................. 42 
12.3 
Reporting of Adverse Events ............................................................................................ 43 
12.3.1 
Diagnoses vs. signs/symptoms.................................................................................... 43 
12.3.2 
Laboratory values ....................................................................................................... 43 
12.3.3 
Pre-existing conditions ............................................................................................... 43 
12.3.4 
Pre-planned surgeries or procedures ........................................................................... 43 
12.3.5 
Insufficient clinical response (lack of efficacy) .......................................................... 43 
12.3.6 
Overdose ..................................................................................................................... 43 
12.4 
Assessment of Adverse Event Severity ............................................................................ 43 
12.5 
Assessment of Adverse Event Causality/Relatedness ..................................................... 44 
12.6 
Assessment of Adverse Event Expectedness.................................................................... 44 
12.7 
Serious Adverse Event Definitions ................................................................................... 45 
12.8 
Suspected Unexpected Serious Adverse Reaction .......................................................... 45 
12.9 
Serious Adverse Event Reporting .................................................................................... 45 
12.10 
Serious Adverse Event Expedited Reporting .............................................................. 47 
12.10.1 
Standards for Expedited Reporting ............................................................................. 47 
12.10.2 
Expedited Reporting Guideline for Other Observations ............................................. 47 
12.11 
Sponsor’s Responsibilities ............................................................................................ 47 
12.12 
Procedures for Reporting Pregnancy Exposure and Birth Events ........................... 48 
12.13 
Data Safety Management Board .................................................................................. 48 
13 Statistical Considerations .............................................................................................. 48 
13.1 
Conventions and Methods................................................................................................. 48 
13.1.1 
Summary Tables, Listings  and Figures ...................................................................... 48 
13.1.2 
Hypothesis Testing and Confidence Intervals ............................................................ 49 
13.1.3 
Comparison of Groups ................................................................................................ 49 
13.1.4 
Missing Outcome Data ............................................................................................... 49 
13.2 
Analysis Sets ....................................................................................................................... 49 
13.3 
Efficacy and Safety Variables ........................................................................................... 50 
13.3.1 
Definitions .................................................................................................................. 50 
13.3.2 
Primary Efficacy Variable .......................................................................................... 50 
13.3.3 
Secondary Efficacy Variables ..................................................................................... 50 
13.3.4 
Exploratory Efficacy Variables................................................................................... 50 
13.3.5 
Safety Variables .......................................................................................................... 51 
13.4 
Analysis of the Conduct of the Study ............................................................................... 51 
13.5 
Demographic and other baseline characteristics ............................................................ 51 
13.6 
Efficacy Analyses ............................................................................................................... 51 
13.6.1 
Primary Efficacy Analysis .......................................................................................... 51 
13.6.2 
Secondary Efficacy Analyses ..................................................................................... 52 
13.6.3 
Exploratory Efficacy Analyses ................................................................................... 52 
13.7 
Safety Analysis ................................................................................................................... 52 
13.8 
Power and Sample Size Considerations ........................................................................... 52 
13.9 
Exploratory Analyses ........................................................................................................ 53 
13.10 
Data Review Meeting .................................................................................................... 53 
13.11 
Deviations from the Planned Statistical Analysis ....................................................... 53 


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14 Responsibilities ............................................................................................................... 53 
14.1 
Investigator Responsibilities ............................................................................................. 53 
14.2 
Ethical Conduct of the Study ............................................................................................ 54 
14.3 
Ethics Committee and Institutional Review Board approval ........................................ 54 
14.4 
Informed Consent .............................................................................................................. 54 
14.5 
Subject Data Protection .................................................................................................... 55 
14.6 
Case Report Forms and QoL questionnaires .................................................................. 55 
14.7 
Data Management ............................................................................................................. 55 
14.8 
Drug Reconcilliation .......................................................................................................... 56 
14.9 
Inspections .......................................................................................................................... 56 
14.10 
Protocol Compliance ..................................................................................................... 56 
14.11 
Sponsor Responsibilities ............................................................................................... 56 
14.11.1 
Indemnity and Compensation ..................................................................................... 56 
14.11.2 
Protocol Modifications ............................................................................................... 57 
14.12 
Study Monitoring .......................................................................................................... 57 
14.13 
Publication Policy .......................................................................................................... 57 
14.14 
Clinical Study Report ................................................................................................... 58 
14.15 
Data Retention and Availability................................................................................... 58 
14.16 
Study Termination ........................................................................................................ 58 
15. References ....................................................................................................................... 58 
Appendix 1 - Sampling Schedule for 24-hour Profiling ..................................................... 61 
Appendix 2 - Haematology and Clinical Chemistry Parameters ...................................... 62 
Appendix 3 - Expected Adverse Events ............................................................................... 63 
Appendix 4 - Sick Day Rules ................................................................................................. 65 
Appendix 5 - Adrenal Insufficiency Checklist..................................................................... 67 
Appendix 6 - SF-36®............................................................................................................... 68 
Appendix 7 - MAF ................................................................................................................. 79 
Appendix 8 - EQ-5D Health Questionnaire ......................................................................... 82 
Appendix 9 - Labelling of IMP and Rescue Medication .................................................... 85 
Appendix 10 - Protocol Amendment History ...................................................................... 89 
 
 


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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 
 
 
 
 
 
 
 
Safety reporting 
 
 


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5. 
Introduction 
 
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 et al. 2014).  
 
There is currently no standard treatment for this condition, and 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 the 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. The proposed study will 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]). 
 
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 
(Cornean 1998), insulin resistance (Azziz 1994; Moran 2000; New 1993; Speiser 1985), and 


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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. 
 
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). The risks of 
Chronocort® are, therefore, expected to be no greater than the risks of an equivalent dose of 
cortisol. 
 
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 (IR) hydrocortisone 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). 
 
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 
viriliation 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.  
 


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Chronocort® is a newly-developed formulation of hydrocortisone that allows for slow 
absorption after oral administration when given at 23:00 hours (20mg) and 07:00 hours (10mg), 
so that cortisol levels peak in the early morning (Whitaker 2014). The compound has 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).  
 
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 Cmax >300nmol/L 
(>10.8 mcg/dL) for the 20mg dose, Tmax approximately 6-8 hours post-dosing to prime waking, 
mean cortisol level >100nmol/L (>3.6mcg/dL) up to 16:00 hours, mean cortisol level 
<100nmol/L (>3.6mcg/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 
National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, USA (Mallappa 
2015). DIUR-003 evaluated the PK profile of cortisol following short-term twice-daily 
administration of Chronocort® (20mg at night and 10mg 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 30mg daily (given as 10mg at 
07:00 and 20mg 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 20mg at 23:00 and 10mg 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 28mg and on Chronocort® was 26mg. 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 
cases of anaemia and 4 cases of 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 are currently being analysed, but preliminary PK data indicate that food 
may have an effect on the dosing of Chronocort®. Thus in this study 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. 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 no there was no causal relationship with 
the study drug. 
 


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Proposed study   
The proposed study aims to build on the results of study DIUR-003 and further evaluate 
whether Chronocort® can provide improved control of serum androgen levels (using 17-OHP 
and A4 as markers) compared to current glucocorticoid treatment regimens. 
 
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 these risks are then 
negligable. 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 total 
blood volume to be withdrawn during this study has been limited to a maximum of 427mL. 
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 would come to the notice of the 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 cortisol 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 


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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 is receiving at entry into this study. However, the delivery of hydrocortisone with 
Chronocort® has been demonstrated to produce a cortisol profile more similar to the 
endogenous cortisol profile than current 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 Objectives 
 To demonstrate the superior efficacy of Chronocort® compared with standard 
glucocorticoid replacement therapy in the treatment of CAH based on 17-OHP. 
6.2 
Secondary Objectives 
In adult subjects with CAH:  
 To assess the safety and tolerability of Chronocort® treatment in adult subjects with 
CAH over a 6-month period. 
 To assess the efficacy of Chronocort® with regard to the effect on A4 levels over the 
6-month treatment period. 
 To assess the impact of Chronocort® on body composition (using dual energy X-ray 
absorbtimetry [DEXA]) – fat mass, lean mass and total bone density – at selected sites. 
6.3 
Exploratory Objectives 
 To assess the efficacy of Chronocort® with regard to the effect on testosterone levels 
over the 6-month treatment period. 
 To assess the impact of Chronocort® on cardiovascular (CV) risk (evaluated using high-
sensitivity C-reactive protein [hsCRP]). 
 To assess the impact of Chronocort® on bone markers of serum C-terminal cross-linked 
telopeptide (CTX) and osteocalcin (after fasting). 
 To assess changes from baseline in glucose and insulin in the morning (after fasting)  
 To assess changes from baseline in glycated haemoglobin (HbA1c) and plasma renin 
activity (PRA) in the morning. 
 To assess the impact of Chronocort® on quality of life (QoL) using SF-36®, 
Multidimensional Assessment of Fatigue (MAF), and EQ-5D™. 
 To assess subject compliance in subjects treated with Chronocort® over a 6-month 
period. 
7. 
Study Endpoints 
7.1 
Primary Endpoint 
The primary efficacy endpoint is the change from baseline to 24 weeks of the mean of the 
24-hour standard deviation score (SDS) profile for 17-OHP. The SDS profile is calculated as 
the SDS of log-transformed 17-OHP concentration unsigned. 


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7.2 
Secondary Endpoints 
1. 
The change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4 
(calculated in the same way as the primary endpoint). 
2. 
The presentation of 17-OHP and A4 by individual baseline treatment strata in the study 
will be presented in the same manner as the primary endpoint (using 24-hour SDS 
profile at 24 weeks). 
3. 
17-OHP and A4 levels at 09:00 as a responder analysis (i.e. the number of subjects 
achieving results in the optimal range). 
4. 
Changes relative to standard glucocorticoid replacement treatment in body composition 
(DEXA) (fat mass, lean mass and total bone density) to be measured at all sites except 
Germany. 
7.3 
Exploratory Endpoints 
1. 
Partial area under the curve (AUC) of 17-OHP at 15:00-23:00, 23:00-07:00, and 07:00-
15:00 (all refer to actual clock time of sampling). 
2. 
The primary endpoint measure will also be presented for the profiles measured at 4 and 
12 weeks for the purposes of titration. 
3. 
Changes relative to standard treatment in the following: 
a. Bone markers – serum CTX and osteocalcin (after fasting) 
b. hsCRP 
c. Assessment of glucose and insulin in the morning (after fasting)  
d. Assessment of HbA1c, total testosterone, and PRA in the morning 
e. QoL using SF-36®, MAF, and EQ-5D™ 
4. 
Use of glucocorticoids at beginning and end of the study will be presented both as 
individual glucocorticoids used, and as calculated hydrocortisone equivalents using 
accepted conversion constants for the calculations. 
7.4 
Safety Endpoints 
1. 
Routine haematology, biochemistry, physical examination, vital signs, urinalysis, 
electrocardiogram (ECG). 
2. 
Clinical AEs – particular note of use of sick day rules and Addisonian crises. Under or 
over-replacement with glucocorticoids will be considered in the efficacy endpoints. 
3. 
Changes relative to the standard treatment in weight, body mass index (BMI), waist 
circumference, and blood pressure (BP). 
8. 
Study Design 
 
This study is designed as a parallel arm, randomised, open-label study, including dose titration 
and admissions for four overnight stays for 24-hour endocrine profiles. It will compare the 
efficacy, safety and tolerability of Chronocort® with standard glucocorticoid replacement 
therapy in the treatment of CAH over a treatment period of 6 months. 
 
A previous phase II study (a two-part, single cohort, open label multiple dose protocol 
[DIUR-003]) demonstrated that Chronocort®, when given in a twice a day regimen in subjects 
with CAH, enables physiological replacement of cortisol, which results in improved control of 
androgens without increasing glucocorticoid exposure (Mallappa 2015). Chronocort®, in 
contrast to hydrocortisone IR, achieved a physiological profile. Dosing times for study 
DIUR-003 were 23:00 hours and 07:00 hours, and these timings will be continued for the 
present phase III study. Subject reported outcomes were used in study DIUR-003, which are 


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also to be included in this phase III study. The results gained in the phase II protocol have been 
used in the design of this phase III study with regard to dosage, endpoint selection and sample 
size. Additionally, a phase I food effect study has recently been completed, with preliminary 
results indicating that food may have an effect on the dosing of Chronocort®. Thus in this study 
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. 
 
There is a wide variation in standard therapy for this indication. In order to ensure treatment is 
standardised, the protocol requires that subjects are on a stable glucocorticoid therapy for a 
minimum of 6 months prior to study participation, and it is this period that will characterise the 
subjects and their baseline characteristics, and is effectively the run-in period for the study.  
 
Due to the wide variance in standard therapy for this condition, this study has been designed 
as an open study rather than a blinded study. The randomisation either to Chronocort® or to 
continue on their original therapy will be stratified with regard to the subject’s prior treatment. 
The number of subjects in the study will be closely monitored via the interactive web response 
system (IWRS) system until a total of 120 subjects are randomised in the study. This number 
of subjects provides greater than 95% power, with a 2-sided alpha of 5% to demonstrate a fall 
in the mean daily unsigned standard deviation SDS of 17-OHP, which is 20% less than that 
seen in the phase II study. 
 
Dose titration decisions in both treatment groups will be made by an independent blinded 
physician, blinded to the treatment arm. This will be carried out within 2 weeks of each 
profiling visit at weeks 4 and 12 using a standard titration algorithm after the subject has been 
re-admitted for 24-hour profiles that include 17-OHP and A4. The use of an independent 
blinded physician will minimise bias in the management of subjects in this open study. Each 
treatment arm will be subject to the same titration rules throughout the study, ensuring that 
opportunities for optimisation and control of androgens are the same in both groups. It is 
intended that dose adjustment should optimise control of CAH according to the current 
standard of care based on subject symptoms and measurement of androgens as is currently 
recommended for clinical practice. 
 
As this is an open study, measures have been taken to minimise any potential bias as follows: 
 
1. Records will be kept of any subjects screened, whether or not they enter the study. This 
will enable an assessment of the representative nature of the subjects randomised. 
2. Randomisation will be carried out by IWRS, stratified by 3 baseline treatment groups 
according to the subjects current treatment: 
a. hydrocortisone only or 
b. prednisone or prednisolone alone or in combination with hydrocortisone  
c. dexamethasone only or in combination with any other glucorticoid 
3. The titration of the subject’s dose of study treatment following the hormone profiles at 
4 weeks and 12 weeks will be directed by an independent blinded physician, minimising 
bias in the management of subjects.  
4. Care will be taken not to dose adjust for the Chronocort® arm of the study at baseline 
by selecting the initial dose following randomisation on the equivalent glucocorticoid 
dose at baseline, rather than basing it on hormone levels or symptoms. By using this 
method both arms will effectively continue on their baseline glucocorticoid dosage. 


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5. The primary endpoint is an objective biochemical measure that is not subject to bias in 
its ascertainment. 
6. Efforts will be made to ensure that all subjects remain in the study and are evaluable. 
Subjects completing the study will become eligible for an open extension study, in 
which all subjects will be offered Chronocort® (this will be conducted under a separate 
protocol). 
7. The statistical analysis plan (SAP) will be completed before randomisation of the first 
subject to the study. 
8. There will be rigorous monitoring of sites to ensure compliance with all study 
procedures. 
9. Treatment will be allocated using block randomisation. The block size will be 
determined by an independent statistician and will not be communicated to the study 
team. 
 
Written informed consent for the study will be obtained from subjects who have been stable on 
their current treatment for a minimum of 6 months. Subjects will be screened and entered in 
the study provided they meet the inclusion/exclusion criteria. 120 subjects will be randomised 
into this study (see Subject Stratification below) to obtain 102 evaluable subjects (individual 
sites should not recruit more than 25 subjects without first consulting the sponsor).  
 
Figure 2: 
Overview of DIUR-005 Study Schema 
 
 
Study Inclusion 
 
Following written informed consent and screening tests (Visit 0), suitable subjects will be 
called back for the baseline visit. The diagnosis of 21-hydroxylase deficiency and adequacy of 
the subject’s CAH management will be confirmed by examination of prior medical records 
prior to Visit 1.  


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Baseline Assessment and Randomisation (2-day visit) 
Subjects will be called in for the Baseline Visit (Visit 1) and admitted overnight for a 24-hour 
endocrine profile whilst remaining on their standard therapy. Subjects will have 17-OHP and 
A4 measured at 13 time points. On the second morning baseline bloods will be taken together 
with all safety measures and all secondary endpoint measurements (see Section 11).  
 
After the completion of the baseline profile, the subject will be randomised either to receive 
Chronocort® or to continue on standard care. 120 subjects will be randomised (see Section 11). 
 
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 prednisone 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)  Chronocort® will be given 
at 23:00 hours (approximately 2/3rd of the total daily dose) and 07:00 hours (approximately 
1/3rd of the total daily dose). The first dose of Chronocort® will be taken at 23:00 hours on Day 
2 of the baseline visit. Subjects will be asked to write on the pack the dose, date and time they 
took the first dose of study medication (Chronocort® or standard therapy). 
 
Dose Adjustment 
 
Dose adjustment in both treatment groups will be made, if necessary, within 2 weeks of Visits 
2 (4 weeks) and 4 (12 weeks). The decision to change dose will be made by an independent 
blinded physician but the actual treatment change will be made by the local investigator. The 
independent blinded physician will determine either that no change is required or that an 
increase/decrease in the morning/midday/evening medication is needed. In the event that a 
change in the midday dose is advised for a subject who is receiving Chronocort or in a subject 
who is receiving twice daily dosing of standard therapy, the local investigator must decide to 
make this dose change at the most appropriate timepoint in their judgement (morning or 
evening), in addition to any changes already advised for morning and evening doses, so that 
the total change advised is accommodated within the day. For each subject, the independent 
blinded physician will record whether or not a treatment change is required in the electronic 
case report form (eCRF). The local investigator will be informed so they can make the change 
to the prescription and the local investigator will document whether or not a change is required 
in the subject notes, using the eCRF as the source document for this information. All subjects 
will receive a telephone call to inform them whether or not their dose will change. The local 
investigator will ensure the subject receives clear instructions in writing (emails are acceptable) 
following the telephone call. All subjects will receive a further telephone call one week after 
the first call (whether or not dose adjustment has been recommended) to assess any AEs and 
reinforce any other protocol requirements. 
 
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. 
Rationale for any dose adjustment, by both the independent blinded physician and also any 
changes made by the local investigator, will be recorded in the eCRF. With intercurrent illness, 
sick day rules apply (see Appendix 4 for an example). In subjects with undetectable androgen 


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levels at baseline who are on regular medication, caution will be taken over dose reduction so 
as to avoid the risk of adrenal insufficiency in subjects with a suppressed pituitary-adrenal axis. 
 
Dose adjustment by the independent blinded physician will be based on clinical symptoms 
using the “signs and symptoms of adrenal insufficiency questionnaire” (Appendix 5) and the 
measurement of the 17-OHP and A4 profiles. The adrenal insufficiency questionnaire should 
only be used to determine if symptoms of under or over replacement of glucocorticoids have 
occurred since the last visit – it should not be used to record AEs due to other causes. 
 
o The independent blinded physician will review the signs and symptoms of adrenal 
insufficiency questionnaire and if there is evidence the subject is undertreated with 
glucocorticoid the glucocorticoid dose will not be reduce and if there is evidence of 
over treatment the glucocorticoid dose will not be increased. 
 
The 5 samples taken between 01:00 and 09:00 will reflect the glucocorticoid dose taken in the 
evening or last thing at night on standard and Chronocort® therapy and the 5 samples taken 
between 11:00 and 19:00 will reflect the morning glucocorticoid dose on standard and 
Chronocort® therapy. Dose adjustments will be considered if 3 or more of the 5 sample times 
show out of range values for 17-OHP or A4.  
 
For subjects continuing on standard therapy the local investigator can change the daytime and 
evening doses of the standard therapy (within the limits set by the independent blinded 
physician) but the timing and the drugs used must not be changed. Dose adjustment will use 
the lowest dose adjustment available with the specific therapy, so generally for hydrocortisone 
this will be 5mg, for prednisolone 1mg and dexamethasone 0.25mg. 
 
Where 17-OHP and A4 show inconsistent trends, the A4 parameter will take precedence in 
directing dose adjustment. 
 
The dose adjustment is to optimise control of CAH according to current standard of care based 
on subject symptoms and the measurement of androgens as is currently recommended for 
clinical practice. No other glucocorticoid dose adjustments will be allowed apart from sick day 
rules. Fludrocortisone dose adjustment will be allowed if medically indicated and will be based 
on BP measurements and laboratory data (goal supine PRA above the lower limit and <1.5 
times upper limit of normal [ULN]).  
 
At 24 weeks, all the baseline tests will be repeated, including the 24-hour profile. All subjects 
who complete the study may then continue to an open-label extension study where they will be 
offered Chronocort®, whatever their randomised treatment (to be conducted under a separate 
protocol). 
9. 
Subject Population 
9.1 
Number of Subjects and Subject Selection 
120 adult subjects will be randomised into this study to account for any dropouts and provide 
an evaluable dataset of 102 (see Section 11). Individual sites should not recruit more than 25 
subjects without first consulting the sponsor. Subjects that are screened and not entered will be 
documented, along with the reasons for screen failure, and will be included in the database. To 


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be eligible for enrolment, subjects must comply with the inclusion and exclusion criteria listed 
in sections 9.2 and 9.3.  
9.2 
Inclusion Criteria 
1.  Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood 
with documented (at any time) elevated 17-OHP and/or A4 and currently treated with 
hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the 
aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum of 
6 months. 
2. Male or female subjects aged 18 and above. 
3. Provision of signed written informed consent. 
4. Non-pregnant, non-lactating females who are:  
a. Post menopausal (defined as at least 12 months natural spontaneous 
amenorrhoea or at least 6 weeks following surgical menopause, i.e. bilateral 
oophorectomy) 
b. Naturally or surgically sterile (hysterectomy, bilateral oophorectomy, bilateral 
tubal ligation with surgery at least 6 weeks prior to study initiation)                           
c. Of childbearing potential with a negative urinary pregnancy test and using a 
medically acceptable method of contraception (see Section 11.7 for details) 
Note: females presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 
years of age should be considered potentially fertile and therefore, as well as undergoing 
pregnancy testing like all other female subjects, will be expected to be using an 
acceptable method of contraception as noted above. 
5. PRA less than 1.5 times ULN at screening or within 3 months prior to screening, except 
in subjects who have been diagnosed with hypertension where the renin is not being 
used to monitor fludrocortisone replacement. 
9.3 
Exclusion Criteria 
1. Co-morbid condition requiring daily administration of a medication (or consumption of 
any material) that interferes with the metabolism of glucocorticoids. 
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the 
ULN or elevated liver function tests (ALT or AST >2 times ULN). 
3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other 
than CAH. 
4. Subjects with any other significant medical or psychiatric conditions that in the opinion 
of the investigator would preclude participation in the trial. 
5. History of malignancy (other than basal cell carcinoma successfully treated >6 months 
prior to entry into the study). 
6. Participation in another clinical trial of an investigational or licensed drug or device 
within the 3 months prior to inclusion in this study. 
7. Subjects with a history of bilateral adrenalectomy. 
8. Subjects having previously been exposed to Chronocort®. 
9. Subjects who routinely work night shifts and so do not sleep during the usual nighttime 
hours.  
10. Subjects unable to comply with the requirements of the protocol. 


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10. 
Study Medication and Administration 
10.1 
Randomisation and Blinding 
There will be a fully stratified randomisation of subjects using an IWRS system. Stratification 
will be based on subjects’ current treatment at the time of entering the study. This is an 
open-label study so there will be no blinding or unblinding procedures. Subjects will be 
allocated an identifying number sequentially per site in the following format: Study No./Site 
No./Screening No. (for example D005/1/001, D005/1/002 etc. for site 1; D005/2/001 etc. for 
site 2). When the subject is randomised, a separate randomisation number will be allocated, 
which will be used internally for the purposes of treatment allocation and stratum identification. 
The screening number will still be used for subject identification purposes, so there will be 
gaps in subject ID numbers for screen failures. 
10.2 
Description and Handling of IMPs 
The Investigational Medicinal Products (IMP) for this study are: 
  Chronocort® (Hydrocortisone Modified Release Capsule). In this study Chronocort® will 
be supplied in three unit dose strengths of 5mg, 10mg and 20mg per capsule.  
 the standard glucocorticoid replacement therapy that the subject is receiving will be used 
for subjects randomised to the comparator arm  
 
Diurnal Ltd will supply the study sites with adequate bulk study medication of Chronocort® 
for the entire study period. Diurnal will also supply the standard glucocorticoid replacement 
therapy used at each site to ensure that subjects remain on the same products throughout the 
study.  
10.2.1 Chronocort® Formulation  
Chronocort® is a modified-release formulation of hydrocortisone for oral administration. 
Chronocort® is available in dose strengths of 5, 10 and 20mg hydrocortisone. The 5mg 
formulation will be presented in white opaque body/blue opaque cap size 1 hard gelatin 
capsules, printed with ‘CHRONOCORT 5mg’ on the capsule body. The 10mg formulation will 
be presented in white opaque body/green opaque cap size 1 hard gelatin capsules, printed with 
‘CHRONOCORT 10mg’ on the capsule body. The 20mg formulation will be presented in 
white opaque body/orange opaque cap size 0 hard gelatin capsules, printed with 
‘CHRONOCORT 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 pack contains 100 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 1 x 100-count bottle. A treatment 
pack for each subject randomised to Chronocort® will be assembled by the pharmacy using the 
required number of clinical packs according to the individual subject prescription. Each dose 


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strength will be identifiable by the unique colour hard gelatin capsule and product/dose 
identifier printed on the capsule. 
 
Chronocort® Treatment pack 1 will be dispensed by the study site pharmacy on Day 2 and 
taken home by the subject. Treatment pack 1 consists of a cardboard carton containing one 
clinical pack of each dose strength (5, 10 and 20mg Chronocort®), with each pack containing 
100 Chronocort® capsules. The initial Chronocort® dose regimen will be determined according 
to the individual subject prescription, based on the hydrocortisone dose equivalent of the 
subject’s previous therapy, with the hydrocortisone dose calculated as prednisone 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).   
 
Treatment pack 2 (dispensed at Visit 2 after 4 weeks) and Treatment pack 3 (dispensed at Visit 
3 after 12 weeks) will be dispensed by the study site pharmacy. Treatment packs 2 and 3 will 
be assembled based on individual prescribed dosing regimen, including any dose adjustment 
required. 
 
Chronocort® will be labelled as shown in Appendix 9. The subject number will be written on 
the study pack by the pharmacist. 
 
Diurnal will also provide appropriate labels for the standard glucocorticoid replacement 
therapy that the pharmacy can use to label the drugs dispensed to subjects (See Appendix 9). 
The subject number will be written on the study pack by the pharmacist. The batch numbers of 
the standard glucocorticoid replacement therapy must be recorded by the pharmacist. 
10.2.3 Storage 
Chronocort® will be securely stored in the study site pharmacy at a temperature not exceeding 
25°C. Subjects dispensed with treatment packs will be advised to store Chronocort® securely 
in a cool (room temperature) and dry place out of the reach of children. The comparator of 
standard glucocorticoid replacement treatment will be stored in line with the manufacturer’s 
labelling. 
10.2.4 Accountability 
Subjects randomised to Chronocort® will return treatment pack 1 to the study team at Visit 2, 
treatment pack 2 to the study team at Visit 3 and treatment pack 3 to the study team at Visit 4. 
The study team will count the number of capsules remaining at each of these visits and enter 
the information in the eCRF, so compliance can be calculated against the treatment and titration 
prescriptions. At Visits 2 and 3 the study team will transfer empty treatment packs to the returns 
pharmacy at the site. At Visit 4 the study team will transfer all supplies returned by the subject 
to the returns pharmacy at the site. All used and unused Chronocort® will be stored at the 
returns pharmacy 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 within 8 weeks of completion of the study 
unless otherwise instructed. If a subject is continuing on the follow-on study, they will be 
consented for this study and undergo the relevant procedures for the first visit and then a 
separate treatment pack that will provide sufficient capsules to last until the next visit will be 
dispensed. 
Dispensing of the comparator treatment will be in accordance with the site’s usual procedure, 
but used and unused medication must be returned to the study site at each visit and 


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accountability conducted along similar lines to that detailed above for Chronocort®. 
Accountability must also be performed at each visit for the safety pack, which  should be used 
in conjunction with the sites “sick day rules”. Any use of the medications in the safety pack 
should be recorded in the eCRF, along with the reason for use.  
10.3 
Dosage and Administration  
Subjects will be randomised on Day 2 of the baseline visit, following the 24-hour endocrine 
profile and baseline blood tests. Further 24-hour endocrine profiles will be carried out at weeks 
4 and 12, and any dose titrations required will be assessed centrally by an independent blinded 
physician.  
 
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. 
Subjects will be asked to self-administer the dose of Chronocort® provided at 23:00 hours 
(approximately 2/3rd of the total daily dose) and 07:00 hours (approximately 1/3rd of the total 
daily dose) with a small drink of water. 
 
The comparator of standard glucocorticoid replacement treatment will be dosed in line with the 
site’s usual practice. 
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” (Appendix 4 for an example). Other dose adjustments will not be allowed, unless 
the local investigator judges that there is a medical reason to alter the dose, and if so this will 
be recorded in the subject notes and the eCRF (see also last bullet point below).  
 Dose adjustment will be based on clinical symptoms using the “signs and symptoms of 
adrenal insufficiency questionnaire” (Appendix 5) and the measurement of the 17-OHP, 
and A4 profile. The adrenal insufficiency questionnaire should only be used to 
determine if symptoms of under or over replacement of glucocorticoids have occurred 
since the last visit – it should not be used to record AEs due to other causes. 
 Dose adjustments in both treatment groups will be made by an independent blinded 
physician, according to the instructions provided in Section 8 under the heading “Dose 
Adjustment” 
 Dose adjustment will be made within 2 weeks of visits when biochemical results are 
reviewed. 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 it is practical to see the subject again in the clinic to tell 
them of the dose adjustment, this is also acceptable.  
 All subjects (whether or not there has been a titration) will receive a telephone call one 
week after any dose-adjustment, to enquire as to whether there have been any AEs, and 
reinforce any other protocol requirements. 
 The rationale for any dose adjustment, by both the independent blinded physician and 
also any changes made by the local investigator, will be recorded in the subject’s notes 
and in the 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 


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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. 
 
Fludrocortisone dose adjustment will be allowed if medically indicated and will be based on 
BP measurements and laboratory data (goal supine PRA above the lower limit and <1.5 times 
ULN). 
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 one-week supply of 20 mg oral hydrocortisone (in 10mg tablets to allow dosage of 
up to 20mg 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) 
 
Diurnal will also provide appropriate labels for the safety pack that the pharmacy can use to 
label the drugs dispensed to subjects (See Appendix 9). The subject number will be written on 
the safety pack by the pharmacist.  
 
Subjects will continue to take Chronocort® twice daily or standard glucocorticoid replacement 
therapy at the usual dosing regimen 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 pack. 
10.6 
Permitted Concomitant Medications/Treatments 
The subjects must be instructed that no additional medication will be 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(s). Medication for sick days does 
not require authorisation. All concomitant medications and treatments will be recorded in the 
subject’s eCRF. 
 
Existing or previous treatments for CAH (last 6 months) will be recorded separately in the 
eCRF from routine medication as part of the subject’s medical history. 
11 
Study Procedures 
 
The study procedures to be conducted for each subject enrolled in the study are summarised in 
Table 1. Subjects will be screened up to 2 weeks prior to the baseline visit. Written informed 
consent must be taken prior to any study related procedures. Subjects will continue on their 
regular medication for CAH until they are randomised at Visit 1.2 (Day 2 of the baseline visit).  
11.1 
Visit Schedule  
At any visit, if multiple assessments are being conducted, then the measurements should be 
made in the following order: demographic data and medical history, AEs, signs and symptoms 
of adrenal insufficiency, waist circumference and weight, physical examination, vital signs, 
ECG, urinalysis, blood tests, and then dosing.  


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11.1.1 Visit 0 (Screening Visit) 
At Dutch centres only, potential subjects will be approached by their own treating physician. 
If the treating physician is also the investigator the subject information sheet can be provided 
immediately. If this is not the case then the treating physician will ask the patient for permission 
for the investigator to approach them about study participation.  
 
Once subjects have consented to the study, the following assessments will be carried out on all 
patients and recorded:  
 All inclusion and exclusion criteria checked 
 Demographic data 
 Medical history taken, together with information on concomitant medications   
 CAH medication will be recorded separately from other concomitant medications   
 AEs 
 Signs and symptoms of adrenal insufficiency 
 Waist circumference will be measured, together with height and weight, and the BMI 
calculated 
 A physical examination 
 Vital signs (BP, heart rate [HR], respiratory rate and body temperature) 
 Urine sample for urinalysis (including urine pregnancy test in females of childbearing 
potential)   
 Blood samples will be taken for routine biochemistry and haematology  
 Blood sample taken for genotyping if possible, unless genotyping has previously been 
performed, in which case the patient will be asked for their permission for this 
information to be taken from their medical records 
 Sample taken for PRA after the subject has been supine for 30 minutes (if this has not 
been done and documented in the subject records during the previous 3 months) 
 
If subjects meets all the inclusion/exclusion criteria they will be asked to attend Visit 1 in a 
maximum of 3 weeks’ (21 days) time. They will be asked to inform the investigator of the time 
and dose of glucocorticoid taken on the morning they are due to attend for Visit 1.  
11.1.2 Visit 1 (Baseline Visit) 
Day 1 
 
Subjects will attend the clinic on the morning of Day 1 and must be prepared for an overnight 
stay. The following assessments will be carried out and recorded: 
 Check of inclusion/exclusion criteria  
 Subjects will asked about any AEs and concomitant medications changes since the last 
visit 
 Record the time and dose of the last glucocorticoid medication taken prior to attending 
for this visit   
 An abbreviated physical examination, if indicated by AEs 
 Vital signs 
 DEXA scan (except Germany) – this needs to be performed at Baseline Visit or within 
2 weeks prior to Baseline Visit, after inclusion/exclusion criteria are checked 
 
If the subject meets all the study criteria and they have been receiving their normal medication 
for the previous 5 days (i.e. sick days rules have not been applied in the preceding 5 days) they 


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will then be admitted to the clinic for their first 24-hour endocrine profile (17-OHP and A4). If 
sick day rules have been applied in the previous 5 days then the 24-hour profiling should be 
postponed until subjects have been receiving their normal medication for 5 days. The 24-hour 
endocrine profile sampling will commence at 15:00 hours on Day 1 followed by 2-hourly 
serum samples, hence 13 samples will be taken; 15:00, 17:00, 19:00, 21:00, 23:00, 01:00 (Day 
2), 03:00, 05:00, 07:00, 09:00, 11:00, 13:00, 15:00h. These blood samples are to be taken 
within ±10 minutes of the stated timepoints.  
 
Day 2 
 
On the second morning of Visit 1, the following assessments will be conducted (the fasting 
samples to be taken at 07:00hrs): 
 AEs 
 Signs and symptoms of adrenal insufficiency 
 The following questionnaires will be completed: MAF, SF-36® and EQ-5D™ 
 Waist circumference will be measured, together with weight, and the BMI calculated 
 Vital signs 
 ECG    
 Urinalysis (including urine pregnancy test for females of childbearing age) 
 Blood sample for fasting osteocalcin and CTX, insulin, glucose, HbA1c, lipids, hsCRP 
and total testosterone 
 Blood samples will be taken for routine biochemistry and haematology 
 Sample taken for PRA after the subject has been supine for 30 minutes 
 
Following these procedures, the subject will be randomised to Chronocort® or to continue on 
standard care. Randomisation will be stratified by baseline treatment (see Section 8). Sufficient 
medication will be dispensed to the subject for the next 4 weeks. Initial dose setting at the start 
of Chronocort® treatment will be made on hydrocortisone dose equivalent of baseline therapy 
(see Section 8).  
 
Study drug will be dispensed and the subject will be asked to attend the clinic for Visit 2 in 4 
weeks’ time. Subjects will be discharged following the end of the endocrine profile. Subjects  
will be asked to record the date, exact time and amount of the first dose of study medication on 
the drug packaging. The first dose of Chronocort® should be taken at approximately 23:00 
hours on an empty stomach at least 2 hours after the last meal of the day. The first dose of 
standard therapy should be taken in accordance with the instructions from the investigator.


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Table 1:  Summary of Study Procedures  
  
Visit 0 
Screening 
up to 3 wks
Telephone (up to 
V2 D2+2wks)
1 wk after 
T2.1
Telephone (up to 
V3 D2+2wks)
1 wk after    
T3.1
Telephone 30 
days after V412
Screening
V1 Day 1
V1 Day 2
V2 Day 1
V2 Day 2
Call T2.110
Call T2.2 
V3 Day 1
V3 Day 2
Call T3.110
Call T3.2
V4 Day 1
V4 Day 2
Call T4
Consent1
X
Medical history
X
Concomitant medications
X
X
X
X
X
Demographic data
X
Inclusion/exclusion criteria
X
X9
Physical examination
X
X
Abbreviated physical examination (If indicated by AEs)
X
X
X
X
Vital signs (blood pressure, heart rate, respiratory rate, temperature)2
X
X
X
X
X
X
X
X
X
17-OHP (24-hour hormone profile)3
A4 (24-hour hormone profile)3
Haematology
X
X
X
X
X
Biochemistry
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine pregnancy test (females)
X
X
X
X
X
Plasma renin (within last 3 months)4
X4
X
X
X
X
Total testosterone
X
X
X
X
Fasting osteocalcin, CTX, lipids, hsCRP
X
X
X
X
ECG
X
X
X
X
DEXA (up to 2 weeks before baseline)5
X
Fasting insulin & glucose 
X
X
X
X
HbA1c
X
X
X
X
Genotyping6
X
QoL (MAF, SF-360®, EQ-5D™)
X
X
Signs & symptoms of adrenal insufficiency
X
X
X
X
X
Height, waist circumference, weight7
X
X
X
X
X
Randomisation
X
Adverse events
X
X
X
X
X
X
Dispense study drug
X
X
X
Dose setting/adjustment8
Set dose
Adjust dose
Adjust dose
Record the time and dose of last glucocorticoid medication taken prior to 
attending for this visit
X
X
X
X
Telephone contact (all subjects)
Confirm dose
X
Confirm dose
X
X
Compliance
X
X
X
Notes:
10  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.
7  Height, waist circumference & weight at first visit, only waist circumference & weight measuremed thereafter
8  First dose of study medication to be taken in evening of Baseline Visit 1 Day 2; dose adjustment must be done within 2 weeks of  Visits 2 and 3.
9  Limited review of inclusion/exclusion criteria
11  If the subject discontinues from the study early then as many assessments as possible should be completed
12  Only for subjects who do not enter the extension study
X
X (x13)
X (x13)
X (x13)
X (x13)
X
X
X
X
1  Consent must be obtained prior to any study related procedures, including a DEXA scan (DEXA to be done everywhere except Germany)
2  Vital signs (blood pressure, heart rate, temperature)
3  If the subject has been receiving their normal medication for the previous 5 days (i.e. sick days rules have not been applied in the preceding 5 days) they will be admitted to the clinic for 24 hour endocrine profile (17-OHP and A4). If sick day rules have been applied in 
the previous 5 days then the 24-hour profiling should be postponed until subjects have been receiving their normal medication for 5 days. Samples to be taken at 15:00, 17:00, 19:00, 21:00, 23:00, 01:00, 03:00, 05:00, 07:00, 09:00, 11:00, 13:00, 15:00h.  Exact times of sampling to 
be recorded in eCRF; samples to be taken within ±10 minutes of stated timepoints. If dosing is done at the same timepoints as the blood sampling, the blood sampling should be conducted first. 
4  Plasma renin must be done at screening unless this has been done within 3 months of screening and documented in the patient notes. 
5  DEXA is part of Baseline Visit 1 (except for Germany) but can be done up to 2 wks prior to baseline if scheduling difficult; consent must be taken prior to this study related procedure (applies only to Screening period).
6  Blood sample taken for genotyping, if possible, unless genotyping has previously been performed in which case the patient will be asked for their permission for this information to be taken from their medical records
Visit 1 Baseline
   Visit 2 -  4 weeks 
±3days
   Visit 3 - 12 weeks 
±3days
   Visit 4 - 24 weeks 
±3days or early 
termination visit11
X (x13)
X (x13)
X (x13)
X (x13)


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11.1.3 Visit 2 (Week 4) 
Day 1 
 
Subjects will attend the clinic on the morning of Day 1 and must be prepared for an overnight 
stay. The following assessments will be carried out and recorded:  
 Subjects will asked about any AEs and concomitant medications changes since the last 
visit  
 An abbreviated physical examination, if indicated by AEs 
 Record the time and dose of the last glucocorticoid medication taken prior to attending 
for this visit  
 Vital signs 
 
If the subject has been receiving their normal medication for the previous 5 days (i.e. sick days 
rules have not been applied in the preceding 5 days) they will be admitted to the clinic for their 
second 24-hour endocrine profile (17-OHP and A4). If sick day rules have been applied in the 
previous 5 days then the 24-hour profiling should be postponed until subjects have been 
receiving their normal medication for 5 days. The 24-hour endocrine profile sampling will 
commence at 15:00h on Day 1 followed by 2-hourly serum samples, hence 13 samples will be 
taken; 15:00, 17:00, 19:00, 21:00, 23:00, 01:00 (Day 2), 03:00, 05:00, 07:00, 09:00, 11:00, 
13:00, 15:00h. These blood samples are to be taken within ±10 minutes of the stated timepoints. 
If dosing needs to be conducted at the same timepoints as the blood sampling, the blood 
sampling should be conducted first before the dose of study medication is given. 
 
Day 2 
 
On the second morning of Visit 1, the following assessments will be conducted (the blood 
samples to be taken at 07:00 hrs before the morning dose of study medication): 
 AEs 
 Signs and symptoms of adrenal insufficiency 
 Waist circumference will be measured, together with weight, and the BMI calculated.  
 Vital signs 
 ECG    
 Urinalysis (including urine pregnancy test for females of childbearing age) 
 Blood samples will be taken for routine haematology and biochemistry 
 Blood sample taken for fasting osteocalcin and CTX, insulin, glucose, HbA1c, lipids, 
hsCRP and total testosterone 
 PRA after the subject has been supine for 30 minutes 
 
The subject will return all of their medication (Chronocort® and the comparator), including any 
unused medication, and the number of tablets 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. 
 
Sufficient medication will be dispensed for the next 8 weeks, including an extra amount in case 
titration is required and the subject will be asked to attend the clinic for Visit 3 in 8 weeks’ 
time. Subjects will be discharged following the end of the endocrine profile. Subjects will be 
asked to record the date, exact time and amount of the first dose of study medication on the 
drug packaging. The dose of Chronocort® should be taken at approximately 23:00 hours on an 


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empty stomach at least 2 hours after the last meal of the day. The first  dose of standard therapy 
should be taken in accordance with the instructions from the investigator.  
11.1.4 Telephone call T2.1 
Following the assessment of the 4 week 24-hour hormone profile and subject’s symptoms and 
androgen levels, a decision will be made by the independent blinded physician as to whether 
to adjust the dose for the subject. The actual dose adjustment will be made by the investigator, 
within 2 weeks of Visit 2. All subjects will be contacted by telephone, whether or not a dose 
adjustment is to be made. 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. 
11.1.5 Telephone call T2.2  
All subjects, whether or not they have received a dose adjustment, will receive a telephone call 
a week after the dose-adjustment call, to enquire as to whether there have been any AEs, and 
to reinforce any other protocol requirements. Any AEs will be recorded in the eCRF.  
11.1.6 Visit 3 (Week 12) 
Day 1 
 
Subjects will attend the clinic on the morning of Day 1 and must be prepared for an overnight 
stay. The following assessments will be carried out and recorded;  
 Subjects will asked about any AEs and concomitant medications changes since the last 
visit  
 Record the time and dose of the last glucocorticoid medication taken prior to attending 
for this visit   
 An abbreviated physical examination, if indicated by AEs 
 Vital signs 
 
If the subject has been receiving their normal medication for the previous 5 days (i.e. sick days 
rules have not been applied in the preceding 5 days) they will be admitted to the clinic for their 
third 24-hour endocrine profile (17-OHP and A4). If sick day rules have been applied in the 
previous 5 days then the 24-hour profiling should be postponed until subjects have been 
receiving their normal medication for 5 days. The 24-hour endocrine profile sampling will 
commence at 15:00 hours on Day 1 followed by 2-hourly serum samples, hence 13 samples 
will be taken; 15:00, 17:00, 19:00, 21:00, 23:00, 01:00 (Day 2), 03:00, 05:00, 07:00, 09:00, 
11:00, 13:00, 15:00 hours. These blood samples are to be taken within ±10 minutes of the stated 
timepoints. If dosing needs to be conducted at the same timepoints as the blood sampling, the 
blood sampling should be conducted first before the dose of study medication is given. 
 
Day 2 
 
On the second morning of Visit 3, the following assessments will be conducted (the blood 
samples to be taken at 07:00 hrs before the morning dose of study medication): 
 AEs 
 Signs and symptoms of adrenal insufficiency 
 Waist circumference will be measured, together with weight, and the BMI calculated 
Vital signs 


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 ECG    
 Urinalysis (including urine pregnancy test for females of childbearing age) 
 Blood samples will be taken for routine haematology and biochemistry 
 Blood sample for fasting osteocalcin and CTX, insulin, glucose, HbA1c, lipids, hsCRP 
and total testosterone 
 PRA after the subject has been supine for 30 minutes 
 
The subject will return their medication (Treatment Pack 2 for subjects randomised to 
Chronocort®) and the number of capsules counted and recorded in the eCRF by the study team 
so compliance can be calculated (for both Chronocort® and the comparator). The safety pack 
should also be returned and checked, with any rescue medication use being recorded. 
 
Following the above procedures, subjects will be dispensed sufficient mediation for the next 
12 weeks, including an amount in case titration is required (treatment pack 3 for subjects taking 
Chronocort®). Subjects will be asked to attend the clinic for Visit 4 in 12 weeks’ time. Subjects  
will be asked to record the date, exact time and amount of the first dose of study medication on 
the drug packaging. The first dose of Chronocort® should be taken at approximately 23:00 
hours on an empty stomach at least 2 hours after the last meal of the day. The first  dose of 
standard therapy should be taken in accordance with the instructions from the investigator. 
11.1.7 Telephone call T3.1 
This telephone call will be the same as for telephone call T2.1 above. All subjects will be 
contacted, whether or not titration is necessary. Subjects will be asked about any AEs at this 
call and any AEs reported will be recorded in the eCRF. 
11.1.8 Telephone call T3.2 
This telephone call will be the same as for telephone call T2.2 above. All subjects will be 
contacted irrespective of whether titration has taken place. Subjects will be asked about any 
AEs at this call and any AEs reported will be recorded in the eCRF. 
11.1.9 Visit 4 (Week 24) or early termination visit 
Day 1 
 
Subjects will attend the clinic on the morning of Day 1 and must be prepared for an overnight 
stay. The following assessments will be carried out and recorded;  
 Subjects will asked about any AEs and concomitant medications changes since the last 
visit 
 An abbreviated physical examination, if indicated by AEs 
 Record the time and dose of the last glucocorticoid medication taken prior to attending 
for this visit   
 Vital signs 
 
If the subject has been receiving their normal medication for the previous 5 days (i.e. sick days 
rules have not been applied in the preceding 5 days) they will be admitted to the clinic for their 
fourth 24-hour endocrine profile (17-OHP and A4). If sick day rules have been applied in the 
previous 5 days then the 24-hour profiling should be postponed until subjects have been 
receiving their normal medication for 5 days. The 24-hour endocrine profile sampling will 
commence at 15:00 hours on Day 1 followed by 2-hourly serum samples, hence 13 samples 
will be taken; 15:00, 17:00, 19:00, 21:00, 23:00, 01:00 (Day 2), 03:00, 05:00, 07:00, 09:00, 


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11:00, 13:00, 15:00 hours. These blood samples are to be taken within ±10 minutes of the stated 
timepoints. If dosing needs to be conducted at the same timepoints as the blood sampling, the 
blood sampling should be conducted first before the dose of study medication is given. 
 
Day 2 
 
On the second morning of Visit 4, the following will assessments will be conducted (the blood 
samples to be taken at 07:00 hrs before the morning dose of study medication): 
 
 AEs 
 Signs and symptoms of adrenal insufficiency 
 Waist circumference will be measured, together with weight, and the BMI calculated 
 The following questionnaires will be completed: MAF, SF-36® and EQ-5D™ 
 A full physical examination 
 Vital signs 
 ECG  
 Urinalysis (including urine pregnancy test for females of childbearing age) 
 Blood sample for fasting osteocalcin and CTX, insulin, glucose, HbA1c, lipids, hsCRP 
and total testosterone 
 Blood samples will be taken for routine biochemistry and haematology 
 PRA after the subject has been supine for 30 minutes 
 DEXA scan at all sites except in Germany (this can be performed within 2 weeks of 
Visit 4) 
 
The subject will return their medication (treatment pack 3 for subjects randomised to 
Chronocort®) and the number of capsules counted and recorded in the eCRF by the study team 
so compliance can be calculated (for both Chronocort® and the comparator). The safety pack 
should also be returned and checked, with any rescue medication use being recorded. An 
appointment will be made for the 30-day follow-up telephone call.  
 
If the subject has completed the 24-week study period, they will then be eligible to take part in 
the extension study.  
 
If the subject discontinues from the study early then as many of the above assessments as 
possible should be completed. Subjects who discontinue from the study early are not eligible 
to take part in the extension study. 
11.1.10Telephone call T4  
If the subject does not enter into the extension study then they will receive a telephone call 30 
days following completion of Visit 4 in which they will be asked about AEs. If the subject 
enters the extension study then any AEs occurring between the two studies will be collected as 
part of the entry procedures for the extension study.  
11.1.11Unscheduled Visits or telephone calls 
If an unscheduled visit is required, e.g. to follow up on an AE, then the details should be 
recorded in the eCRF, along with the results of any tests carried out. If laboratory results are 
needed urgently these can be processed at the local laboratory. Additional telephone calls may 
also be required inbetween visits to maintain contact with the subject and to ensure AEs and 


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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 BP, HR, 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 biochemistry and haematology tests  (see Appendix 2) 
o measurement of PRA after the subject has been supine for 30 minutes (not 
required at the screening visit if this has been done and documented in the 
subject’s records during the previous 3 months; otherwise required at all visits) 
o genotyping, unless genotyping has previously been performed, in which case 
the patient will be asked for their permission for this information to be taken 
from their medical records 
o 24-hour endocring profiles 
 
To minimise the risk of anaemia associated with the withdrawal of multiple blood samples for 
laboratory testing (as seen in DIUR-003), the planned total blood volume to be withdrawn 
during this study will be limited to a maximum of 427mL. The date and time of collection of 
all blood and urine samples will be recorded in the subject’s eCRF. With regard to the profile 
sampling, a draw window of ±10 minutes from the prescribed timepoints for blood sampling 
is permitted, but exact times of sampling must be recorded in the source documents and eCRF. 
Copies of laboratory accreditation certificates and reference ranges will be provided prior to 
the analysis of the first subject sample. 
 
On Day 2 of each overnight stay, blood samples will be taken at 07:00 hrs before the morning 
dose of study medication, then the study medication will be given at least 1 hour before 
breakfast. These samples are for fasting osteocalcin, CTX, insulin, glucose, lipids, HbA1c, 
hsCRP, and total testosterone. Subjects will fast from 23:00 to 0700 hour on Day 1 of each 
visit until this sample is taken. 
 
All analyses, with the exception of the genotyping, will be carried out by the central laboratory, 
. Genotyping will be carried out by a specialist laboratory. By specific 
exception agreed with the Sponsor for logistical reasons, sites may use a local laboratory to 
determine inclusion and exclusion criteria. This must be agreed with the Sponsor prior to the 
start of the study. In addition, 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 
Urine samples will be tested for the following; 
o Pregnancy test in females of childbearing potential (this test will be done 
locally at the site) 
o Protein, glucose, specific gravity, ketones, urobilinogen, bilirubin, pH, blood 
 


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 DEXA scans (except Germany) 
To be performed up to 2 weeks prior to the baseline visit (Visit 1) and again within 2 
weeks of Visit 4. 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 after breakfast 
on the day when the subject is not fasted and completed in a quiet environment. To be 
administered at baseline and Visit 4. 
 
 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 and recorded in the eCRF.  
 
 ECG 
ECG will be performed and reported locally, and the result recorded in the eCRF.  
 
 Physical examination 
A full physical examination to assess the subject’s general appearance and overall 
health will be carried out at screening 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 
in the eCRF. At the other visits, an abbreviated physical examination will be conducted 
if indicated by AEs, noting any changes from the screening assessment. Any abnormal 
findings will be recorded on 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 4 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 (as per Visit 4). 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 
primary endpoint) 
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 violation, 
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.  
 
If a subject withdraws from the study they will not be eligible to participate in the extension 
study. 
11.6 
Replacement of Withdrawn Subjects 
120 subjects will be randomised to account for withdrawals anticipated during the course of 
the study and to provide 102 evaluable subjects. 
11.7 
Additional Information for the Study Population 
Females presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 years of age 
should be considered potentially fertile and therefore, as well as undergoing pregnancy testing 
like all other female subjects, will be expected to be using an acceptable method of 
contraception as noted below. 
 
Acceptable forms of contraception include: 
1. Established use of oral, injected or implanted hormonal methods of contraception (including 
oestrogen-containing products) – note that use of these methods of contraception must 
remain the same throughout the study in both nature and dose. The type of contraception 
should have been ongoing for ≥90 days prior to the study and at least 7 days after the final 
dose. If <90 days prior to the study, additional use of a double barrier method until 90 days 
is reached is required.  
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. The following should be noted:  
 
Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception. Therefore the use of additional 
spermicides does confer additional theoretical contraceptive protection.  
 
However, spermicides alone are inefficient at preventing pregnancy when the 
whole ejaculate is spilled. Therefore, spermicides are not a barrier method of 
contraception and should not be used alone.  


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4. Male sterilisation (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner 
should be the sole partner for that subject].  
5. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence, such as calendar, ovulation, symptothermal, post ovulation methods, 
and withdrawal are not acceptable methods of contraception 
11.8 
Completion of the Study 
The study will be completed when all subjects have completed the last visit or telephone call 
of this study.  
11.9 
Subject Payment Schedule 
Reasonable subject travel costs will be reimbursed. Where appropriate, costs for overnight 
accommodation prior to clinic admittance will be reimbursed, and in some cases a 
compensation or inconvenience payment may be made to subjects. 
11.10 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®. 
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 phone call T4 (30 days ± 
3 days) following the last visit or, if applicable, the Early Withdrawal visit. Any ongoing AEs 
post study will be followed to resolution or stabilisation if resolution is not expected. Only 
treatment emergent AEs 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 it 
returns to the baseline condition or becomes stable with no further change 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 equally for both study treatments, 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 ECG findings) 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 (note that both 
Chronocort® and the standard glucocorticoid replacement therapy used in the comparator arm 
are considered IMPs in this study): 
 
 Not related 
 Related to the IMP  
 Related to sick day medication 
 Related to an interaction between IMP and sick day medication 
 Related to either IMP or sick day medication 
 
All AEs judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to an IMP, or are due to an interaction with an IMP, qualify as adverse drug 
reactions (ADRs).  
 
Appendix 3 provides a comprehensive list of events that are anticipated to occur in the targeted 
study entry population of subjects with congenital adrenal hyperplasia when disease treatment 
is not optimum. In general, if events as listed in Appendix 3 occur and are considered serious, 
they will not be reported to regulatory authorities in an expedited safety report since causality 
will likely be due to the underlying medical condition, rather than to study drug. 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 Investigator Brochure or is not listed 
at the specificity or severity that has been observed. "Unexpected," as used in this definition, 
also refers to AEs that are mentioned in the Investigator Brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
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. 


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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): 
 
 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 in the eCRF. Any SAE that occurs between administration of the first dose of either 
of the study treatments and 30 days after the last dose of the study treatments 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. 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 ethics 
committee/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 physician, 
 
 and to 
 
 
 
 
. 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. 
 
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. 


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 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 should 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 
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 
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 
clearly stating that the event is an improvement in the condition, and these events will be coded 


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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 
Contract Research Organisation (CRO), as necessary, to Regulatory Authorities and ethics 
committees/IRB (the latter may be through the local investigator, as required by local 
regulations). 
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 adverse reaction, 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 
12.11 Sponsor’s Responsibilities  
The sponsor is responsible for the ongoing safety evaluation of the IMP. The 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.  
 


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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 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 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 Pharmacovigilance 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 primary endpoint). The event must be reported to 
the sponsor immediately upon receipt of information by the study staff. 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 Data Safety Management Board (DSMB) will meet on a regular basis during 
the study in order to review safety data. The DSMB will meet several times during the study, 
and operate in accordance with a charter, which is a separate document. 
13 Statistical Considerations 
 
A detailed and comprehensive SAP will be prepared and signed-off before the first subject has 
been randomised. 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. 
 
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. 
 
All efficacy variables, vital signs and laboratory assessments, together with their changes from 
baseline, will be summarised by treatment group (Chronocort®, standard therapy), stratum 


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(previous stable therapy: hydrocortisone only, prednisone or prednisolone with hydrocortisone 
[but not dexamethasone], dexamethasone alone or in combination with either prednisolone, 
prednisone or hydrocortisone) and timepoint.  
 
Baseline and demographic data will be summarised by treatment group and stratum. Shift 
tables from baseline will be provided for vital signs and laboratory assessments. 
 
Data on dose changes indicated by the independent blinded physician, non-implemented 
changes and reasons for non-implementation will be presented descriptively by treatment 
group. 
 
Where appropriate, graphical displays of variables assessed serially over time may be 
presented. 
 
The summary tables and figures will be supported by full subject listings. 
13.1.2 Hypothesis Testing and Confidence Intervals 
All significance probabilities will be reported as two tailed. Confidence intervals will be 
reported as 95% two-sided. 
13.1.3 Comparison of Groups 
In general, continuous variables will be compared across treatment groups using a Normal 
analysis of covariance (ANCOVA) linear model including pre-baseline standard therapy and, 
if appropriate, the baseline assessment of the variable as covariates in the model. In the case of 
change-from-baseline variables, baseline will always be included as a covariate. 
Binary variables, such as response, will be compared using logistic regression with adjustment 
for covariates as in the continuous data case. 
13.1.4 Missing Outcome Data 
Missing 17-OHP and A4 values (including those considered missing due to being taken outside 
the permitted time window) within the 24-hour hormone profile will be imputed by linear 
interpolation of the two closest non-missing measurements to the scheduled missing time point 
(including out-of-window measurements). In the event that several values are missing from a 
single profile, a decision will be made about the validity of the whole profile will be made at 
the Data Review Meeting on a case-by-case basis (see Section 13.10) 
 
Subjects who withdraw from the study will be assessed on the basis of the latest available 
24-hour profile. This is a conservative procedure as subjects enter the study already receiving 
a suitable dose of their standard therapy.  
 
Exploratory and sensitivity analyses will be performed to assess the effect of any missing data 
on the efficacy conclusions.  
13.2 
Analysis Sets 
The safety analysis set comprises all subjects who were randomised into the study and who 
subsequently received at least one dose of Chronocort® or standard therapy. 
 


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The full analysis set comprises all subjects who were randomised into the study, who received 
at least one dose of Chronocort® or standard therapy, and who have at least one post-
randomisation 17-OHP 24-hour hormone profile. 
 
The efficacy evaluable analysis set comprises all subjects who were randomised into the study, 
who received at least one dose of Chronocort® or standard therapy, and who have a week 24 
17-OHP 24-hour hormone profile, and who have no major protocol violations. 
 
The efficacy evaluable analysis set is the primary analysis set for the evaluation of efficacy. 
The final determination of the membership of analysis sets will be made at a data review 
meeting convened by the sponsor before database lock. 
13.3 
Efficacy and Safety Variables 
13.3.1 Definitions 
Standard Deviation Score  
The SDS is the absolute (unsigned) number of standard deviations above or below the average 
of the lower and upper limit of normal, with the value of the limits and standard deviation – 
which may depend on age and gender – being obtained from the laboratory and reference range. 
 
Mean over a 24-hour SDS profile 
The mean over a 24-hour profile is the arithmetic mean over all the 24-hour SDS with the first 
and last observations weighted one half relative to intermediate observations (this definition is 
equivalent to a normalised AUC calculated by the trapezoidal rule). 
13.3.2 Primary Efficacy Variable 
The primary efficacy variable is the natural logarithm of the mean over the 24-hour hormonal 
profile of the SDS for the natural logarithm of 17-OHP.  
13.3.3 Secondary Efficacy Variables 
The secondary efficacy variables are: 
 
1. 
The change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4 
(calculated in the same way as the primary endpoint). 
2. 
The presentation of 17-OHP and A4 by individual baseline treatment strata in the study 
will be presented in the same manner as the primary endpoint (using 24-hour SDS 
profile at 24 weeks). 
3. 
17-OHP and A4 levels at 09:00 as a responder analysis (i.e. the number of subjects 
achieving results in the optimal range). 
4. 
Changes relative to standard treatment in body composition (DEXA) (fat mass, lean 
mass and total bone density) to be measured at all sites except Germany. 
13.3.4 Exploratory Efficacy Variables 
The exploratory efficacy variables are: 
1. 
The natural logarithm of the means over the partial profiles of 17-OHP at 15:00-23:00, 
23:00-07:00, and 07:00-15:00 (all refer to actual clock time of sampling). 
2. 
The primary endpoint measure will also be presented for the profiles measured at 4 and 
12 weeks for the purposes of titration. 
3. 
Changes relative to standard treatment in the following: 
a. Bone markers – serum CTX and osteocalcin 


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b. hsCRP 
c. Assessment of glucose and insulin morning and evening (after fasting), HbA1c, 
total testosterone, and PRA  
d. QoL using SF-36®, MAF, and EQ-5D™ 
5. 
Use of glucocorticoids at beginning and end of the study will be presented both as 
individual glucocorticoids used, and as calculated hydrocortisone equivalents using 
accepted conversion constants for the calculations. 
13.3.5 Safety Variables 
The safety variables are: 
1. weight, BMI and waist circumference 
2. routine haematology and clinical chemistry 
3. physical examination 
4. vital signs 
5. urinalysis 
6. ECG 
7. the incidence, nature, severity, relatedness, duration, outcome and seriousness of 
treatment emergent AEs 
8. the incidence, nature, severity, relatedness, duration, outcome and seriousness of 'sick 
days' and Addisionian crises. 
13.4 
Analysis of the Conduct of the Study 
Data concerning the conduct of the study (e.g. allocation to analysis sets, inclusion/exclusion 
criteria, 
subject 
disposition/withdrawals, 
compliance, 
protocol 
deviations, 
study 
termination/duration) will be listed and summarised descriptively. Details will be described in 
the SAP. 
 
Protocol Violations/Deviations 
 
As will be described in the SAP, following trial completion, but prior to database lock, any/all 
protocol deviations will be reviewed and classified as either ‘minor’ (unlikely to appreciably 
affect trial outcomes) or ‘major’ (likely to affect outcomes) and this classification will be 
utilised to define the various study populations for analysis purposes. 
13.5 
Demographic and other baseline characteristics 
Demographic and other baseline characteristics for all randomised subjects will be listed and 
summarised.  
13.6 
Efficacy Analyses 
13.6.1 Primary Efficacy Analysis 
The primary efficacy analysis is the comparison of the mean change from baseline to 24 weeks 
in the primary efficacy variable (natural logarithm of the mean over the 24-hour SDS profile 
for the natural logarithm of 17-OHP) between the Chronocort® treatment group and the 
standard therapy treatment group within the efficacy evaluable analysis set. 
This is the primary efficacy analysis for this study. All other analyses of this outcome variable 
and all analyses of other efficacy variables are secondary or exploratory analyses. 


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13.6.2 Secondary Efficacy Analyses 
The secondary efficacy analyses are: 
 
1. The primary analysis repeated for A4. 
2. The above analyses repeated within each pre-baseline treatment stratum. 
3. The comparison of the frequency of the 17-OHP and A4 09:00 responders at 24-weeks 
(i.e. the number of subjects achieving results in the optimal range). 
4. Changes relative to standard treatment in body composition (DEXA) (fat mass, lean 
mass and total bone density) to be measured at all sites except Germany. 
5. The above analyses repeated in the full analysis set.  
13.6.3 Exploratory Efficacy Analyses 
1. Partial AUCs of 17-OHP at 15:00-23:00, 23:00-07:00, and 07:00-15:00 (all refer to 
actual clock time of sampling). 
2. The primary endpoint measure will also be presented for the profiles measured at 4 
weeks and 12 weeks for the purposes of titration. 
3. Changes relative to standard treatment in the following: 
a. Bone markers – serum CTX and osteocalcin 
b. hsCRP 
c. Assessment of glucose and insulin morning and evening (after fasting), HbA1c, 
total testosterone, and PRA  
d. QoL using SF-36®, MAF, and EQ-5D™. 
4. The comparison of the dose of individual glucocorticoids used, and as calculated 
hydrocortisone equivalents, and its change from baseline at 24-weeks. 
13.7 
Safety Analysis 
Safety variables, will be listed and summarised by treatment, stratum and timepoint. 
The nature, severity, relatedness, duration, outcome and seriousness and outcome of all AEs 
will be listed. The subject incidence of treatment emergent AEs will be tabulated by system 
organ class, preferred term, severity and relatedness. Tables will be provided of AEs of special 
interest, SAEs, SUSARs, AEs leading to withdrawal and fatal AEs. 
Shift tables will be presented for laboratory variables and vital signs. Abnormal findings on 
physical examination and from ECG will be tabulated. Listings of laboratory data, vital signs, 
physical examination and ECG will have abnormal findings marked, together with an 
indication of whether or not that finding was clinically significant. 
 
The versions of the following international dictionaries current at the time of study conduct 
will be used for medical coding: 
 Diagnoses: 
MedDRA 
 Medications: 
WHO Drug Dictionary including ATC classification 
 Adverse events: MedDRA 
13.8 
Power and Sample Size Considerations 
A sample size of 102 subjects provides greater than 95% power and 2-sided alpha 5% to 
demonstrate a fall in the logarithm of the mean daily unsigned standard deviation score of 
17-OHP relative to the standard glucocorticoid replacement therapy group. It is assumed that 
(i) the mean fall in the Chronocort® group will be the same (0.78) as that observed in the phase 


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II study (DIUR-003) (ii) the mean fall in the standard therapy group will be 0.2 (approximately 
25% of the Chronocort® phase II study fall) and (iii) the standard deviation of the fall (0.681) 
is that seen in the phase II study. The study is powered to ensure that there can be a reasonable 
description of the comparison of Chronocort® with a variety of standard therapies. 120 subjects 
will be randomised to this study which will account for an inevaluability rate of 15%. 
Individual sites should not recruit more than 25 subjects without first consulting the sponsor. 
13.9 
Exploratory Analyses 
Additional exploratory and sensitivity analyses may include, but are not limited to: 
 an assessment of the efficacy results in subgroups; 
 an assessment of the effect of missing data on the efficacy conclusions; 
 an assessment of the effect of baseline variables on efficacy 
 a comparison between the treatment groups of the number of direction of dose 
changes made during the study period. 
Any exploratory analyses not specified in the SAP must be clearly described as such in the 
clinical study report. 
13.10 Data Review Meeting 
The sponsor will convene a Data Review Meeting after the data has been cleaned and the 
database locked but before analysis has commenced. The review will be performed within the 
framework of the requirements of the ICH Guideline E9. 
 
The terms of reference for the Data Review Meeting will include, but will not be limited to: 
 the determination of whether protocol violations are 'major' or 'minor', or not a 
protocol violation at all 
 the allocation of subjects to analysis sets 
 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 
 a review of whether additional covariates need to be included in the analyses 
 revisions to SAP in light of any Data Review Meeting findings  
 
All persons taking part in the Data Review Meeting must only have access to datasets masked 
to treatment allocation. Treatment group allocations will be scrambled using a dummy 
randomisation list and presented using generic treatment labels (for example, “Group A” and 
“Group B” 
13.11 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). 


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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 ethics 
committee/REC review and approval meet EU and/or 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/or 21 CFR 312.64 (US sites only).  
6. 
Have read and understood the Investigator 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 ethics committee/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 ethics committee/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. Not make any changes in the research study without approval, except when necessary to 
eliminate hazards to the subjects. 
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 study will be conducted according to ICH GCP, the Declaration of Helsinki (1996), and 
ethics committees/IRBs in accordance with the US Code of Federal Regulations on Protection 
of Human Rights (21 CFR 50) (US site). 
14.3 
Ethics Committee and Institutional Review Board approval 
The final study protocol and subject informed consent form will be approved by the ethics 
committee/IRB for the site participating in the study. Approval will be received in writing 
before initiation of the study at site. 
 
Any changes to the study design will be formally documented in protocol amendments and 
approved by the ethics committee/IRB prior to implementation, except in the case of changes 
made to protect subject safety, which will be implemented immediately. 
14.4 
Informed Consent 
The principles of informed consent in the Declaration of Helsinki (1996), in the current 
requirements of GCP published by the ICH and local regulation, whichever affords the greater 
subject protection will be implemented before any protocol-specified procedures or 
interventions are carried out.  
 
At Dutch centres only, potential subjects will be approached by their own treating physician. 
If the treating physician is also the investigator the subject information sheet can be provided 
immediately. If this is not the case then the treating physician will ask the patient for permission 
for the investigator to approach them about study participation. 
 


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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 ethics committee/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 ethics committee/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 eCRF, 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 (visits 1 and 4). 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.  
 
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 
 standard operating procedures.  
 Complete efficacy and end-point reporting. 


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 Generate safety data listings to include AEs coded using the latest version of the 
MedDRA coding dictionary. 
 
The exact time of the PK blood draws will be recorded. All deviations will be listed to enable 
 to make the necessary adjustments during the PK analysis. 
14.8 
Drug Reconcilliation 
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. 
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. 


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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 must be submitted to the ethics committee/IRB in accordance with local 
requirements.  
 
Approval by the sponsor, FDA, other regulatory authorities as necessary, and ethics 
committee/IRB must be obtained before changes can be implemented. 
14.12 Study Monitoring 
The CRO will be responsible for the monitoring of the study.  
 
 
 
 
 
 
 
At all sites the study monitor will review the progress of the study on a regular basis, 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 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 communications, between the sponsor, designated study representative, and investigator 
should be documented for the study file.  
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 liability to publish the data in appropriate scientific forms. Announcements made 
prior to the first scientific publication of the data will be reviewed 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. 


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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 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, ethics 
committee/IRB and regulators including the FDA. 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. 
14.16 Study Termination 
The study may be terminated prior to completion of the specified number of subjects at the 
request of the sponsor, the investigator, the ethics committee/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. 
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.  
 
Beser A, Sorjonen K, Wahlberg K, et al. Construction and evaluation of a self rating scale for 
stress induced exhaustion disorder, the Karolinska Exhaustion Disorder Scale. Scand J Psychol. 
2014;55:72-82. 
 
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.  
 


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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, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-2136.  
 
Merke DP, Cutler GB Jr. New ideas for medical treatment of congenital adrenal hyperplasia. 
Endocrinol Metab Clin North Am. 2001;30(1):121-135. 
 
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.  
 
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.  
 
Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 
21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin 
Endocrinol Metab. 2010;95(9):4133-4160. 
 
Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin 
North Am. 2001;30(1):15-30.  
 


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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 - Sampling Schedule for 24-hour Profiling  
 
Sample Number 
Clock time in 
hours 
1 
15:00 
2 
17:00 
3 
19:00 
4 
21:00 
5 
23:00 
6 
01:00 
7 
03:00 
8 
05:00 
9 
07:00 
10 
09:00 
11 
11:00 
12 
13:00 
13 
15:00 
 
Endocrine profile: Beginning at 15:00h on Day 1  (Visit 1.1) and finishing 15:00h on Day 2 
(Visit 1.2): two hourly serum for: 
 
17-OHP 
 
A4  
Exact times of samples to be recorded; allowable deviation from above times is ±10 minutes 
 
The above will be repeated on respective Days for Visits 2 (2.1 and 2.1), 3 (3.1 and 3.2) and 
4 (4.1 and 4.2). 
 
If dosing with the study medication needs to be conducted at the same timepoints as the 
blood sampling, the blood sampling should be conducted first before the dose of study 
medication is given. 
 
 


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Appendix 2 - 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, glucose, insulin, Hb1Ac, total cholesterol, high 
density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, 
triglycerides, hsCRP, osteocalcin, CTX, plasma renin 
 
 
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 3 - 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.  
 
For US NIH clinical centre only (new text in bold): 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 Summary of Product Characteristics (SmPC) of hydrocortisone is used as the reference for 
expected AEs (http://www.medicines.org.uk/emc/medicine/27652). However, some of the data 
in the hydrocortisone SmPC clearly relates to anti-inflammatory immunosuppressive doses of 
glucocorticoid, which will not be used in this study of Chronocort®. Should such 
immunosuppressive events be observed they would be unexpected so are not included. 
 
The following is reproduced from section 4.8 of the 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. 
 


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


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Appendix 6 - SF-36® 
 
SF-36v2® HEALTH SURVEY (FOUR-WEEK RECALL) 
 
SCRIPT FOR INTERVIEW ADMINISTRATION 
 
 
These first questions are about your health now and your current daily activities. 
 
Please try to answer every question as accurately as you can. 
 
 
 
1. 
In general, would you say your health is…     [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
Excellent .......................................................................................................................... 1 
 
 
Very good ......................................................................................................................... 2 
 
 
Good ................................................................................................................................ 3  
 
 
Fair .................................................................................................................................. 4 
 
 
or Poor ............................................................................................................................. 5 
 
 
2. 
Compared to one year ago, how would you rate your health in general now?  
Would you say it is…    [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
Much better now than one year ago ................................................................................... 1 
 
 
Somewhat better now than one year ago ........................................................................... 2 
 
 
About the same as one year ago ........................................................................................ 3 
 
 
Somewhat worse now than one year ago ........................................................................... 4 
 
 
or Much worse now than one year ago ............................................................................... 5 
 
 
Now I'm going to read a list of activities that you might do during a typical day.  
As I read each item, please tell me if your health now limits you a lot, limits you a little, or 
does not limit you at all in these activities. 
 
 
3a. 
First, vigorous activities, such as running, lifting heavy objects, participating in 
strenuous sports. Does your health now limit you a lot, limit you a little, or not 
limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 


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3b. 
. . . moderate activities, such as moving a table, pushing a vacuum cleaner, 
bowling, or playing golf. Does your health now limit you a lot, limit you a little, or 
not limit you at all? [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3c. 
. . . lifting or carrying groceries. Does your health now limit you a lot, limit you a 
little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3d . 
. . . climbing several flights of stairs. Does your health now limit you a lot, limit 
you a little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3e. 
. . . climbing one flight of stairs. Does your health now limit you a lot, limit you a 
little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 


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3f . 
. . . bending, kneeling, or stooping. Does your health now limit you a lot, limit you 
a little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3g. 
. . . walking more than a mile. Does your health now limit you a lot, limit you a 
little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
 
 
(Circle one number)  
   
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3h . 
. . . walking several hundred yards. Does your health now limit you a lot, limit you 
a little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
3i . 
. . . walking one hundred yards. Does your health now limit you a lot, limit you a 
little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 


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3j. 
. . . bathing or dressing yourself. Does your health now limit you a lot, limit you a 
little, or not limit you at all?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
 
[IF RESPONDENT SAYS S/HE DOES NOT DO ACTIVITY, PROBE:  Is that because of your 
health?] 
 
(Circle one number) 
 
 
Yes, limited a lot ............................................................................................................... 1 
 
 
Yes, limited a little ............................................................................................................ 2 
 
 
No, not limited at all .......................................................................................................... 3 
 
 
The following four questions ask you about your physical health and your daily activities. 
 
 
4a. 
During the past four weeks, how much of the time have you had to cut down on 
the amount of time you spent on work or other daily activities as a result of your 
physical health?  [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
4b. 
During the past four weeks, how much of the time have you accomplished less 
than you would like as a result of your physical health?  [READ RESPONSE CHOICES] 
 
(Circle one number)  
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 


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4c. 
During the past four weeks, how much of the time were you limited in the kind of 
work or other regular daily activities you do as a result of your physical health?   
[READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
4d. 
During the past four weeks, how much of the time have you had difficulty 
performing work or other regular daily activities as a result of your physical 
health, for example, it took extra effort?  [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
The following three questions ask about your emotions and your daily activities. 
 
 
5a. 
During the past four weeks, how much of the time have you had to cut down the 
amount of time you spent on work or regular daily activities as a result of any 
emotional problems, such as feeling depressed or anxious?  [READ RESPONSE 
CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 


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5b. 
During the past four weeks, how much of the time have you accomplished less 
than you would like as a result of any emotional problems, such as feeling 
depressed or anxious?  [READ RESPONSE CHOICES] 
 
(Circle one number)  
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
5c. 
During the past four weeks, how much of the time did you do work or other 
regular daily activities less carefully than usual as a result of any emotional 
problems, such as feeling depressed or anxious?  [READ RESPONSE CHOICES] 
 
(Circle one number)  
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
6. 
During the past four weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups?  Has it interfered . . . [READ RESPONSE CHOICES] 
 
(Circle one number)  
 
Not at all .......................................................................................................................... 1 
 
Slightly ............................................................................................................................. 2 
 
Moderately ....................................................................................................................... 3 
 
Quite a bit ........................................................................................................................ 4 
 
or Extremely ..................................................................................................................... 5 
 
 
7. 
During the past four weeks, how much did pain interfere with your normal work, 
including both work outside the home and housework?  Did it interfere . . . [READ 
RESPONSE CHOICES] 
 
(Circle one number) 
 
Not at all .......................................................................................................................... 1 
 
A little bit ......................................................................................................................... 2 
 
Moderately ....................................................................................................................... 3 
 
Quite a bit ........................................................................................................................ 4 
 
or Extremely ..................................................................................................................... 5 


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8. 
How much bodily pain have you had during the past four weeks?  Have you had . .  
[READ RESPONSE CHOICES] 
 
(Circle one number) 
 
None ................................................................................................................................ 1 
 
Very mild .......................................................................................................................... 2 
 
Mild .................................................................................................................................. 3 
 
Moderate .......................................................................................................................... 4 
 
Severe.............................................................................................................................. 5 
 
or Very severe .................................................................................................................. 6 
 
 
The next questions are about how you feel and how things have been with you during the 
past four weeks. 
 
As I read each statement, please give me the one answer that comes closest to the way 
you have been feeling; is it all of the time, most of the time, some of the time, a little of 
the time, or none of the time? 
 
 
9a. 
How much of the time during the past four weeks . . . did you feel full of life?  
[READ RESPONSE CHOICES] 
 
(Circle one number) 
 
All of the time ................................................................................................................... 1 
 
Most of the time ............................................................................................................... 2 
 
Some of the time .............................................................................................................. 3 
 
A little of the time ............................................................................................................. 4 
 
or None of the time ........................................................................................................... 5 
 
 
9b. 
How much of the time during the past four weeks . . . have you been very 
nervous?  [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 


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9c. 
How much of the time during the past four weeks . . . have you felt so down in the 
dumps that nothing could cheer you up?  [READ RESPONSE CHOICES ONLY IF 
NECESSARY] 
 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
9d. 
How much of the time during the past four weeks . . . have you felt calm and 
peaceful?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
9e. 
How much of the time during the past four weeks . . . did you have a lot of 
energy?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
9f. 
How much of the time during the past four weeks . . . have you felt downhearted 
and depressed?  [READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 


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9g. 
How much of the time during the past four weeks . . . did you feel worn out?  
[READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
9h. 
How much of the time during the past four weeks . . . have you been happy?  
[READ RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
9i. 
How much of the time during the past four weeks . . . did you feel tired?  [READ 
RESPONSE CHOICES ONLY IF NECESSARY] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
 
10. 
During the past four weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities like visiting with friends 
or relatives?  Has it interfered . . . [READ RESPONSE CHOICES] 
 
(Circle one number) 
 
 
All of the time ................................................................................................................... 1 
 
 
Most of the time ............................................................................................................... 2 
 
 
Some of the time .............................................................................................................. 3 
 
 
A little of the time ............................................................................................................. 4 
 
 
or None of the time ........................................................................................................... 5 
 
  
 


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These next questions are about your health and health-related matters. 
 
Now, I'm going to read a list of statements. After each one, please tell me if it is definitely 
true, mostly true, mostly false, or definitely false. If you don't know, just tell me. 
 
11a. 
I seem to get sick a little easier than other people. Would you say that's . . . [READ 
RESPONSE CHOICES] 
 
(Circle one number) 
 
 
Definitely true ................................................................................................................... 1 
 
 
Mostly true ....................................................................................................................... 2 
 
 
Don't know ....................................................................................................................... 3 
 
 
Mostly false ...................................................................................................................... 4 
 
 
or Definitely false .............................................................................................................. 5 
 
11b. 
I am as healthy as anybody I know. Would you say that's . . . [READ RESPONSE 
CHOICES] 
 
(Circle one number) 
 
 
Definitely true ................................................................................................................... 1 
 
 
Mostly true ....................................................................................................................... 2 
 
 
Don't know ....................................................................................................................... 3 
 
 
Mostly false ...................................................................................................................... 4 
 
 
or Definitely false .............................................................................................................. 5 
 
11c. 
I expect my health to get worse. Would you say that's . . . [READ RESPONSE 
CHOICES] 
 
 
(Circle one number) 
 
 
Definitely true ................................................................................................................... 1 
 
 
Mostly true ....................................................................................................................... 2 
 
 
Don't know ....................................................................................................................... 3 
 
 
Mostly false ...................................................................................................................... 4 
 
 
or Definitely false .............................................................................................................. 5 
 
11d. 
My health is excellent. Would you say that's . . . [READ RESPONSE CHOICES] 
 
 
(Circle one number) 
 
 
Definitely true ................................................................................................................... 1 
 
 
Mostly true ....................................................................................................................... 2 
 
 
Don't know ....................................................................................................................... 3 
 
 
Mostly false ...................................................................................................................... 4 
 
 
or Definitely false .............................................................................................................. 5 
 
 


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DO NOT read the following text to the survey respondent 
 
Important Instruction for Interviewer:  
When using this script for interview administration of the SF-36v2 survey, note that items 7 and 
8 from the Bodily Pain health domain scale are administered in reverse order from the way they 
appear on the printed SF-36v2 self-administered paper form. Reversing the order of the 
presentation of these two items facilitates the flow of the interview administration.  
 
When recording responses from interview administration of the SF-36v2, the response to Item 7 
from the interview script should be entered in the Item 8 response area on the paper form, and 
vice versa.  
 
Note: All QualityMetric scoring solutions only support the scoring of items as ordered on the 
printed SF-36v2 self-administered paper form.  


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Appendix 7 - MAF 
 
 
 
 
 
 


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Appendix 8 - EQ-5D Health Questionnaire 
 
 
 


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Appendix 9 - Labelling of IMP and Rescue Medication 
 
EU Primary (Blister) label (version number: DIUR-005.IMP.EU.01.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
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-005         
Subject No.: YY  
 
EudraCT-No. 2015-000711-40 
Keep out of reach of children 
 
EU Secondary (Blister) label (version number: DIUR-005.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-005         
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., Cardiff, U.K.   Phone: +44 2920682069  
CRO: 
 
 
EudraCT-No. 2015-000711-40 
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
 
EU Primary (Bottle) label (version number: DIUR-005.IMPBOT.EU.01.001) 
 
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-005         
Subject No.: YY  
Pack No.: YY 


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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., Cardiff Medicentre, Heath Park, Cardiff, U.K.   Phone: +44 2920682069  
CRO: 
 
 
EudraCT-No. 2015-000711-40 
No special precautions for unused product: refer to accompanying documents 
Keep out of reach of children 
 
EU comparator label (version number: DIUR-005.COMP.EU.02.001) 
 
Protocol No.: DIUR-005         
Subject No.: YY  
 
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
PI: 
 
EudraCT-No. 2015-000711-40 
 
EU safety pack label (version number: DIUR-005.SAFE.EU.02.001) 
 
Protocol No.: DIUR-005         
Subject No.: YY  
 
Contents: YY 
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
PI: 
 
EudraCT-No. 2015-000711-40 
 
US Primary (Blister) label (version number: DIUR-005.IMP.US.01.001) 
 
Chronocort® Hydrocortisone Modified Release Capsules X mg 
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
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-005         
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 
 


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US Secondary (Blister) label (version number: DIUR-005.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-005         
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., Cardiff, U.K. Phone: +44 2920682069  
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 
 
US Primary (Bottle) label (version number: DIUR-005.IMPBOT.US.01.001) 
Chronocort® Hydrocortisone Modified Release Capsules Xmg 
Quantity: 100 capsules 
Batch No.: XXXX 
Storage: Store at no more than 25°C 
Expiry: MM/YYYY 
Protocol No.: DIUR-005        
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 
Keep out of reach of children 
No special precautions for unused product: refer to accompanying documents 
CAUTION: New Drug Limited by Federal (or United States Law) for Investigational Use 
IND No.: 076485 
Sponsor: Diurnal Ltd., Cardiff Medicentre, Heath Park, Cardiff, U.K. Phone: +44 2920682069 
PI: 
 
CRO: 
 
 
 


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US comparator label (version number: DIUR-005.COMP.US.02.001) 
 
Protocol No.: DIUR-005         
Subject No.: YY  
 
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
PI: 
 
IND No.: 076485 
 
US safety pack label (version number: DIUR-005.SAFE.US.02.001) 
 
Protocol No.: DIUR-005         
Subject No.: YY  
Contents: YY  
Sponsor: Diurnal Ltd., Cardiff, U.K. Phone: +44 2920682069 
PI: 
 
IND No.: 076485 
 
 


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Appendix 10 - Protocol Amendment History 
 
Protocol Version 1.0 dated 03 July 2015 
Original protocol. 
 
Protocol Version 2.0 dated 03 September 2015 
The protocol was amended to address MHRA comments on the protocol and to make a small 
administerative change to the Adrenal Insufficieny Checklist. The following changes were 
made:  
 
1) Modification of the RSI in the Investigator’s Brochure (IB) necessitated an update to 
Appendix 3 (Expected Adverse Events) in the protocol. 
2) Clarification was added that the DSMB is independent.  
3) The inclusion criteria of PRA less than 2 x ULN was reduced to PRA less than 1.5 x ULN. 
4) Appendix 5 was updated to a newer version of the Adrenal Insufficiency Checklist (minor 
administrative change). 
Protocol Version 3.0 dated 03 December 2015 
The protocol was amended to address the Swedish Medicines Agency and the US National 
Institutes of Health comments on the protocol that a separate benefit/risk assessment should be 
added. The following changes were made:  
 
1) Section 5: new section added at the end of Section 5 titled Benefit/Risk Assessment. 
Protocol Version 4.0 dated 28 May 2016 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
. 
 
2) 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 mineralocorticoid 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. 
 
3) The protocol stated that blood samples should be taken for genotyping, unless genotyping 
had previously been performed. It was clarified that if previous genotyping had been 
performed the patient has to be asked for their permission for this information to be taken 
from their medical records. 


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4) Subjects who routinely work night shifts and so do not sleep during the usual nighttime 
hours was added to the exclusion criteria. 
 
5) At the request of the Dutch ethics committee, the following sentence has been added to the 
procedures for the screening visit (Section 11.1.1) and also in Section 11.4 (Informed 
Consent): At Dutch centres only, potential subjects will be approached by their own 
treating physician. If the treating physician is also the investigator the subject information 
sheet can be provided immediately. If this is not the case then the treating physician will 
ask the patient for permission for the investigator to approach them about study 
participation. 
 
6) It was noted that the terminology for the independent blinded physician was not consistent 
throughout the protocol so this was corrected throughout.  
 
7) 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.’ 
 
Protocol Version 5.0 dated 23 September 2016 
 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
 
 
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. 
 
Protocol Version 6.0 dated 13 April 2017 
 
The following changes were made to the protocol: 
 
1) The statistician was changed from 
. 
 
2) The sample size was increased from 110 to 120 patients due to a higher level of protocol 
deviations than originally anticipated. As such, the inevaluability rate has been increased 
from 7% to 15%. 
 
3) The titration instructions in Section 8 (Dose Adjustment) has been modified to provide 
guidance if the independent blinded physician states that a change to the midday dose is 
needed but the patient is either receiving Chronocort or is receiving twice daily dosing of 
standard therapy. In such cases the local investigator is instructed to decide whether to 


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adjust the morning or evening dose, based on their judgement, in addition to any changes 
already advised for morning and evening doses, thus ensuring that the total change advised 
is accommodated within the day. 
 
4) The screening period has been extended by 1 week (21 days) to allow extra time for the 
study site to obtain the results of the screening PRA test.  
 
5) Clarification added to Sections 9.2 and 11.7 and the synopsis that female subjects 
presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 years of age should 
be considered potentially fertile and therefore, as well as undergoing pregnancy testing 
like all other female subjects, will be expected to be using an acceptable method of 
contraception, as listed in Section 11.7. 
 
6) 
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.  
 
Protocol Version 7.0 dated 23 August 2017 (administrative local amendment for US only) 
 
Following comments from the IRB, an additional statement has been added in Appendix 3 
(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 NIH clinical centre 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).  

SAP_001.pdf: 
Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 1 of 54 
 
 
 
 
Title: Statistical Analysis Plan for DIUR-005: A Phase III study of efficacy, safety 
and tolerability of Chronocort® compared with standard glucocorticoid 
replacement therapy in the treatment of congenital adrenal hyperplasia  
 
 
Compound Name/Number: Chronocort® 
 
Effective Date: 13 Sep 2018  
 
Subject: Congenital Adrenal Hyperplasia 
 
 
 
 
Author’s Name, Title and Functional Area: 
. 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright © 2018 
. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 2 of 54 
Signature pages 
The signatories on the following pages have all read and approved this present version of the 
document. 
The following signatures are required: 
Medical Director 
 
Statistician 
  
 
 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 3 of 54 
Approved by: 
 
STUDY SPONSOR: 
Diurnal Ltd. 
Cardiff Medicentre  
Heath Park 
Cardiff 
CF14 4UJ 
UK 
 
I certify that I have read this version of the Statistical Analysis Plan and approve its contents. 
 
Signed: 
 
                  
 
 
 




Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 5 of 54 
 
Table of Contents 
Signature pages ....................................................................................................................................... 2 
Table of Contents .................................................................................................................................... 5 
Abbreviations .......................................................................................................................................... 8 
Trademark Information ........................................................................................................................... 9 
Revision history ..................................................................................................................................... 10 
1. 
Introduction .................................................................................................................................. 18 
2. 
Study objectives and endpoints .................................................................................................... 19 
2.1. 
Study objectives .................................................................................................................... 19 
2.1.1. 
Primary objective .......................................................................................................... 19 
2.1.2. 
Secondary objectives .................................................................................................... 19 
2.2. 
Study endpoints .................................................................................................................... 19 
2.2.1. 
Primary endpoints ......................................................................................................... 19 
2.2.2. 
Secondary endpoints .................................................................................................... 19 
2.2.3. 
Safety endpoints ........................................................................................................... 19 
2.3. 
Statistical hypotheses ........................................................................................................... 19 
2.3.1. 
Primary hypothesis ....................................................................................................... 19 
2.3.2. 
Secondary hypotheses .................................................................................................. 20 
2.3.3. 
Multiple testing strategy ............................................................................................... 20 
2.4. 
Exploratory objectives, endpoints and hypotheses .............................................................. 20 
2.4.1. 
Exploratory objectives .................................................................................................. 20 
2.4.2. 
Exploratory endpoints ................................................................................................... 21 
3. 
Study design .................................................................................................................................. 21 
4. 
Timing of planned analyses ........................................................................................................... 22 
4.1. 
Data Review Meeting ............................................................................................................ 22 
4.2. 
Interim analyses .................................................................................................................... 22 
4.3. 
Final analysis ......................................................................................................................... 22 
5. 
Sample size considerations ........................................................................................................... 23 
6. 
Analysis populations ..................................................................................................................... 23 
6.1. 
Full analysis set ..................................................................................................................... 23 
6.2. 
Efficacy evaluable set ............................................................................................................ 23 
6.3. 
Safety analysis set ................................................................................................................. 23 
7. 
Treatment comparisons ................................................................................................................ 24 
7.1. 
General .................................................................................................................................. 24 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 6 of 54 
7.2. 
Data display (treatments and other subgroups) descriptors ................................................ 24 
8. 
General considerations for data analyses ..................................................................................... 25 
8.1. 
Standard summary statistics ................................................................................................. 25 
8.2. 
Standard comparison methods ............................................................................................. 25 
8.3. 
Statistical significance and multiple testing strategy ............................................................ 25 
8.4. 
Strata and covariates ............................................................................................................ 25 
8.5. 
Examination of subgroups .................................................................................................... 26 
9. 
Data handling conventions ........................................................................................................... 26 
9.1. 
Premature withdrawal and missing data .............................................................................. 26 
9.2. 
Derived and transformed data.............................................................................................. 26 
9.2.1. 
Baseline and demographic derivations ......................................................................... 26 
9.2.2. 
Derivations of SDS scores .............................................................................................. 27 
9.2.3. 
Conversion factors ........................................................................................................ 28 
9.2.4. 
Coding of adverse events, concomitant medications, etc. ........................................... 29 
9.3. 
Assessment time windows .................................................................................................... 30 
9.3.1. 
Definition of permissible time windows ....................................................................... 30 
9.3.2. 
Baseline Assessment ..................................................................................................... 30 
9.3.3. 
Methods for handling out-of-window observations ..................................................... 30 
9.3.4. 
Other clinical laboratory values below the lower limit of quantification ..................... 31 
9.4. 
Handling outliers ................................................................................................................... 31 
10. 
Study population ....................................................................................................................... 31 
10.1. 
Disposition of subjects ...................................................................................................... 31 
10.2. 
Protocol deviations ........................................................................................................... 31 
10.3. 
Demographic and baseline characteristics ....................................................................... 32 
10.4. 
Treatment compliance ...................................................................................................... 32 
10.5. 
Primary efficacy analysis ................................................................................................... 33 
10.6. 
Secondary efficacy analyses .............................................................................................. 33 
10.6.1. 
Secondary hormonal profile analysis ............................................................................ 33 
10.6.2. 
DEXA scans .................................................................................................................... 34 
10.7. 
Other efficacy analysis ...................................................................................................... 34 
10.7.1. 
Exploratory hormonal profile analysis .......................................................................... 34 
10.7.2. 
Bone markers and laboratory assessments of special interest .................................... 35 
10.7.3. 
Quality of life (QoL) questionnaires .............................................................................. 35 
10.7.4. 
Use of glucocorticoids ................................................................................................... 37 
10.7.5. 
Sensitivity analyses ....................................................................................................... 37 
11. 
Safety analyses .......................................................................................................................... 38 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 7 of 54 
11.1. 
Extent of exposure ............................................................................................................ 38 
11.2. 
Adverse events .................................................................................................................. 38 
11.3. 
Adverse events of special interest .................................................................................... 40 
11.3.1. 
Use of “sick days” .......................................................................................................... 40 
11.3.2. 
Adrenal crises ................................................................................................................ 40 
11.3.3. 
Unexpected therapeutic benefit ................................................................................... 40 
11.4. 
Routine clinical laboratory evaluations............................................................................. 40 
11.4.1. 
Naming conventions ..................................................................................................... 40 
11.4.2. 
Haematology ................................................................................................................. 40 
11.4.3. 
Clinical biochemistry ..................................................................................................... 42 
11.4.4. 
Urinalysis ....................................................................................................................... 43 
11.5. 
Vital signs .......................................................................................................................... 43 
11.6. 
Electrocardiogram (ECG) ................................................................................................... 44 
11.7. 
Other safety evaluations ................................................................................................... 44 
11.7.1. 
Physical examination..................................................................................................... 44 
11.7.2. 
Concomitant medications excluding glucocorticoid steroids ....................................... 45 
11.7.3. 
Use of dispensed sick day medications and steroids taken in addition to IMP ............ 45 
11.7.4. 
Adrenal insufficiency ..................................................................................................... 46 
12. 
Changes from the planned analyses ......................................................................................... 46 
13. 
References ................................................................................................................................ 47 
14. 
Appendix A – List of tables, listings and figures ........................................................................ 48 
14.1. 
List of planned tables ........................................................................................................ 48 
14.2. 
List of planned listings ....................................................................................................... 50 
14.3. 
List of planned figures ....................................................................................................... 52 
14.3.1. 
Summary figures ........................................................................................................... 52 
14.3.2. 
Individual patient figures .............................................................................................. 52 
15. 
Appendix B – Laboratory test display names and SDTM standard nomenclature ................... 53 
 
 
 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 8 of 54 
Abbreviations 
17-OHP 
17-hydroxyprogesterone  
A4 
Androstenedione 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
‘Anatomical Therapeutic Chemical’ drug classification (WHO) 
AUC 
Area under the curve  
BMI 
Body mass index 
BP 
Blood pressure; Bodily pain 
BUN 
Blood urea nitrogen  
CAH 
Congenital adrenal hyperplasia  
CK 
Creatine kinase  
Cmax 
The maximum concentration achieved after a single dose 
CO2 
Carbon dioxide  
CSR 
Clinical study report  
CTX 
C-terminal cross-linked telopeptide 
CV 
Cardiovascular 
DBP 
Diastolic blood pressure  
DEXA 
Dual Energy X-ray Absorptiometry  
ECG 
Electrocardiogram 
EQ-5D™ 
EQ-5D™ Standardised Health Questionnaire (5-level) 
GC 
Glucocorticoid 
GFI 
Global Fatigue Index 
GH 
General health  
Hb 
Haemoglobin 
HbA1c 
Glycated haemoglobin  
Hct 
Haematocrit 
HDL 
High density lipoprotein  
HOMA-IR 
Homeostasis model assessment of insulin resistance 
hsCRP 
High sensitivity C-reactive protein  
IMP 
Investigational medicinal product  
LDH 
lactate dehydrogenase  
LDL 
low density lipoprotein  
LLOQ 
lower limit of quantification  
LLT 
Lowest Level Term (MedDRA®) 
LS 
Least Squares 
MAF 
Multidimensional Assessment of Fatigue 
MCH 
Mean cell haemoglobin 
MCHC 
Mean cell haemoglobin concentration 
MCV 
Mean corpuscular volume 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 9 of 54 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MH 
Mental health 
PF 
Physical functioning  
PK 
Pharmacokinetic 
PLT 
Platelet count  
PRA 
Plasma renin activity  
PT 
Preferred term 
QoL 
Quality of life  
QTcB 
Bazett’s QTc interval 
QTcF 
Fridericia’s QTc interval 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RE 
Role-emotional 
RP 
Role-physical 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan  
SBP 
Systolic blood pressure  
SD 
Standard deviation  
SDS 
Standard deviation score  
SDTM 
Study Data Tabulation Model  
SF 
Social functioning 
SF-36®  
Medical Outcome Short Form Health Survey Form 36 (Subject Questionnaire) 
SI 
International system of units 
SOC 
System Organ Class 
VAS 
Visual analogue scale 
VT 
Vitality 
WBC 
White blood cell 
WHO 
World Health Organisation 
Trademark Information 
SAS 
SAS (Statistical Analysis Software) is a registered trademark of SAS 
Institute Inc. 
Chronocort 
Chronocort is a registered trademark of Diurnal Ltd 
SF-36v2 
SF-36v2 is a registered trademark of QualityMetric Incorporated 
EQ-5D 
EQ-5D is a registered trademark of the EuroQol Research Foundation  
QualityMetric Health 
Outcomes™ Scoring 
Software 4.5 
QualityMetric Health Outcomes™ Scoring Software 4.5 is a registered 
trademark of QualityMetric Incorporated 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 10 of 54 
Revision history  
Version 
Date 
Summary of revisions 
1.0 
30 Sept 2015 
Initial version 
2.0 
 
 
11 Sept 2017 
Section 1 Introduction:  
Clarified that SAP Version 1.0 was written using Protocol Version 2.0 
dated 3 September 2015 and that at the time of writing SAP Version 2.0 
the most recent version of the Protocol was Protocol Version 7.0 dated 
23 August 2017.  
 
 
Section 3 Study design and Section 5 Sample size considerations: 
The SAP text was updated to reflect the change to the sample size in 
Protocol Version 6.0 dated 13 April 2017 which states ‘The sample size 
was increased from 110 to 120 patients due to a higher level of protocol 
deviations than originally anticipated. As such, the inevaluability rate 
has been increased from 7% to 15%.’ 
Note: The original rate of 7% was estimated from a single site 16 
subject Phase II study and hence has been updated to reflect the rate 
expected in a Phase III multiple site study in this patient population. 
 
 
Section 3 Study design: 
Additional information regarding titration instructions which was added 
to Protocol Section 8 (Dose Adjustment) has been included.  
 
 
Section 7.2 Data display (treatments and other subgroups): 
In Table 7 the Full data display descriptor has been updated to 
‘Prednisone or Prednisolone’ for the ‘Pre-baseline therapy of 
prednisone or prednisolone (alone or in combination with 
hydrocortisone)’ stratification factor/subgroup. 
 
 
Section 9.1 Premature withdrawal and missing data: 
Text has been added for imputation/handling of missing or partial 
dates. Text has been added to specify how middle doses for subjects 
receiving standard care will be handled. 
 
 
Section 9.2.1 Baseline and demographic derivations: 
Derivation of Age in years has been corrected. 
Derivation of Time since CAH diagnosis added. 
 
 
Section 9.2.2 Derivations of SDS scores: 
References and justification for Normal reference ranges for 17-OHP 
and A4 which will be used in the derivation of the SDS scores for 
17-OHP and A4. These have been added as footnotes to Tables 2 and 3. 
Removal of text stating that ‘These reference ranges are to be reviewed 
by the contracted laboratories and are subject to change.’ 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 11 of 54 
 
 
Section 9.2.3 Conversion factors: 
Included Finkielstain 2012 reference for conversion factors used. 
Added restriction for Dexamethasone conversion to Chronocort® from 
Protocol Version 4.0 in Table 4. 
Updated text to state that laboratory data will be presented in both SI 
and conventional units. 
 
 
Section 9.2.4 Coding of adverse events, concomitant medications, 
etc.: 
Removed physical examinations as these are not coded. 
Included prior CAH medication which are coded using the World Health 
Organisation (WHO) Drug Dictionary including Anatomical Therapeutic 
Chemical (ATC) drug classification 
 
 
Section 9.3.1 Definition of permissible time windows: 
Derivation of actual study day has been updated so that it is 
appropriate for subjects whose dosing regimen does not include an 
evening dose. 
Clarified that all assessments which are performed at the baseline visit 
(Visit 1, Days 1 and 2) will be considered prior to randomised study 
treatment 
Target study day ranges added to Table 7. A per CDISC standards there 
is no study day 0, hence the target study day for Baseline (Visit 1) has 
corrected (i.e. updated from target study day 0, 1 to -1, 1). 
 
 
Section 10.2 Protocol deviations: 
Cross-reference to Section 6.2 fixed. 
Specified that summary and listing would also include protocol 
category. 
 
 
Section 10.3 Demographic and baseline characteristics: 
Listing of demographic information added. 
Summary and listing of baseline disease characteristics added. 
Listing of genotyping information added. 
Signs and symptoms of adrenal insufficiency moved to new Section 
11.7.4 under Section 11.7 Other safety evaluations. 
 
 
Section 10.4 Treatment compliance: 
Derivation of visit intervals updated so they apply to all dosing regimens 
and do not depend on whether a subject has a morning or evening 
dose. 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
CONFIDENTIAL 
Page 12 of 54 
Additional detail added specifying how each interval will be split to take 
account of dose titrations. 
Summaries of sick day medications moved to new section - Section 
10.7.3 Use of dispensed sick day medications and steroids taken in 
addition to IMP. 
Listing of dispensed sick day medication pack accountability added. 
 
 
Section 10.5 Primary efficacy analysis: 
Residuals plots to check model fit of primary analysis model added. 
As the Normal reference ranges in Table 2 have been finalised the 
following paragraph was removed ‘The reference ranges given in Table 
2 are currently under review. The concentration-time plot may need to 
include separate panels if it is decided that there will be different 
reference ranges for different groups. If this is the case, the plot of the 
SDS score will also be produced with a different panel for each group to 
check the validity of the reference ranges.’ 
 
 
Section 10.6.1 Secondary hormonal profile analysis: 
References and justification for the optimal reference range for 17-OHP 
and Normal reference range for A4 which will be used to define 
whether a subject is a responder. These have been added as footnotes 
to Tables 7. Removal of text stating that ‘These reference ranges are to 
be reviewed by the contracted laboratories and are subject to change.’ 
 
 
Section 10.7.2 Bone markers and laboratory assessments of special 
interest: 
Biomarkers updated to bone biomarkers in the Section heading and 
throughout the text in this Section. 
Shift tables to each visit relative to baseline replaced with shift tables to 
minimum on-treatment versus baseline and to maximum on-treatment 
versus baseline.  
 
 
Section 10.7.3 Quality of life (QoL) questionnaires: 
Additional descriptive text has been added for each questionnaire. 
References have been added for SF-36 and EQ-5DTM (derivation of 
single index score). 
 
 
Section 10.7.4 Use of glucocorticoids 
Text has been updated to reflect study team requested improvements 
of these summaries. 
Table of hydrocortisone dose increments versus baseline added.  
 
 
Section 11.1 Extent of exposure: 
Minor updates made specific to each treatment arm included. 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 13 of 54 
 
 
Section 11.2 Adverse events: 
Minor correction of typographical errors – ‘action taken’ updated to 
‘action taken with study drug’ and ‘effect of study drug’ removed from 
text. 
Text added to describe the Overview of AEs summary table which will 
be produced.  
 
 
Section 11.3.1 Use of “sick days rules” 
Section title updated to ‘Use of “sick day rules”’. 
Additional summary table of AEs leading to sick day rules by PT, route 
and sick day medication included.  
Listing updated to include information on sick day medications. 
 
 
Section 11.3.3 Unexpected therapeutic benefit: 
New Section added describing the additional summary and listing that 
will be produced for these events. 
 
 
Section 11.4.1 Naming conventions: 
Biomarkers updated to bone biomarkers. 
 
 
Section 11.4.2 Haematology: 
Clarification added regarding central and local laboratory results and 
reference ranges.  
Shift tables to each visit relative to baseline replaced with shift tables to 
minimum on-treatment versus baseline and to maximum on-treatment 
versus baseline. 
Haematology (1) will be summarised together across males and females 
for all summary tables. 
Formula to derive RDW-CV(%) using RDW-SD(fL) and MCV added. 
Formulae to derive 1) WBC differentials as percentages of WBCs when 
only WBC differential counts and WBC counts are provided and 2) WBC 
differential counts when only percentages of WBCs and WBC counts are 
provided, have been added.  
 
 
Section 11.4.3 Clinical biochemistry: 
Clarification added regarding central and local laboratory results and 
reference ranges.  
Shift tables to each visit relative to baseline replaced with shift tables to 
minimum on-treatment versus baseline and to maximum on-treatment 
versus baseline. 
 
 
Section 11.4.4 Urinalysis: 
Shift table of baseline to worst on-treatment added. 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 14 of 54 
 
 
Section 11.5 Vital signs: 
Split by dose level removed from summaries of absolute and change 
from baseline over time. 
Shift tables specified as being to minimum on-treatment versus 
baseline and to maximum on-treatment versus baseline. 
 
 
Section 11.6 Electrocardiogram (ECG): 
Split by dose level removed from summary of abnormal findings. 
 
 
Section 11.7.1 Physical examination: 
Abnormal findings tabulation replaced with shift table. 
Derivation of ‘Normal’ physical examination status based on 
information captured in eCRF added. 
 
 
Section 11.7.2 Concomitant medications excluding steroids: 
Section updated to reflect decision to exclude steroids from 
concomitant medication summary and listing. Steroids taken in addition 
to IMP will be summarised alongside use of sick day medications. 
 
 
Section 11.7.3 Use of dispensed sick day medications and steroids 
taken in addition to IMP: 
New section created using information regarding sick day medication 
use previously in Section 10.4 and steroids taken in addition to IMP 
which have been separated out from other concomitant medications. 
 
 
Section 11.7.4 Adrenal insufficiency: 
New section created. Information previously included in Section 10.3 
Demographic and baseline characteristics. 
 
 
Section 14 Appendix A – List of tables, listings and figures: 
Minor addition/removal of tables/listings following review of mock 
shells and SAP updates. 
3.0 
 
 
13 Aug 2018 
Section 1 Introduction:  
Added that at the time of writing SAP Version 3.0 the most recent 
version of the Protocol was Protocol Version 7.0 dated 23 August 2017. 
 
 
Section 9.1 Premature withdrawal and missing data Introduction: 
Subjects who have withdrawn prior to Week 12 will be assessed on the 
basis of the latest available 24-hour profile. 
 
 
Section 9.2.3 Conversion factors: 
Added conversion factor for PRA.   


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Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 15 of 54 
 
 
Section 9.3.4 Clinical laboratory values below the lower limit of 
quantification:  
New section created to outline how to handle values below the LLOQ.  
 
 
Section 10.2 Protocol deviations: 
Text added describing high level categories of protocol deviations that 
will be implemented. 
 
 
Section 10.3 Demographic and baseline characteristics: 
Text added describing the age categories that will be implemented.  
Medical history split out into two separate summary tables and listings: 
CAH medical history and Other medical history excluding CAH events. 
 
 
Section 10.4 Treatment compliance: 
Section updated to reflect decision that only overall treatment 
compliance will be derived.  
A listing of treatment compliance will be produced. 
 
 
Section 10.7.2 Bone markers and laboratory assessments of special 
interest: 
Glucose units in HOMA-IR derivation updated to mmol/L. 
Boxplots of change from baseline over time added for all bone marker 
and laboratory assessment of special interest parameters. 
 
 
Section 11.1 Extent of exposure: 
Summary of unplanned dose changes added.  
Listing of study drug dosing instructions added.  
 
 
Section 11.2 Adverse events: 
Updated text to reflect that AE summaries will include AEs occurring 
after the last day of study treatment for subjects who enter the 
extension study or the last day of study treatment plus 30 days for 
subjects who do not enter the extension study. 
 
 
Section 11.2.3 Adrenal crises: 
Section title updated to ‘Adrenal crises’. 
Section text updated to replace ‘Addisonian’ with ‘adrenal’. 
 
 
Section 11.4.2 Haematology: 
Boxplots of change from baseline over time added for all haematology 
parameters. 
 
 
Section 11.4.3 Clinical biochemistry: 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 16 of 54 
Boxplots of change from baseline over time added for all biochemistry 
parameters. 
 
 
Section 11.4.4 Urinalysis: 
Boxplots of change from baseline over time added for all continuous 
urinalysis parameters. 
 
 
Section 11.5 Vital signs: 
Boxplots of change from baseline over time added for all vital sign 
parameters. 
Reference ranges added for systolic blood pressure and diastolic blood 
pressure. 
 
 
Section 11.6 Electrocardiogram (ECG): 
Values with a change from baseline > 30 msec in QT interval, QTcB and 
QTcF will be flagged in the listing. 
Reference ranges added for all ECG parameters.  
 
 
Section 11.7.2 Concomitant medications excluding glucocorticoid 
steroids: 
Title updated to ‘Concomitant medication excluding glucocorticoid 
steroids’. 
Table added specifying which glucocorticoid steroids will be excluded 
from summary and listing. 
 
 
Section 12 Changes from the planned analyses: 
Updated to reflect the version of the SAP the changes from the planned 
analyses were made. 
 
 
Appendix 14.1 List of planned tables:  
Updated list of planned tables. 
 
 
Appendix 14.2 List of planned listings:  
Updated list of planned listings. 
 
 
Appendix 14.3.1 Summary figures: 
Updated list of planned summary figures. 
4.0 
 
 
11 Sep 2018 
Section 9.3.3 Methods for handling out-of-window observations 
In order to use all available endocrine samples the evaluable window 
was increased from +/- 15 minutes to +/- 60 minutes from the planned 
time point. The decision to implement this change was based on a case-
by-case review of blinded endocrine profiles with 2 or more missing (or 
out of window) at the Data Review Meeting prior to database lock and 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
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unblinding of the study. It was judged that this was more appropriate 
than the existing rule for handling out of window samples. 
Imputation rule added to handle completely missing endocrine results 
at the 15:00 planned time points within a 24-hour profile. 
 
 
Section 9.3.4 Other clinical laboratory values below the limit of 
quantification 
Section header updated to clarify the section does not refer to 17-OHP 
and A4.  
 
 
Signature pages 
The Sponsor signatory was changed from 
 
 
 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
CONFIDENTIAL 
Page 18 of 54 
1. Introduction 
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 et al. 2014).  
There is currently no standard treatment for this condition, and 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 
the 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. The proposed 
study will 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]). 
A phase II study (DIUR-003) was conducted in 16 subjects to evaluate the pharmacokinetic (PK) 
profile of cortisol following short-term twice-daily administration of Chronocort® (20mg at night and 
10mg 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 PK 
profile of Chronocort® was characterised by an overnight rise in cortisol levels reaching a maximal 
concentration approximately 8 hours post-dosing, consistent with the endogenous profile of cortisol 
reported in normal individuals. The variation in the maximum concentration achieved after a single 
dose (Cmax) and area under the curve (AUC) was similar to that seen in physiological cortisol levels in 
healthy volunteers.  
This 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 
28mg and on Chronocort® was 26mg. 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. 
The proposed study aims to build on the results of study DIUR-003 and further evaluate whether 
Chronocort® can provide improved control of serum androgen levels (using 17-OHP and A4 as 
markers) compared to current glucocorticoid treatment regimens. The purpose of this document is 
to formally set out the primary, secondary and safety statistical analyses to be conducted for this 
study. SAP version 1.0 was written using protocol version 2.0 dated 3 September 2015.  At the time 
of writing SAP version 2.0, the most recent version of the protocol is version 7.0 dated 
23 August 2017.  At the time of writing SAP version 3.0, the most recent version of the protocol is 
version 7.0 dated 23 August 2017. At the time of writing SAP version 4.0, the most recent version of 
the protocol was version 7.0 dated 23 August 2017. 


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2. Study objectives and endpoints 
2.1. 
Study objectives 
2.1.1. Primary objective 
To demonstrate the superior efficacy of Chronocort® compared with standard glucocorticoid 
replacement therapy in the treatment of CAH based on 17-OHP. 
2.1.2. Secondary objectives 
In adult subjects with CAH:  
• 
To assess the safety and tolerability of Chronocort® treatment in adult subjects with CAH 
over a 6-month period. 
• 
To assess the efficacy of Chronocort® with regard to the effect on A4 over the 6-month 
treatment period. 
• 
To assess the impact of Chronocort® on body composition (using dual energy X-ray 
absorptimetry [DEXA]) – fat mass, lean mass and total bone density – at selected sites. 
2.2. 
Study endpoints 
2.2.1. Primary endpoints 
The primary efficacy endpoint is the change from baseline to 24 weeks in the natural logarithm of 
the mean of the 24-hour standard deviation score (SDS) profile for 17-OHP. The SDS profile is 
calculated as the SDS of log-transformed 17-OHP concentration unsigned. 
2.2.2. Secondary endpoints 
1. The change from baseline to 24 weeks in the natural logarithm of the mean of the 24-hour SDS 
profile for A4 (calculated in the same way as the primary endpoint). 
2. The presentation of 17-OHP and A4 by individual baseline treatment strata in the study will be 
presented in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks). 
3. 17-OHP and A4 levels at 09:00 as a responder analysis (i.e. the number of subjects achieving 
results in the optimal or reference range respectively). 
4. Changes relative to standard glucocorticoid replacement therapy in body composition (DEXA) 
(fat mass, lean mass and total bone density) to be measured at all sites except Germany. 
2.2.3. Safety endpoints 
1. Routine haematology, biochemistry, physical examination, vital signs, urinalysis, 
electrocardiogram (ECG). 
2. Clinical adverse events (AEs) – particular note of use of sick day rules and Addisonian crises. 
Under or over-replacement with glucocorticoids will be considered in the efficacy endpoints. 
3. Changes relative to the standard treatment in weight, body mass index (BMI), waist 
circumference, and blood pressure (BP). 
2.3. 
Statistical hypotheses 
2.3.1. Primary hypothesis 
The primary comparison of interest is to test the null hypothesis H0: There is no difference between 
the mean change from baseline to 24 weeks in the primary efficacy variable (the natural logarithm of 


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the mean of the 24-hour SDS profile for 17-OHP) in Chronocort® compared to standard glucocorticoid 
replacement therapy, versus the alternative hypothesis H1: There is a difference in the mean change 
from baseline to 24 weeks in the primary efficacy variable in Chronocort® compared to standard 
glucocorticoid replacement therapy. The difference analysed will be the mean of the primary 
efficacy analysis variable for Chronocort® minus the mean of the primary efficacy analysis variable 
for standard glucocorticoid replacement therapy. This means that a negative difference will be in 
favour of Chronocort®. 
2.3.2. Secondary hypotheses 
For the secondary endpoint of the change from baseline to 24 weeks of the logarithm of the mean of 
the 24-hour SDS profile for A4, the same hypothesis as the primary analysis will be tested, with A4 in 
place of 17-OHP. 
The responder analysis will test the null hypothesis H01: The odds of response for Chronocort® is the 
same as the odds of response for standard glucocorticoid replacement therapy i.e. the odds ratio is 
1, versus the alternative hypothesis H11: The odds of response for Chronocort® is different to the 
odds of response for standard glucocorticoid replacement therapy. An odds ratio of greater than 1 
favours Chronocort®. Response is defined as the number of subjects achieving results in the optimal 
or reference ranges (See 10.6). The hypothesis will be tested separately for 17-OHP and A4.  
For the secondary endpoint of the change from baseline in body composition (DEXA), the results 
from the three tests: fat mass, lean mass, total bone density will be analysed separately. The results 
from each test will be used in turn to test the null hypothesis H02: There is no difference between the 
mean change from baseline to 24 weeks in the result for Chronocort® compared to standard 
glucocorticoid replacement therapy, versus the alternative hypothesis H12: There is a difference in 
the mean change from baseline to 24 weeks in the result for Chronocort® compared to standard 
glucocorticoid replacement therapy. 
 
2.3.3. Multiple testing strategy 
There will be no adjustment for multiple testing as the primary analysis will be considered the main 
analysis with the secondary and exploratory endpoints intended as support for the primary analysis.  
2.4. 
Exploratory objectives, endpoints and hypotheses 
The purpose of this document is to set out the primary, secondary and safety analyses, however 
several exploratory objectives will also be addressed in this study. The following were specified in 
the protocol, other analyses may be added on an ad hoc basis.  
2.4.1. Exploratory objectives 
• 
To assess the efficacy of Chronocort® with regard to the effect on testosterone levels over the 
6-month treatment period. 
• 
To assess the impact of Chronocort® on cardiovascular (CV) risk (evaluated using high-
sensitivity C-reactive protein [hsCRP]). 
• 
To assess the impact of Chronocort® on bone markers of serum C-terminal cross-linked 
telopeptide (CTX type I) and osteocalcin (after fasting). 
• 
To assess changes from baseline in glucose and insulin in the morning (after fasting)  
• 
To assess changes from baseline in glycated haemoglobin (HbA1c)  
• 
To assess changes from baseline in plasma renin activity (PRA) in the morning. 


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• 
To assess the impact of Chronocort® on quality of life (QoL) using SF-36®, Multidimensional 
Assessment of Fatigue (MAF), and EQ-5D™. 
• 
To assess subject compliance in subjects treated with Chronocort® over a 6-month period. 
 
2.4.2. Exploratory endpoints 
1. 
Partial AUC of 17-OHP at 15:00-23:00, 23:00-07:00, and 07:00-15:00 (all refer to actual clock 
time of sampling). 
2. 
The primary endpoint measure will also be presented for the profiles measured at 4 and 12 
weeks for the purposes of titration. 
3. 
Changes relative to standard treatment in the following: 
a. Bone markers – serum CTX and osteocalcin (after fasting) 
b. hsCRP 
c. Assessment of glucose and insulin in the morning (after fasting)  
d. Assessment of HbA1c, total testosterone, and PRA in the morning 
e. QoL using SF-36®, MAF, and EQ-5D™ 
4. 
Use of glucocorticoids at beginning and end of the study will be presented both as individual 
glucocorticoids used, and as calculated hydrocortisone equivalents using accepted conversion 
constants for the calculations. 
3. Study design 
This study is designed as a parallel arm, randomised, open-label study, including dose titration and 
admissions for four overnight stays for 24-hour endocrine profiles. It will compare the efficacy, 
safety and tolerability of Chronocort® with standard glucocorticoid replacement therapy in the 
treatment of CAH over a treatment period of 24 weeks. 
An overview of the study plan is illustrated in Figure 1. Written informed consent for the study will 
be obtained from subjects who have been stable on their current treatment for a minimum of 6 
months. Subjects will be screened and entered in the study provided they meet the 
inclusion/exclusion criteria. 120 subjects will be randomised into this study to obtain 102 evaluable 
subjects (individual sites should not recruit more than 25 subjects without first consulting the 
sponsor).  The randomisation either to Chronocort® or to continue on their original therapy will be 
stratified with regard to the subject’s prior treatment: 
1. Hydrocortisone only  
2. Prednisone or prednisolone, alone or in combination with hydrocortisone 
3. Dexamethasone only or in combination with any other glucocorticoid 
Dose titration decisions will be made within two weeks of each profiling visit at weeks 4 and 12 using 
a standard titration algorithm after the subject has been re-admitted for 24-hour profiles that 
include 17-OHP and A4. These decisions will be made by a central independent physician, blinded to 
the treatment arm to minimise bias. The actual treatment change will be made by the local 
investigator. The independent blinded physician will determine either that no change is required or 
that an increase/decrease in the morning/midday/evening medication is needed. In the event that a 
change in the midday dose is advised for a subject who is receiving Chronocort or in a subject who is 
receiving twice daily dosing of standard therapy, the local investigator must decide to make this 
dose change at the most appropriate timepoint in their judgement (morning or evening), in addition 


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to any changes already advised for morning and evening doses, so that the total change advised is 
accommodated within the day. 
Subjects completing the study will become eligible for an open extension study, in which all subjects 
will be offered Chronocort®. 
Figure 1: Overview of DIUR-005 Study Schema 
 
 
4. Timing of planned analyses 
4.1. 
Data Review Meeting 
The sponsor will convene a Data Review Meeting after the data has been cleaned and the database 
locked but before analysis has commenced. The review will be performed within the framework of 
the requirements of the ICH Guideline E9. The datasets used in the review will be masked to 
treatment allocation and dummy treatment groups with generic treatment labels will be used. The 
terms of reference for the Data Review Meeting are outlined in Section 13.10 of the protocol. 
4.2. 
Interim analyses 
No formal interim analysis is planned. 
4.3. 
Final analysis 
The final analysis will take place after the Data Review Meeting described in Section 4.1. 


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5. Sample size considerations 
A sample size of 102 subjects provides greater than 95% power and 2-sided alpha 5% to 
demonstrate a fall in the logarithm of the mean 24-hour unsigned SDS of 17-OHP relative to the 
standard glucocorticoid replacement therapy group. It is assumed that (i) the mean fall in the 
Chronocort® group will be the same (0.78) as that observed in the phase II study (DIUR-003) (ii) the 
mean fall in the standard therapy group will be 0.2 (approximately 25% of the Chronocort® phase II 
study fall) and (iii) the standard deviation of the fall (0.681) is that seen in the phase II study. The 
study is powered to ensure that there can be a reasonable description of the comparison of 
Chronocort® with a variety of standard therapies. 120 subjects will be randomised to this study 
which will account for an inevaluability rate of 15%. Individual sites should not recruit more than 25 
subjects without first consulting the sponsor. 
6. Analysis populations 
6.1. 
Full analysis set 
The full analysis set comprises all subjects who were randomised into the study, who received at 
least one dose of Chronocort® or standard therapy, and who had at least one evaluable 
post-randomisation 17-OHP 24-hour hormone profile. 
Subjects in the full analysis set will be analysed according to the actual treatment received (the first 
dose of treatment they actually took post randomisation).  
6.2. 
Efficacy evaluable set 
The efficacy evaluable analysis set comprises all subjects who were randomised into the study, who 
received at least one dose of Chronocort® or standard therapy, and who have an evaluable week 24 
17-OHP 24-hour hormone profile, and who have no major protocol violations. 
It is difficult to conduct trials in this indication.  This is the first comparative trial of a re-formulation 
of a standard therapy for CAH. The efficacy evaluable analysis set is therefore the primary analysis 
set for the evaluation of efficacy. The robustness of the conclusions will be assessed by repeating key 
efficacy analyses using the full analysis set. 
The final determination of the membership of analysis sets will be made at a Data Review Meeting 
convened by the sponsor before database lock. 
Subjects in the efficacy evaluable set will be analysed according to the actual treatment received. 
6.3. 
Safety analysis set 
The safety analysis set comprises all subjects who were randomised into the study and who 
subsequently received at least one dose of Chronocort® or standard therapy. 
Subjects in the safety analysis set will be analysed according to the actual treatment received.  
A summary will be produced of the number of subjects in each analysis population, together with 
reasons for exclusion from each analysis set. 


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7. Treatment comparisons 
7.1. 
General 
The comparison in all analyses will be between the Chronocort® treatment group and standard 
glucocorticoid replacement therapy. 
For the stratified secondary and exploratory analyses and the stratified analysis of the primary 
endpoint, comparisons will be presented for subgroups defined by the pre-baseline standard 
treatment. 
7.2. 
Data display (treatments and other subgroups) descriptors 
The treatment group descriptors to be used in outputs are listed in Table 1 below. The full data 
display descriptor is preferred, although the abbreviated option in the third column may be used if 
there is not enough space on the page. 
In general, where subgroups are presented in a table as three separate columns (optionally together 
with a “Total” column), then these columns should preferably be displayed using the full treatment 
group descriptor spanning all three columns (four including a “Total” column) as a “super-header” 
and either the full or abbreviated stratification descriptor underneath. 
Table 1: Treatment group and stratification subgroup descriptors 
Treatment group/stratification factor 
Full data display descriptor  
Abbreviated data 
display descriptor 
Treatment groups 
Chronocort® (Any pre-baseline standard 
therapy) 
Chronocort 
Cct 
Standard glucocorticoid replacement therapy 
(All groups combined) 
Standard GC therapy  
SGC 
Stratification factors (subgroups) 
Pre-baseline therapy of hydrocortisone only 
Hydrocortisone only 
Hydro 
Pre-baseline therapy of prednisone or 
prednisolone (alone or in combination with 
hydrocortisone) 
Prednisone or Prednisolone 
Pred 
Pre-baseline therapy of dexamethasone (alone 
or in combination with any other 
glucocorticoid) 
Dexamethasone 
Dex 
Combined treatment group/subgroups 
Chronocort® with pre-baseline therapy of 
hydrocortisone only 
Chronocort - Hydrocortisone only 
Cct - Hydro 


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Chronocort® with pre-baseline therapy of 
prednisone or prednisolone (alone or in 
combination with hydrocortisone) 
Chronocort – Prednisone or 
Prednisolone 
Cct - Pred 
Chronocort® with pre-baseline therapy of 
dexamethasone (alone or in combination with 
any other glucocorticoid) 
Chronocort - Dexamethasone 
Cct - Dex 
Standard glucocorticoid replacement therapy, 
hydrocortisone only 
Standard GC - Hydrocortisone 
only 
SGC - Hydro 
Standard glucocorticoid replacement therapy, 
prednisone or prednisolone (alone or in 
combination with hydrocortisone) 
Standard GC – Prednisone or 
Prednisolone 
SGC - Pred 
Standard glucocorticoid replacement therapy, 
dexamethasone (alone or in combination with 
any other glucocorticoid) 
Standard GC - Dexamethasone 
SGC - Dex 
8. General considerations for data analyses 
All statistical analyses will be performed using the software package SAS® version 9.1 or higher. 
8.1. 
Standard summary statistics 
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. 
8.2. 
Standard comparison methods 
In general, continuous variables will be compared across treatment groups using a Normal analysis 
of covariance (ANCOVA) linear model including pre-baseline standard therapy and, if appropriate, 
the baseline assessment of the variable as covariates in the model. In the case of change-from-
baseline variables, baseline will always be included as a covariate. 
Binary variables, such as response, will be compared using logistic regression with adjustment for 
covariates as in the continuous data case. 
8.3. 
Statistical significance and multiple testing strategy 
All significance probabilities will be reported as two tailed. Confidence intervals will be reported as 
95% two-sided. There will be no adjustment for multiple testing. 
8.4. 
Strata and covariates 
Pre-baseline standard therapy refers to the standard glucocorticoid replacement therapy the subject 
was receiving for at least 6 months prior to joining the study, namely the strata used for 
randomisation: 


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• 
Hydrocortisone only  
• 
Prednisone or prednisolone, alone or in combination with hydrocortisone 
• 
Dexamethasone only or in combination with any other glucocorticoid 
8.5. 
Examination of subgroups 
Additional exploratory and sensitivity analyses of the assessment of the efficacy results in subgroups 
may be required if appropriate. 
9. Data handling conventions 
9.1. 
Premature withdrawal and missing data 
Missing 17-OHP and A4 values (including those considered missing due to being taken outside the 
permitted time window) within the 24-hour hormone profile will be imputed by linear interpolation 
of the two closest non-missing measurements to the scheduled missing time point  (including out-of-
window measurements). Further details are given in Section 9.3.3. In the event that several values 
are missing from a single profile, a decision will be made about the validity of the whole profile at 
the Data Review Meeting on a case-by-case basis. 
For efficacy analyses based on the Week 12 and Week 24 visits, subjects who have withdrawn from 
the study will be assessed on the basis of the latest available 24-hour profile. This is a conservative 
procedure as subjects enter the study already receiving a suitable dose of their standard therapy.  
When calculations must be based upon incomplete dates the following process will be used.  If year 
is missing do not impute. The value should be considered missing.  If year is populated but both 
month and day are missing then the date defaults to 1st July.  If day only is missing then the day 
defaults to the 15th of the month.   
For adverse events and concomitant medications, if year is missing do not impute.  If start year is 
populated but both month and day are missing, or if month is missing and day is present, then the 
date defaults to 1st January.  If day only is missing then the day defaults to the 1st of the month.  If 
end year is populated but both month and day are missing, or if month is missing and day is present, 
then the date defaults to 31st December.  If day only is missing then the day defaults to last day of the 
month.   For definition of treatment emergent and ongoing, if partial dates are only available for start 
and end, then we are conservative and assume treatment emergent/ongoing. 
For those subjects with one middle dose then this is considered as “middle 1”, and middle2 is blank 
for all subjects except those with a second middle dose. 
Exploratory and sensitivity analyses will be performed to assess the effect of any missing data on the 
efficacy conclusions. This will be discussed at the Data Review Meeting and a decision will be made 
on the appropriate analyses. 
9.2. 
Derived and transformed data 
9.2.1. Baseline and demographic derivations 
The age of the subject in years will be determined using the date of birth (recorded at screening) and 
the date of consent. Since year only is being collected for this study, age will be calculated as the 
difference between the year of the screening visit and date of birth as: 
• 
Year of consent – year of birth + 1. 


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Time since CAH diagnosis will be determined using the date of CAH diagnosis captured in the 
electronic case record form (eCRF) and will be calculated as: 
• 
Date of randomisation – date of CAH diagnosis + 1 / 365.25. 
In the derivation of age at study entry and time since CAH diagnosis partial dates will be handled as 
described in Section 9.1. 
9.2.2. Derivations of SDS scores 
The primary efficacy variable is the natural logarithm of the mean of the 24-hour hormonal profile of 
the SDS for the natural logarithm of 17-OHP. The primary analysis is focused on the change from 
baseline to week 24 in the primary efficacy variable. 
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. 
The change from baseline to week 24 in the primary efficacy variable will be calculated in the 
following way: 
• Step 1: Calculate the SDS profile of log-transformed 17-OHP 
For each of the 13 concentrations at each visit (baseline, week 24), take the natural 
logarithm and then calculate the SDS by counting the number of standard deviations (given 
in Table 3) which are above or below the mean of the log transformed range (given in Table 
3). 
• Step 2: Calculate the mean of the SDS profile 
Calculate the arithmetic mean over all 24-hour SDSs at each visit with the first and last 
observations weighted one half relative to the intermediate observations, e.g. for 13 
observations (n1, … n13) this is calculated by (½n1+n2+...+n12+ ½n13)/12. Lower values of the 
mean of the SDS profile should be interpreted as “better” hormonal control. 
• Step 3: Change from baseline to 24 weeks 
Take the natural logarithm of the mean of the SDS profile for the week 24 visit and subtract 
the natural logarithm of the mean of the SDS profile for the baseline visit. Negative values of 
this result should be interpreted as an improvement in hormonal control compared with 
baseline. 
 


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Table 2: Normal reference ranges for 17-OHP and A4 
 
Male 
Female 
17 OHP 
1.2* – 6.7 nmol/L 
1.2* – 8.6 nmol/L 
A4 
1.4 -  5.2 nmol/L 
1.0 – 7 nmol/L 
Source: Mayo Clinic.  
17-OHP: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9231.  
Please note the upper reference range for females is during the Luteal phase. 
*There is no lower reference range available for 17-OHP, hence the lower limit of the optimal range (provided in 
Table 7) will be used in the derivation of the average SDS score. This will enable calculation of an ‘unsigned’ SDS 
score which can be used to assess potential overtreatment as well as undertreatment. 
A4: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9709 
 
Table 3: Mean and SD of normal log-transformed range 
Analyte 
Sex 
mean of loge-transformed range 
[ loge (nmol/L) ] 
SD of loge-transformed range 
[ loge (nmol/L) ] 
17-OHP 
Male 
1.042 
0.430 
Female 
1.167 
0.492 
A4 
Male 
0.993 
0.328 
Female 
0.973 
0.486 
Source: Mayo Clinic.  
17-OHP: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9231.  
Please note the upper reference range for females is during the Luteal phase. 
A4: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9709 
The mean of the “normal” log-transformed range was calculated by taking the natural logarithm of 
the upper and lower limit given in Table 2, calculating the range of the log-transformed values and 
finding the midpoint of the range. The SD of the log-transformed range was approximated by 
dividing the range of the log-transformed values by four. 
9.2.3. Conversion factors 
For the conversion of standard glucocorticoid replacement therapy to hydrocortisone, the 
conversion factors (Finkielstain 2012) are given in Table 4. 
 
 


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Table 4: Conversion factors for standard glucocorticoid replacement therapy to hydrocortisone 
Standard glucocorticoid 
replacement therapy 
Conversion factor 
Prednisone or prednisolone 
5 
Dexamethasone 
80 (up to a maximum starting dose of Chronocort® 30mg, split as 20mg at 
night and 10mg in the morning) 
Note: The conversion factor for Chronocort® is 1. 
For example, if a subject was previously taking 6mg daily of prednisone daily, this would be 
multiplied by a conversion factor of five and the equivalent hydrocortisone daily dose would be 
30mg. 
If a subject was previously taking prednisone in combination with hydrocortisone, then a conversion 
factor of five would be applied to the prednisone component of the dose, and a conversion factor of 
one would be applied to the hydrocortisone component of the dose, and the two added together. 
All laboratory results will be reported in SI and conventional units. If for any reason the results are 
not collected in SI or conventional units, a conversion will be performed. Examples of some 
conversions to SI units are given in Table 5. 
Table 5: SI unit conversions 
Quantity 
Conversion to SI units 
 
17-OHP 
    1 ng/dL  
= 0.0303  
nmol/L 
ACTH 
    1 pg/mL  
= 0.22  
pmol/L 
Androstenedione 
    1 ng/dL  
= 0.0349  
nmol/L 
Glucose 
    1 mg/dL  
= 0.0555  
mmol/L 
Insulin 
    1 μIU/mL 
= 6.945  
pmol/L 
Osteocalcin 
    1 μg/L                 = 0.171 
nmol/L 
PRA 
    1 NG/ML/HR     = 0.2778 
NG/L/S 
 
9.2.4. Coding of adverse events, concomitant medications, etc. 
AEs and medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.0 or later (the exact version to be determined when coding is done). Coding 
will be to the level of the lowest level term (LLT). Concomitant medications and pre-treatment CAH 
medications will be coded using the World Health Organisation (WHO) Drug Dictionary including 
Anatomical Therapeutic Chemical (ATC) drug classification. 
 
 


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9.3. 
Assessment time windows 
9.3.1. Definition of permissible time windows 
Actual study day will be calculated by: 
• 
Date of assessment - Date of randomisation + 1   
Participants will receive their first dose of randomised treatment in the evening of the second 
baseline visit (Day 2 of Visit 1) after they have been randomised.  As such study day 1 will be 
considered the day of randomisation.  All assessments which are performed at the baseline visit 
(Visit 1, Days 1 and 2) will be considered prior to randomised study treatment.    
All assessments that are summarised by visit (endocrine profile, DEXA, ECG, laboratory results, Vitals 
etc.) will be summarised according to the scheduled visit. Any extreme deviations between the 
actual study day of the scheduled visit and the target study day (see Table 6) will be discussed at the 
Data Review Meeting. A deviation will be considered extreme if more than +/- 3 weeks from visit 2, 
or +/- 4 weeks from visit 3 or 4.  
Table 6: Target study day for visit assessments 
Visit number 
Visit description 
Target study day 
Target study day range 
Visit 0 
Screening 
 
<-1 
Visit 1 
Baseline 
-1,1 
 
Visit 2 
Week 4 
29,30 
>8 to <51 
Visit 3 
Week 12 
85,86 
>57 to <114 
Visit 4 
Week 24 
169,170 
>141 to <198 
Note: There is no study day 0 as per CDISC standards.  Study day 1 is first day of dosing. 
 
9.3.2. Baseline Assessment 
Baseline, used in calculations for change from baseline summaries, will be defined as the latest pre-
dose measurement. This is expected to be the visit 1 assessment, however if a result is missing and 
there is a suitable result available at the screening visit (taking account of fasting requirements 
where needed), this will be used in its place.   
9.3.3. Methods for handling out-of-window observations 
Missing 17-OHP and A4 values will be handled as follows: 
• 
If the Day 1 15:00 sample of a 24-hour profile is completely missing, the result from the 
17:00 planned time point will be used. 
• 
If the Day 2 15:00 sample of a 24-hour profile is completely missing, the result from the 
13:00 planned time point will be used. 


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• 
For all other time points where the result is completely missing, the average of the two 
closest results will be calculated and used for the missing time point. 
• 
If the result at any time point is below the lower limit of quantification (LLOQ), a value of 
half the LLOQ will be substituted.  
• 
For the purpose of analysis, a result will be considered to be out-of-window if more than 
+/-60 minutes from the scheduled time point1. For each time point where the result is ‘out-
of-window’: 
- 
If the out-of-window result is >60 minutes after the scheduled time point then the 
average of the previous scheduled time point and the out-of-window result will be 
calculated and used for the scheduled time point with the out-of-window result. 
- 
If the out-of-window result is >60 minutes before the scheduled time point then the 
average of the next scheduled time point and the out-of-window result will be 
calculated and used for the scheduled time point with the out-of-window result. 
Subjects with 2 or more of the expected results missing (or outside of a +/-15 minute window) for a 
particular 24hr period were discussed on a case-by-case basis at the Data Review Meeting which 
occurred prior to database lock and study unblinding.  
9.3.4. Other clinical laboratory values below the lower limit of quantification 
If a clinical laboratory result is below the LLOQ at any time point, a value equal to the LLOQ will be 
substituted. 
9.4. 
Handling outliers 
Any extreme values which are considered to have potential to impact the interpretation of results 
will be discussed at the Data Review Meeting (See 4.1) and sensitivity analyses may be performed as 
required.  
10. 
Study population 
10.1. Disposition of subjects 
Subject disposition will be listed and summarised by treatment group (including screen failures) and 
pre-baseline standard therapy. The summary will include reason for withdrawal and whether the 
subject is continuing into the extension study. 
10.2. Protocol deviations 
Any deviations from the protocol will be reviewed at the Data Review Meeting following trial 
completion but prior to database lock. Each protocol deviation will be classified as either 'minor' 
(unlikely to affect trial outcomes) or 'major' (likely to affect outcomes). Any subject considered to 
have a major protocol deviation will be excluded from the Efficacy Analysis set (See 6.223).  In 
addition, protocol deviations will be grouped into the following high-level categories: 
• 
Inclusion criteria – subject failed to meet all inclusion criteria, 
• 
Exclusion criteria – subject met at least one exclusion criteria, 
                                                          
1 This differs from the +/- 10 minute window specified for investigators in the protocol so that results within a 
wider window can be considered acceptable for analysis. 


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• 
Study procedure – site or subject did not follow procedures specified in protocol, 
• 
Titration – site or subject deviated from the titration process, 
• 
Treatment – IMP not taken as per protocol, 
• 
Local sampling – site performed endocrine sampling locally. 
Protocol deviations will be listed and summarised by randomised treatment group, classification 
(major or minor) and protocol deviation category.  
10.3. Demographic and baseline characteristics 
The following demographic and baseline characteristics will be summarised and listed at the 
screening visit: age (calculated in whole years), gender, race, ethnicity, height, weight, BMI, waist 
circumference.  Age will be split into four groups and will be included in the demographic and 
baseline characteristics summary table. The following age groups will be displayed: 
• 
>=18 - <30 
• 
>=30 - <50 
• 
>=50 - <70 
• 
>= 70 
 
Baseline disease characteristics including time since CAH diagnosis, whether the subject was 
hospitalized in the last year due to CAH, the number of adrenal crises in the past year and prior CAH 
medications will be summarised and detailed listings will be produced. 
Congenital adrenal hyperplasia medical history, other medical history excluding CAH related events 
and prior medications will each be summarised and detailed listings will be produced.  Mutation 
status will also be listed. 
10.4. Treatment compliance 
For treatment compliance, overall compliance will be calculated and the overall period will start 
from the first dose of randomised study treatment up to the last dose taken.   
The overall compliance will be calculated as a percentage for each subject by 
actual total dose
expected total dose × 100. 
 
To calculate the expected total dose, dose titrations are to be taken into account.  For each dose 
regimen the expected total dose will be calculated by summing the total daily dose for the duration 
of the dose regimen.  If a subject has their dose changed then the expected total dose will be 
calculated by summing the total daily dose of all the dosing regimens.  If the study end day of a 
dosing regimen overlaps with the study start day of the next dosing dose regimen then the average 
total daily dose of the two dosing intervals will be used for the overlapping study day.  
 
The actual total dose will be calculated by subtracting the number and dose of capsules returned 
from the number and dose of capsules dispensed.  
Actual total dose and expected total dose will only be calculated when a subject has a full record of 
drug accountability.   


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Summary statistics will be produced for the overall subject compliance.  A listing of subject 
compliance (including flags for when this is <80% or >120%) and a listing of drug accountability will 
be produced. 
 A listing of dispensed sick day medication accountability will be produced detailing the quantity 
dispensed and returned. 
10.5. Primary efficacy analysis 
The primary efficacy analysis is the comparison of the mean change from baseline to 24 weeks in the 
primary efficacy variable (natural logarithm of the mean over the 24-hour SDS profile for the natural 
logarithm of 17-OHP) between the Chronocort® treatment group and the standard therapy 
treatment group within the efficacy evaluable analysis set. The calculation of the primary efficacy 
variable is described 9.2.2. The comparison will performed using an ANCOVA linear model as 
described in 8.2. The unadjusted mean of the primary efficacy variable will be presented along with 
the least squares (LS) estimated mean. The difference in LS means will be presented with the 
associated 95% two-sided confidence interval and p-value. Residual plots of scaled residuals will be 
used to check the fit of the model and assess whether there is any evidence of non-normality.  
Summary statistics will be produced for the absolute values and change from baseline at each visit 
(weeks 4, 12 and 24) for the primary efficacy variable by treatment group and pre-baseline standard 
therapy.   The geometric mean of the 17-OHP concentration will be plotted along with the 95% 
confidence intervals at each time point over the 24hr sampling period (15:00h to 15:00h) for each 
treatment group and pre-baseline standard therapy for week 24 for the primary analysis. The plot 
will be repeated for the baseline, week 4 and week 12 visits as part of the exploratory analyses. 
Three subject profile plots will be created for each subject displaying the following results over the 
24hr sampling period (15:00h to 15:00h) for week 24: 17-OHP concentration-time (on a logarithmic 
scale) and absolute (unsigned) deviations from the “normal” mean (SDS score) (See 9.2.2). The two 
subject profiles will be repeated for the baseline, week 4 and week 12 visits as part of the 
exploratory analyses.  
All summary tables and plots above will be repeated for A4 for the secondary hormonal profile 
analysis. 
The above analyses will be repeated in the full analysis set as part of the secondary analyses. 
10.6. Secondary efficacy analyses 
10.6.1. Secondary hormonal profile analysis 
There will be a comparison of the mean change from baseline to 24 weeks in the natural logarithm 
of the mean over the 24-hour SDS profile for the natural logarithm of A4 between the Chronocort® 
treatment group and the standard therapy treatment group within the efficacy evaluable analysis 
set. The comparison will performed using an ANCOVA linear model as described in 8.2. The same 
summary statistics will be produced for A4 as the primary efficacy analysis (see 10.5). 
This analysis will be repeated for each of the individual baseline treatment strata for both 17-OHP 
and A4. 
A responder analysis to compare the response between the Chronocort® treatment group and the 
standard therapy treatment group within the efficacy evaluable analysis set will be performed using 
logistic regression with adjustment for pre-baseline standard therapy. A subject will be considered a 
responder if their 09:00h result at week 24 is in the optimal and reference ranges as defined in Table 
7. The number and percentage of subjects with a response will be presented together with the 


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adjusted response rate and the odds ratio will be estimated together with two-sided confidence 
interval and p-value. 
Summary Statistics will be produced for the 09:00h result at week 24.  
Table 7: Optimal and reference ranges for responder analysis 
17-OHP 
1.2- 36.4 nmol/L 
Androstenedione (A4) 
Males:  1.4 – 5.2 nmol/L 
Females: 1.0 – 7.0 nmol/L 
Source:  
# 17-OHP: Note the Mayo Clinic laboratory normal ranges for 17-OHP were derived from a very small 
number of volunteers, who did not have CAH and for whom nothing else was known, e.g. time of day, 
comorbidities. The appropriateness of trying to drive the CAH population into this range is questionable and 
therefore based on verbal feedback from clinicians who manage these patients, a broader "optimal range" 
has been used for 17-OHP). 
 
*Mayo Clinic.  
A4: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9709 
The above analyses will be repeated in the full analysis set. 
 
10.6.2. DEXA scans 
The mean change from baseline to 24 weeks in body composition (DEXA) between the Chronocort® 
treatment group and the standard therapy treatment group will be compared separately for fat 
mass, lean mass and total bone density using an ANCOVA linear model as described in 8.2. This will 
be based on the efficacy evaluable analysis set excluding Germany (as DEXA scans were not 
performed at sites in Germany). 
Summary statistics will be produced for the absolute values and change from baseline in body 
composition (DEXA) at each visit (weeks 4, 12 and 24). 
10.7. Other efficacy analysis 
The following analyses described in this section are considered exploratory, in order to aid better 
understanding of the effect of Chronocort® in CAH. As such, a limited number of analyses are 
described to cover the key exploratory objectives outlined in the protocol and in section 2.4. 
10.7.1. Exploratory hormonal profile analysis 
The natural logarithm of the means over the partial profiles of 17-OHP and A4 at 15:00-23:00, 23:00-
07:00, and 07:00-15:00 (all refer to actual clock time of sampling) for week 24. 
The natural logarithm of the mean SDS profile will be calculated in the same way as described in 
Section 9.2.2, with the first and last observations weighted half compared with the others. 
The primary endpoint measure (natural logarithm of the 24 hour 17-OHP profile) will also be 
presented for the profiles measured at 4 and 12 weeks for the purposes of titration as described in 
section 10.5. 


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The ANCOVA analysis for 8-hour profiles at 24 weeks and the 24-hour profiles at 4 and 12 weeks will 
be conducted following the method described in Section 10.5. These analyses will be repeated for 
the separate pre-baseline strata. 
10.7.2. Bone markers and laboratory assessments of special interest 
Changes relative to standard treatment in: 
a. Bone markers – serum CTX and osteocalcin (after fasting) 
b. hsCRP 
c. Assessment of glucose and insulin in the morning (after fasting)  
d. Assessment of HbA1c, total testosterone, and PRA in the morning 
 
For the assessment of glucose and insulin, the homeostasis model assessment of insulin resistance 
(HOMA-IR) value (Wallace TM, 2004) will be calculated using fasting values with following formula: 
HOMA-IR = [glucose (mmol/L) * insulin (µU/mL)/22.5]. 
 
Change from baseline will be calculated at each visit (Week 4, Week 12, and Week 24) and summary 
statistics will be presented for both absolute values and change from baseline for all bone markers 
and laboratory assessments of special interest listed above by treatment group, pre-baseline 
standard therapy and visit. Shift tables of baseline to minimum and maximum on-treatment will be 
produced for the appropriate parameters displaying the number and percentage of subjects in each 
of the categories (High, Low and Normal) relative to the category of their baseline assessment. 
Results considered clinically significant by the investigator will be summarised. Detailed listings will 
be produced for all bone markers and laboratory assessments of special interest.  In addition, 
boxplots of change from baseline over time for each bone marker or laboratory assessment of 
special interest will be produced along with a line connecting the mean change through time. 
10.7.3. Quality of life (QoL) questionnaires 
Changes relative to standard treatment in QoL at 24 weeks, measured using three instruments: SF-
36®, MAF, EQ-5D™. 
SF-36® 
The SF-36® questionnaire is a multipurpose, generic, short-form health survey containing 36 
questions (4-week recall) yielding 8 health domain scales and 2 psychometrically based physical and 
mental component summary measures (Maruish 2011). For each questionnaire, standardised scores 
will be generated using a validated scoring software package (QualityMetric Health Outcomes™ 
Scoring Software 4.5) to calculate scores for for the 8 health domain scales and 2 summary measures 
using algorithms specific to the questionnaire. 
The two summary measures are referred to as the physical component score and mental component 
score.  
The 8 health domain scales to be summarised are: 
• 
Physical Functioning (PF) 
• 
Role-Physical (RP) 
• 
Bodily Pain (BP) 
• 
General Health (GH) 


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• 
Vitality (VT) 
• 
Social Functioning (SF) 
• 
Role-Emotional (RE) 
• 
Mental Health (MH) 
For each summary measure and scale, the change from baseline and percentage change from 
baseline at week 24 will be calculated. Summary statistics for absolute values at each visit, change 
and percentage change from baseline at week 24 will be tabulated by treatment group and pre-
baseline standard therapy. 
Individual question scores, summary measure scores and scale scores will be listed. 
Multidimensional Assessment of Fatigue (MAF) 
The MAF is a self-administered questionnaire consisting of 16 questions.  The Global Fatigue Index 
(GFI) will be calculated using a standard method specific to the MAF questionnaire. This combines 
the responses to the questionnaire to give one score ranging from 1 (no fatigue) to 50 (severe 
fatigue). 
To calculate the GFI: Convert item #15 to a 0-10 scale by multiplying each score by 2.5 and then sum 
items #1, 2, 3, average #4-14, and newly scored item #15. 
Scores range from 1 (no fatigue) to 50 (severe fatigue).  Do not assign a score to items #4-14 if 
respondent indicated they "do not do any activity for reasons other than fatigue."  If respondents 
select no fatigue on item #1, assign a zero to items #2-16. Item #16 is not included in the GFI. 
The change from baseline and percentage change from baseline in GFI at week 24 will be calculated. 
Summary statistics for absolute values of GFI, change and percentage change from baseline at week 
24 will be tabulated by treatment group and pre-baseline standard therapy. 
Individual question scores and Global Fatigue index will be listed. 
EQ-5D™ 
The EQ-5D™ questionnaire consists of two parts, the EQ-5D™ descriptive system and the EQ visual 
analogue scale (VAS). The descriptive system consists of 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. The EQ VAS is a visual scale in which the subject 
gives a single score between 0 and 100.   
The results from the dimensions from will be combined using a standard method specially designed 
for the EQ-5D™ questionnaire to give a single index value (EuroQol Research Foundation). Two 
methods will be used to calculate the single index value: 
Method 1 will use the directly elicited 5L value set for the EQ-5D™ questionnaire as specified in 
Devlin 2016. 
Method 2 will use mapping approach described in van Hout 2012. 
A table showing the frequency and percent of subjects with each score for each of the domains will 
be produced by treatment group and pre-baseline standard therapy.  The change from baseline and 
percentage change from baseline will be calculated for both the single index value calculated from 
the 5 dimensions and the VAS score. Summary statistics for the absolute values of these two scores 
as well as change and percentage change from baseline at week 24 will be tabulated by treatment 


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group and pre-baseline standard therapy.  Shift table of baseline to end of study will be produced by 
domain, pre-baseline therapy and treatment group. 
Individual question scores for the EQ-5D™ descriptive system, the calculated single index value and 
EQ VAS score will be listed. 
10.7.4. Use of glucocorticoids 
Use of glucocorticoids at visit 1 (baseline) and visit 4 (week 24) of the study will be presented as 
individual glucocorticoids used.  Change in dose of last glucocorticoid from baseline to each visit will 
be presented as hydrocortisone equivalents using accepted conversion constants for the calculations 
(see Section 9.2.3).  
A summary of the frequency and percent of subjects with total hydrocortisone dose equivalent 
increments versus baseline at each visit falling within the following categories: 
• 
Dose increases versus baseline: 
o No increase observed (≤ 0mg), 
o > 0 to ≤ 5mg increase, 
o > 5 to ≤ 10mg increase, 
o > 10 to ≤ 15mg increase, 
o > 15 to ≤ 20 mg increase, 
o > 20 to ≤ 25 mg increase, 
o > 25 to ≤ 30 mg increase and 
o > 30 mg increase. 
• 
Dose decreases versus baseline: 
o No decrease observed (≤ 0mg), 
o > 0 to ≤ 5mg decrease, 
o > 5 to ≤ 10mg decrease 
o > 10 to ≤ 15mg decrease, 
o > 15 to ≤ 20 mg decrease, 
o > 20 to ≤ 25 mg decrease, 
o > 25 to ≤ 30 mg decrease and 
o > 30 mg decrease. 
10.7.5. Sensitivity analyses 
If the primary analysis demonstrates favourability towards Chronocort®, sensitivity analyses will be 
performed using different definitions of the SDS to check the robustness of the result. 


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11. 
Safety analyses 
11.1. Extent of exposure 
Summary statistics will be presented for both the total duration and actual duration of exposure in 
days. Total treatment duration will be calculated as follows: 
Date of first dose of study drug – Date of last dose of study drug + 1. 
Actual treatment duration will consider dose interruptions and will be the total number of days in 
which the subject took at least one dose of study medication. 
The recommended dose titrations which are made by a central independent blinded physician 
within 2 weeks of each profiling visit will be summarised by treatment group for week 4 and week 
12. The summary will show frequency and percentage of subjects requiring a dose adjustment, as 
well as the dose adjustment required (for both treatment groups: increase morning dose, increase 
evening dose, decrease morning dose, decrease evening dose; and additional doses for standard GC 
therapy: increase middle dose, decrease middle dose). A listing of dose titration decisions which are 
contrary to those directed by the blinded physician will be produced showing the reason for the 
deviation. 
A summary of unplanned dose changes will be produced showing the number of increases and 
decreases in dose that were unplanned i.e. not at the scheduled timepoints.  
A summary of the number and percentage of subjects with dose increases, reductions and 
interruptions will be produced also showing the number of dose increases, reductions and 
interruptions per subject, and summary of reason for dose increases, reductions and interruptions. 
All treatment exposure data will be listed in detail.  In addition to this, the study drug dosing 
instructions given to the subject by the investigator will be listed in detail. 
11.2. Adverse events 
All AEs, in terms of MedDRA system organ class (SOC) and preferred term (PT), will be listed and 
summarised descriptively by count (n) and percentage (%) for each treatment group. For the 
purpose of the CSR, only AEs up to the follow up-telephone call after the week 24 visit will be 
included in summaries. Any AE occurring before randomised Chronocort®/ standard glucocorticoid 
replacement therapy treatment (i.e. before the first dose of randomised treatment on Day 2 of 
visit 1) will be included in listings but not summaries, unless there is an increase in severity occurring 
after the start of treatment. Similarly, any AE occurring after the last day of study treatment for 
subjects who enter the extension study or the last day of study treatment plus 30 days for subjects 
who do not enter the extension study will be listed but not summarised. 
All reported AEs will be listed along with the study day of onset, resolution, duration, seriousness, 
severity, action taken with study drug, relationship to study drug, treatments administered and 
outcome. Frequencies and percentages of subjects reporting each PT will be presented (i.e. multiple 
events per subject will not be accounted for, apart from on the episode level summaries). Where 
severity is displayed, if a subject has more than one AE of the same term, the maximum severity will 
be used. 
An overview table of AEs displaying the number of AEs by treatment group as well as the number 
and percent of subjects with the following categories will be produced: 
• 
Any AE 
• 
Any AE causally related to IMP 


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• 
Any AE leading to sick day rules 
• 
Any AE leading to sick day rules causally related to IMP 
• 
Any AE leading to Addisonian crisis 
• 
Any AE leading to Addisonian crisis causally related to IMP 
• 
Any AE leading to unexpected therapeutic benefit 
• 
Any AE leading to unexpected therapeutic benefit causally related to IMP 
• 
Any AE leading to death 
• 
Any AE leading to death causally related to IMP 
• 
Any AE leading to discontinuation 
• 
Any AE leading to discontinuation causally related to IMP 
• 
Any SAE 
• 
Any SAE causally related to IMP 
• 
Any SAE leading to discontinuation 
• 
Any SAE leading to discontinuation causally related to IMP. 
The number and percent of subjects experiencing each AE will be summarised by treatment, SOC and 
PT for the following:  
• 
All AEs 
• 
All serious adverse events (SAEs) 
• 
SAEs with outcome of death  
• 
AEs leading to discontinuation of study treatment 
• 
SAEs leading to discontinuation of study treatment 
Separate summaries for AEs and SAEs will be created, split by the following: 
• 
Causality (not related, related to the investigational medicinal product (IMP), related to sick 
day medication, related to an interaction between IMP and sick day medication, related to 
either IMP or sick day medication) 
• 
Action taken (dose unchanged, dose increased, dose decreased, drug interrupted, drug 
withdrawn) 
• 
Outcome (Resolved, resolved with sequelae, resolving, not resolved, unknown, fatal) 
• 
By severity (Mild, moderate, severe) 
Additionally, all summaries above have the potential to be repeated to show the number of episodes 
in each category (using total number of patient-years exposed to IMP as the denominator). This is 
optional and to be done only if there are differences in exposure between treatment groups. A 
decision as to whether this is required will be made at the Data Review Meeting.  


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Tables of most common AEs (frequency of >10%) and common SAEs (>1% of subjects overall), will be 
summarised by preferred term, by decreasing frequency.  These thresholds may be adjusted 
downwards at the Data Review Meeting if there are relatively few subjects with AEs. 
11.3. Adverse events of special interest 
11.3.1. Use of “sick days” 
As per the protocol 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 system organ class, preferred term and treatment group.  
In addition, all AEs leading to use of “sick day rules” will also be summarised (frequency and 
percentage of subjects) by preferred term, route of, and specific sick day medication by treatment 
group. 
There will be a separate listing showing details of all AEs leading to use of sick day rules and specific 
sick day medication. 
11.3.2. Adrenal crises 
All AEs leading to adrenal crises as defined in the protocol will be summarised (frequency and 
percentage of subjects) by SOC, PT and treatment group. There will be a separate listing showing 
details of all AEs leading to adrenal crises. 
11.3.3. Unexpected therapeutic benefit 
All AEs leading to unexpected therapeutic benefit will be summarised (frequency and percentage of 
subjects) by SOC, PT and treatment group. There will be a separate listing showing details of all AEs 
leading to unexpected therapeutic benefit. 
11.4. Routine clinical laboratory evaluations 
11.4.1. Naming conventions 
The laboratory test names will be displayed using test names consistent with the protocol for all 
reporting. Study Data Tabulation Model (SDTM) standard names will be derived in the dataset, but 
not displayed. Where needed, an abbreviated version of the laboratory test names may be 
displayed. 
A full list of laboratory display names (full and an acceptable abbreviation) together with their SDTM 
laboratory test code and name is given in Appendix B for haematology, clinical biochemistry, bone 
markers and laboratory parameters of special interest, and urinalysis tests. 
11.4.2. Haematology 
The following haematology parameters will be collected:  
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 (PLT), white blood cell count (WBC), WBC differential count: 
neutrophils, eosinophils, basophils, lymphocytes, monocytes (absolute). 
All laboratory analyses will be carried out by the central laboratory Q2 Solutions. If laboratory results 
are needed urgently for safety reasons during the study, these can be processed at the local 


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laboratory and the results recorded in the electronic case report form (eCRF). For the local lab data, 
the local reference ranges will be used and if for any reason these are missing, the central ranges will 
be used, with any such occurrences clearly marked in the listings.  
Change from baseline will be calculated at each visit (Week 4, Week 12, and Week 24) and summary 
statistics will be presented for both absolute values and change from baseline for all haematology 
parameters by treatment group, pre-baseline standard therapy and visit. Shift tables of baseline to 
minimum and maximum on-treatment will be produced for the appropriate parameters displaying 
the number and percentage of subjects in each of the categories (High, Low and Normal) relative to 
the category of their baseline assessment. Haematology results considered clinically significant by 
the investigator will be summarised at each visit. Detailed listings will be produced for all 
haematology parameters.  In addition, boxplots of change from baseline in haematology parameters 
over time will be produced along with a line connecting the mean change through time. 
For the purpose of both Listings and Summary Tables, the haematology results will be divided into the 
following groups of related items: 
Haematology (1) 
• 
Red blood cell count (RBCs) 
• 
haemoglobin (Hb) 
• 
haematocrit (Hct) 
 
Haematology (2) 
• 
red cell distribution width (RDW) 
• 
mean corpuscular volume (MCV) 
• 
mean cell haemoglobin (MCH) 
• 
mean cell haemoglobin concentration (MCHC) 
• 
platelet count (PLTs) 
 
RDW-CV(%) will be provided by the central laboratory. In any local laboratories provide RDW-SD (fL) 
measurements, RDW-CV(%) will be calculated from the RDW-SD (fl) and MCV measurements using 
the formula: 
• 
RDW-CV(%) = (RDW-SD(fL)/MCV)*100.   
 
Haematology (3) 
• 
total white blood cell count (WBCs) 
• 
lymphocyte count 
• 
monocyte count 
• 
neutrophil count 
• 
basophil count 
• 
eosinophil count 
 
White blood cells (Leukocytes) are made up of Neutrophils + Eosinophils + Basophils +Lymphocyte + 
Monocyte.  
Therefore, to express any of the components as a percentage of Leukocytes, the formula is: 
• 
Components cell count/Leukocytes counts*100, (e.g. Neutrophils count/Leukocytes 
counts*100) 


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However, if the percentage is given and to derive the cell count, the formula is: 
• 
(Components percentage/100)*Leukocytes counts, (e.g. (Neutrophils % /100)*Leukocytes 
counts) 
• 
Note it is important that the component cell count and white blood cell count (Leukocytes) 
are expressed in the same units when applying these derivations. 
11.4.3. Clinical biochemistry 
The following routine biochemistry parameters will be collected: 
Sodium, potassium, chloride, total carbon dioxide (CO2), creatinine, glucose, blood urea nitrogen 
(BUN), albumin, total calcium, total magnesium, inorganic phosphorus, alkaline phosphatase, alanine 
aminotransferase (ALT/GPT), aspartate aminotransferase (AST/GOT), total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), total protein, total creatinine kinase (CK), uric acid, total cholesterol, 
high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides. 
All laboratory analyses will be carried out by the central laboratory Q2 Solutions. If laboratory results 
are needed urgently for safety reasons during the study, these can be processed at the local 
laboratory and the results recorded in the electronic case report form (eCRF). For the local lab data, 
the local reference ranges will be used and if for any reason these are missing, the central ranges will 
be used, with any such occurrences clearly marked in the listings.  
 
Change from baseline will be calculated at each visit (Week 4, Week 12, and Week 24) and summary 
statistics will be presented for both absolute values and change from baseline for all clinical 
biochemistry parameters by treatment group, pre-baseline standard therapy and visit. Shift tables of 
baseline to minimum and maximum on-treatment will be produced for the appropriate parameters 
displaying the number and percentage of subjects in each of the categories (High, Low and Normal) 
relative to the category of their baseline assessment. Biochemistry results considered clinically 
significant by the investigator will be summarised. Detailed listings will be produced for all routine 
biochemistry parameters.  In addition, boxplots of change from baseline in clinical biochemistry 
parameters over time will be produced along with a line connecting the mean change through time. 
For the purpose of both Listings and Summary Tables, the clinical biochemistry results will be divided 
into the following groups of related items: 
Biochemistry (1) 
• 
Sodium 
• 
potassium 
• 
chloride 
• 
total CO2 
• 
total calcium 
• 
total magnesium 
• 
inorganic phosphorus 
 
Biochemistry (2) 
• 
creatinine 
• 
blood urea nitrogen (BUN) 
• 
glucose 


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• 
uric acid 
• 
total protein 
• 
albumin 
 
Biochemistry (3) 
• 
alkaline phosphatase 
• 
ALT/GPT 
• 
AST/GOT 
• 
total creatinine kinase 
• 
lactate dehydrogenase 
• 
total bilirubin 
• 
direct bilirubin  
 
Biochemistry (4) 
• 
total cholesterol 
• 
high density lipoprotein (HDL) cholesterol 
• 
low density lipoprotein (LDL) cholesterol 
• 
triglycerides 
11.4.4. Urinalysis 
The following urinalysis parameters will be collected: protein, specific gravity, ketones, urobilinogen, 
bilirubin, pH, blood.   
For the continuous results (pH and specific gravity), change from baseline will be calculated at each 
visit (Week 4, Week 12, and Week 24) and summary statistics will be presented for both absolute 
values and change from baseline by treatment group, pre-baseline standard therapy and visit.  In 
addition, boxplots of change from baseline in continuous urinalysis parameters over time will be 
produced along with a line connecting the mean change through time. 
For all other urinalysis parameters, the frequency and percentage of subjects with results in each 
category, and shift table of baseline to worst on-treatment will be presented by treatment group, 
pre-baseline standard therapy and visit. Urinalysis variables will be listed by subject and time point. 
Values outside the normal ranges (provided with the laboratory report) will be flagged in the subject 
data listings. 
Urinalysis results considered clinically significant by the investigator will be summarised. 
A pregnancy test will also be carried out in female subjects of child bearing potential and the results 
will be listed.  
11.5. Vital signs 
The following vital signs will be collected:  systolic blood pressure (SBP), diastolic blood pressure 
(DBP), pulse rate, respiratory rate, temperature, height, waist circumference, weight, BMI. 
The change from baseline will be calculated and summary statistics will be tabulated for both 
absolute values and change from baseline by treatment group, pre-baseline standard therapy, and 
visit. Shift tables of baseline to minimum and maximum on-treatment will be created for the 
following vital signs: SBP and DBP.  In addition, boxplots of change from baseline in vital signs over 
time will be produced along with a line connecting the mean change through time.   


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Vital signs will be listed and abnormal findings will be marked. 
The following reference ranges will be used to determine the categories for the vital signs shift table, 
and to mark the abnormal (high/low) findings in the vital signs listing: 
• 
Systolic blood pressure: Low < 100 mmHg; Normal ≥ 100 mmHg to ≤ 150 mmHg; High > 150 
mmHg 
• 
Diastolic blood pressure: Low < 60 mmHg; Normal ≥ 60 mmHg to ≤ 95 mmHg; High > 95 
mmHg 
11.6. Electrocardiogram (ECG) 
The following ECG data will be collected: heart rate, PR interval, QRS width, QT interval and Bazett’s 
and Fridericia QTc interval (QTcB and QTcF).  
The change from baseline will be calculated and summary statistics will be tabulated for both 
absolute values and change from baseline by treatment group, visit and dose level. Abnormal 
findings will be tabulated by visit showing a frequency count and percentage of subjects with at least 
one abnormal finding. 
ECG results will be listed and abnormal findings will be marked, together with an indication of 
whether or not that finding was clinically significant.  Values with a change from baseline > 30 msec 
in QT interval, QTcB and QTcF will be flagged in the listing.  
The following reference ranges will be used to determine the categories for the ECG shift table, and 
to mark the abnormal (high/low) findings in the ECG listing: 
• 
Heart rate: Low < 40 msec; Normal ≥ 40 msec to ≤ 110 msec; High > 110 msec 
• 
PR interval: Low < 120 msec; Normal ≥ 120 msec to ≤ 220 msec; High > 220 msec 
• 
QRS width: Low < 70 msec; Normal ≥ 70 msec to ≤ 120 msec; High > 120 msec 
• 
QT interval: Low < 330 msec; Normal ≥ 330 msec to ≤ 450 msec; High > 450 msec 
• 
QTcB: Low < 350 msec; Normal ≥ 350 msec to ≤ 450 msec; High > 450 msec 
• 
QTcF: Low < 350 msec; Normal ≥ 350 msec to ≤ 450 msec; High > 450 msec 
11.7. Other safety evaluations 
11.7.1. Physical examination 
A shift table of baseline assessment of full physical examination to week 24/End of Study (EOS) by 
category, pre-baseline therapy and treatment group will be produced.  At screening and week 
24/EOS, if the eCRF confirms the physical examination has been performed and there are no 
abnormalities, a ‘Normal’ status will be imputed for each of the physical examination categories: 
• 
General 
• 
Cardiovascular 
• 
Neurological 
• 
Gastrointestinal 
• 
Respiratory 
• 
Skin 
• 
Head, eyes, ears, nose & throat 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
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• 
Musculoskeletal including extremities 
• 
Genitourinary 
• 
Other 
Abnormal physical examination status categories are captured in the eCRF, together whether the 
finding was clinically significant. 
Physical examination results will be listed and abnormal findings will be marked, together with an 
indication of whether or not that finding was clinically significant. 
11.7.2. Concomitant medications excluding glucocorticoid steroids 
Concomitant medications excluding glucocorticoid steroids[a], which include medications that began 
prior to date of randomisation but were ongoing after first dose of randomised treatment or started 
after the start of randomised treatment, will be summarised descriptively by ATC text, generic term, 
and treatment group using counts and percentages as appropriate.   
A detailed listing of all concomitant medications excluding glucocorticoid steroids will be listed. 
[a] The following list of steroids will be excluded from the summaries and listings of concomitant 
medications and instead will be reported under sick day medications and steroids taken in addition 
to IMP (see section 11.7.3). 
ATCCODE LEVEL ATC Text 
D07AC 
4 Corticosteroids, potent (group III) 
D07AD 
4 Corticosteroids, very potent (group IV) 
H02 
2 CORTICOSTEROIDS FOR SYSTEMIC USE 
H02A 
3 CORTICOSTEROIDS FOR SYSTEMIC USE, PLAIN 
H02AA 
4 Mineralocorticoids 
H02AB 
4 Glucocorticoids[b] 
H02B 
3 CORTICOSTEROIDS FOR SYSTEMIC USE, COMBINATIONS 
H02BX 
4 Corticosteroids for systemic use, combinations 
R01AD 
4 Corticosteroids 
R03BA 
4 Glucocorticoids 
S01BA 
4 Corticosteroids, plain 
S02B 
3 CORTICOSTEROIDS 
S02BA 
4 Corticosteroids 
S03B 
3 CORTICOSTEROIDS 
S03BA 
4 Corticosteroids 
[b] Excluding Fludrocortisone, which will be summarised alongside concomitant medication.  
11.7.3. Use of dispensed sick day medications and steroids taken in addition to IMP 
Use of dispensed sick day medications by route and drug name and steroids taken in addition to IMP 
(which includes medications that began prior to the date of randomisation but were ongoing after 
first dose of randomised treatment or started after randomised treatment) by ATC text and generic 
term will be summarised by treatment group. 
A detailed listing of all dispensed sick day medications and steroids taken in addition to IMP will be 
produced. 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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11.7.4. Adrenal insufficiency 
Signs and symptoms of adrenal insufficiency will be summarised by treatment group and visit. A 
listing of all signs and symptoms of adrenal insufficiency will be produced flagging any significant 
findings and significant findings related to under/over replacement of steroid. 
12. 
Changes from the planned analyses  
At the time of finalising the SAP version 2.0, there are minor changes from the planned analyses 
specified in the protocol. For routine clinical laboratory variables (haematology and clinical 
biochemistry) shift tables to each visit relative to baseline have been replaced with shift tables to 
minimum on-treatment versus baseline and to maximum on-treatment versus baseline. This is 
judged to be a more conservative approach to detecting potential safety signals from clinical 
laboratory data. For vital signs, the split by dose level has been removed from the summaries of 
absolute values and change from baseline over time, due to the low number of subjects per 
category. Instead this will be assessed via listings. For a similar reason, the split by dose level has 
been removed from the summary of abnormal ECG results.  
 
 


Statistical Analysis Plan 
Phase III study of Chronocort® 
Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Page 47 of 54 
13. 
References 
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. 
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. 
Devlin, N., Shah, K., Feng, Y., Mulhern, B. and Van Hout, B. Valuing Health-Related Quality of Life: An 
EQ-5D-5L Value Set for England. Office of Health Economics Research Paper 2016.  
EuroQol Research Foundation. euroqol.org. Retrieved (Sept 2015) from  
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
5L_UserGuide_2015.pdf 
EuroQol Research Foundation. euroqol.org. Retrieved (Sept 2017) from 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf   
Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, et al. Clinical characteristics of a 
cohort of 244 patients with congenital adrenal hyperplasia. Journal of Clinical Endocrinology & 
Metabolism 2012;97(12): 4429-38. 
Maruish, M.E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed, 2011). Lincoln, RI: 
QualityMetric Incorporated. 
Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-2136. 
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 
Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 
2001;30(1):15-30. 
van Hout B, Janssen MF, Feng Y, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, Kind P, 
Pickard S. Interim Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L Value Sets. Value in 
Health. 2012; 15: 708-715.Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modelling. 
Diabetes Care. 2004 Jun;27(6):1487-95. 
 
 
 


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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14. 
Appendix A – List of tables, listings and figures 
14.1. List of planned tables 
Study population 
Subject disposition (All subjects) 
Protocol deviations (All subjects) 
Analysis sets (All subjects) 
Demographic characteristics (Safety analysis set) 
Baseline disease characteristics (Safety analysis set) 
CAH medical history (Safety analysis set) 
Other medical history excluding CAH events (Safety analysis set) 
Prior medications (Safety analysis set) 
Concomitant medications excluding steroids (Safety analysis set) 
Use of sick day medication and steroids taken in addition to IMP (Safety analysis set) 
Subject compliance (Safety analysis set) 
Use of glucocorticoids: last dose prior to each visit (Safety analysis set) 
Table of change from baseline to each visit in dose (hydrocortisone equivalent) of last 
glucocorticoid (Safety analysis set) 
Categories of hydrocortisone dose equivalent increments versus baseline (Safety analysis set) 
Safety 
Duration of exposure (Safety analysis set) 
Dose titrations recommended by the independent blinded physician (Safety analysis set) 
Reasons for dose increases and reductions recommeded by the independent blinded physician 
(Safety analysis set) 
Table of dose titrations instructed by the Investigator (Safety analysis set) 
Reasons for dose changes instructed by the Investigator (Safety analysis set) 
Adverse event in any category - subject level (Safety analysis set) 
Adverse event in any category - episode level (Safety analysis set) 
Listing of deaths (Safety analysis set) 
Adverse events leading to death (Safety analysis set) 
Listing of adverse events leading to death (safety analysis set) 
All adverse events (Safety analysis set) 
All serious adverse events (Safety analysis set) 
Listing of all serious adverse events (Safety analysis set) 
Adverse events leading to discontinuation of study treatment (Safety analysis set) 
Listing of adverse events leading to discontinuation of study treatment (Safety analysis set) 
Adverse events by causality (Safety analysis set) 
Adverse events by action taken (Safety analysis set) 
Adverse events by outcome (Safety analysis set) 
Adverse events by severity (Safety analysis set) 
Repeat above 6 tables for SAEs 
Most common (frequency of >10%) adverse events (Safety analysis set) 
Most common (frequency of >1%) SAEs (Safety analysis set) 
Adverse events leading to use of "sick day rules" (Safety analysis set) 


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Adverse events leading to use of “sick day rules” by sick day medication (Safety analysis set) 
Adverse events leading to Adrenal crises (Safety analysis set) 
Adverse events of unexpected therapeutic benefit (Safety analysis set)  
Repeat of AE Tables at episode level to be decided at Data Review meeting 
Signs and symptoms of adrenal insufficiency and over treatment (Safety analysis set) 
Haematology (1) laboratory variables (Safety analysis set) 
Change from baseline in Haematology (1) laboratory variables (Safety analysis set) 
Shift table of baseline to minimum on-treatment for Haematology (1) laboratory variables 
(Safety analysis set) 
Shift table of baseline to maximum on-treatment for Haematology (1) laboratory variables 
(Safety analysis set) 
Haematology (1) results considered clinically significant by the investigator (Safety analysis 
set) 
Repeat above 5 tables for Haematology (2), Haematology (3) 
Biochemistry (1) laboratory variables (Safety analysis set) 
Change from baseline in Biochemistry (1) laboratory variables (Safety analysis set) 
Shift table of baseline to minimum on-treatment for Biochemistry (1) laboratory variables 
(Safety analysis set) 
Shift table of baseline to maximum on-treatment for biochemistry (1) laboratory variables 
(Safety analysis set) 
Biochemistry (1) results considered clinically significant by the investigator (Safety analysis set) 
Repeat above 5 tables for Biochemistry (2), Biochemistry (3), Biochemistry (4) 
Urinalysis results - continuous parameters (Safety analysis set) 
Change from baseline for urinalysis results - continuous parameters (Safety analysis set) 
Categorical urinalysis parameters (Safety analysis set) 
Shift table of baseline to worst on-treatment for categorical urinalysis laboratory variables 
(Safety analysis set) 
Continuous urinalysis parameters - results considered clinically significant by the investigator 
(Safety analysis set) 
Categorical urinalysis parameters - results considered clinically significant by the investigator 
(Safety analysis set) 
Vital signs variables (Safety analysis set) 
Vital signs variables, change from baseline (Safety analysis set) 
Vital signs shift table for SBP and DBP, baseline to minimum on-treatment (Safety analysis set) 
Vital signs shift table for SBP and DBP, baseline to maximum on-treatment (Safety analysis set) 
Electrocardiogram variables over time (Safety analysis set) 
Electrocardiogram variables, change from baseline (Safety analysis set) 
Abnormal electrocardiogram findings (Safety analysis set) 
Physical examination - baseline versus end of study assessment (Safety analysis set) 
Efficacy 
Primary efficacy analysis for 17-OHP, change from baseline to 24 weeks in primary efficacy 
variable, analysis of covariance model (Efficacy evaluable analysis set) 
Repeat above 1 table for weeks 4 and 12 


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 
weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis 
set)) 
Repeat above 1 table weeks 4 and 12 
Summary of absolute values of primary efficacy variable for 17-OHP, by visit (Efficacy 
evaluable analysis set) 
Summary of change in baseline in primary efficacy variable for 17-OHP, by visit (Efficacy 
evaluable analysis set) 
Secondary efficacy analysis of responders at 09:00h week 24 for 17-OHP, logistic regression 
model (Efficacy evaluable analysis set) 
Summary of the 17-OHP results at 09:00h week 24 (Efficacy evaluable analysis set) 
Repeat all 17-OHP only Efficacy outputs above for the A4 hormone (including repeats) 
Repeat all Efficacy outputs above in the Full analysis set (including repeats) 
Secondary efficacy analysis of change from baseline to 24 weeks in body composition - Dual 
Energy X-ray Absorptiometry, analysis of covariance model (Efficacy evaluable analysis set) 
Summary of absolute values of body composition - Dual Energy X-ray Absorptiometry (Efficacy 
evaluable analysis set) 
Summary of change from baseline in body composition - Dual Energy X-ray Absorptiometry 
(Efficacy evaluable analysis set) 
Exploratory analysis of 17-OHP 8-hour profiles: change from baseline to 24 weeks in primary 
efficacy variable, analysis of covariance model (Efficacy evaluable analysis set) 
Above partial profile ANCOVA table to be repeated for separate pre-baseline strata 
All partial profile outputs above to be repeated for A4 hormone (total of 2 tables) 
Summary of change from baseline for bone markers and laboratory assessments of special 
interest (Efficacy evaluable analysis set) 
Summary of absolute values for bone markers and laboratory assessments of special interest 
(Efficacy evaluable analysis set) 
Shift table of baseline to minimum on-treatment for bone markers and laboratory 
assessments of special interest (Efficacy evaluable analysis set) 
Shift table of baseline to maximum on-treatment for bone markers and laboratory 
assessments of special interest (Efficacy evaluable analysis set) 
Summary of clinically significant results for bone markers and laboratory assessments of 
special interest (Efficacy evaluable analysis set) 
Summary of SF-36 scores (Efficacy evaluable analysis set) 
Summary of SF-36 change from baseline (Efficacy evaluable analysis set) 
Summary of SF-36 percentage change from baseline (Efficacy evaluable analysis set) 
Repeat above 3 tables for GFI, MAF and EQ-5D™ 
 
14.2. List of planned listings 
Study population 
Subject disposition (All subjects) 
Protocol deviations (All subjects) 
Listing of subjects with extreme visit deviations (All randomised subjects) 


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Subjects excluded from the safety analysis set 
Subjects excluded from the full analysis set 
Subjects excluded from the efficacy evaluable analysis set 
Demographic characteristics (Safety analysis set) 
Congenital adrenal hyperplasia medical history (Safety analysis set) 
Mutation status 
Other medical history excluding CAH related events (Safety analysis set) 
Pre-baseline therapy strata (Safety analysis set) 
Prior medications (Safety analysis set) 
Safety 
Sick day pack accountability (Safety analysis set) 
Steroids and other glucocorticoids taken in addition to IMP (Safety analysis set) 
Sick day medication administration (Safety analysis set) 
Treatment exposure (Safety analysis set) 
Dose titrations recommended by the independent blinded physician (Safety analysis set) 
Study drug accountability (Safety analysis set) 
Unscheduled dose changes (Safety analysis set) 
Investigator adherence to protocol defined dose titrations (Safety analysis set) 
Dosing instructions provided to subjects from investigator (Safety analysis set) 
Subject compliance (Safety analysis set) 
All Adverse events (Safety analysis set) 
Serious adverse events leading to death (Safety analysis set) 
Adverse events leading to use of sick day rules (Safety analysis set) 
Adverse events leading to adrenal crises (Safety analysis set) 
Adverse events of unexpected therapeutic benefit (Safety analysis set) 
Signs and symptoms of adrenal insufficiency and over treatment (Safety analysis set) 
Haematology (1) laboratory variables (Safety analysis set) 
Repeat for Haematology (2), Haematology (3) 
Biochemistry (1) laboratory variables (Safety analysis set) 
Repeat for Biochemistry (2), Biochemistry (3), Biochemistry (4) 
Urinalysis laboratory variables (Safety analysis set) 
Pregnancy test results (Safety analysis set) 
Vital signs (Safety analysis set) 
Electrocardiogram parameters (Safety analysis set) 
Physical examination (Safety analysis set) 
Concomitant medications excluding steroids (Safety analysis set) 
Efficacy 
Bone markers and laboratory assessments of special interest (Efficacy evaluable analysis set) 
DEXA scan parameters (Efficacy evaluable analysis set) 
17-OHP and A4 (Full analysis set) 
SF-36 scores (Efficacy evaluable analysis set) 
MAF scores and GFI (Efficacy evaluable analysis set) 
EQ-5D scores (Efficacy evaluable analysis set) 


Statistical Analysis Plan 
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Protocol No.: DIUR-005 
Version: Final 4.0  
 
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14.3. List of planned figures 
14.3.1. Summary figures 
Safety 
Boxplot of change from baseline over time for red blood cell count (Safety analysis set) 
Repeat above figure for all remaining haematology (1), haematology (2) and haematology (3) 
parameters 
Boxplot of change from baseline over time for sodium (Safety analysis set) 
Repeat above figure for all remaining biochemistry (1), biochemistry (2), biochemistry (3) and 
biochemistry (4) parameters 
Boxplot of change from baseline over time for pH (Safety analysis set) 
Repeat above figure for specific gravity 
Boxplot of change from baseline over time for systolic blood pressure (Safety analysis set) 
Repeat above figure for the following vital signs parameters: diastolic blood pressure, pulse 
rate, respiratory rate, temperature, weight, waist circumference and BMI 
Efficacy 
Geometric mean +/- 95% CI for 17-OHP week 24 profile (Efficacy evaluable analysis set) 
 
Repeat above figure for weeks 4 and 12 
Repeat all 17-OHP only Efficacy figures above for the A4 hormone (including repeats) 
Repeat all 17-OHP and A4 hormone figures for separate pre-baseline strata (including repeats) 
Repeat all 17-OHP and A4 hormone figures for SDS score (including repeats) 
Boxplot of change from baseline over time for serum CTX (Efficacy evaluable analysis set) 
Repeat boxplot of change from baseline over time for the following bone markers and 
laboratory assessments of special interest parameters: osteocalcin, total testosterone, fasting 
insulin, fasting glucose, HOMA-IR, HbA1c, hsCRP and plasma renin activity 
14.3.2. Individual patient figures 
Efficacy 
Concentration-time plot for 17-OHP over 24 hours at week 24 (Efficacy evaluable analysis set) 
SDS profile showing unsigned deviations from the "normal" mean at week 24 of 17-OHP (Efficacy 
evaluable analysis set) 
Repeat above 2 figures for weeks 4 and 12 
Note: Additional figures may be required, depending on the final decision on the grouping of 
reference ranges 
Repeat all 17-OHP only Efficacy figures above for the A4 hormone (including repeats) 
 
 
 


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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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15. 
Appendix B – Laboratory test display names and SDTM standard 
nomenclature 
The preferred display names and SDTM standard names for all laboratory tests to be conducted in 
this study are given in Table 8. The protocol lab name is preferred for display in all outputs, however 
the abbreviated display name may be used instead if space is limited on the page. SDTM lab test 
codes and names are to be included in SDTM-compliant datasets, but will not be displayed in the 
tables, figures and listings. Note: British English is used for the protocol lab names; American English 
is used for the SDTM standard names. 
Table 8: Lab parameter SDTM test codes and abbreviated display names 
Protocol lab name (for display) 
Abbreviated 
display name 
 
SDTM lab 
test code 
SDTM lab test name 
Haematology 
Red blood cell count 
RBC 
 
RBC 
Erythrocytes 
Haemoglobin 
Hb 
 
HGB 
Hemoglobin 
Haematocrit 
Hct 
 
HCT 
Hematocrit 
Red cell distribution width 
RDW 
 
RDW 
Erythrocytes Distribution Width 
Mean corpuscular volume 
MCV 
 
MCV 
Ery. Mean Corpuscular Volume 
Mean cell haemoglobin 
MCH 
 
MCH 
Ery. Mean Corpuscular Hemoglobin 
Mean cell haemoglobin 
concentration 
MCHC 
 
MCHC 
Ery. Mean Corpuscular HGB 
Concentration 
Platelet count 
PLT 
 
PLAT 
Platelets 
Total white blood cell count 
WBC 
 
WBC 
Leukocytes 
Lymphocyte count 
Lymph. 
 
LYM 
Lymphocytes 
Monocyte count 
Mono. 
 
MONO 
Monocytes 
Neutrophil count 
Neut. 
 
NEUT 
Neutrophils 
Basophil count 
Baso. 
 
BASO 
Basophils 
Eosinophil count 
Eosi. 
 
EOS 
Eosinophils 
Chemistry 
Sodium 
Sodium 
 
SODIUM 
Sodium 
Potassium 
K 
 
K 
Potassium 
Chloride 
Cl 
 
CL 
Chloride 
Total CO2 
CO2 
 
CO2 
Carbon Dioxide 
Total calcium 
Ca 
 
CA 
Calcium 
Total magnesium 
Mg 
 
MG 
Magnesium 
Inorganic phosphorus 
Phos. 
 
PHOS 
Phosphate 
Creatinine 
Creat. 
 
CREAT 
Creatinine 
Blood urea nitrogen 
BUN 
 
BUN 
Blood Urea Nitrogen 
Glucose 
Gluc. 
 
GLUC 
Glucose 
Insulin 
Insulin 
 
INSULIN 
Insulin 
Uric acid 
Urate 
 
URATE 
Urate 
Total protein 
Prot. 
 
PROT 
Protein 
Albumin 
ALB 
 
ALB 
Albumin 
Alkaline phosphatase 
ALP 
 
ALP 
Alkaline Phosphatase 
ALT/GPT 
ALT 
 
ALT 
Alanine Aminotransferase 
AST/GOT 
AST 
 
AST 
Aspartate Aminotransferase 
Total creatine kinase 
CK 
 
CK 
Creatine Kinase 
Lactate dehydrogenase 
LDH 
 
LDH 
Lactate Dehydrogenase 


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Protocol No.: DIUR-005 
Version: Final 4.0  
 
13 Sep 2018 
 
 
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Total bilirubin 
Bili. 
 
BILI 
Bilirubin 
Direct bilirubin  
Bili. Dir. 
 
BILDIR 
Direct Bilirubin 
Total cholesterol 
Chol. 
 
CHOL 
Cholesterol 
High density lipoprotein 
cholesterol 
HDL 
 
HDL 
HDL Cholesterol 
Low density lipoprotein 
cholesterol 
LDL 
 
LDL 
LDL Cholesterol 
Triglycerides 
Trig. 
 
TRIG 
Triglycerides 
Special interest 
HbA1c 
HbA1c 
 
HBA1C 
Hemoglobin A1C 
Total testosterone 
Testos. 
 
TESTOS 
Testosterone 
Plasma renin activity 
PRA 
 
RENIN 
Renin 
hsCRP 
hsCRP 
 
CRP 
C Reactive Protein 
C-terminal cross-linked 
telopeptide 
CTX 
 
CTXI 
Type I Collagen C-Telopeptides 
Osteocalcin 
Osteoc. 
 
OSTEOC 
Osteocalcin 
Urinalysis 
Protein 
Prot. 
 
PROT 
Protein 
Specific gravity 
Spec. grav. 
 
SPGRAV 
Specific Gravity 
Ketones 
Ketones 
 
KETONES 
Ketones 
Urobilinogen  
Urobil. 
 
UROBIL 
Urobilinogen 
Bilirubin 
Bili. 
 
BILI 
Bilirubin 
pH 
pH 
 
PH 
pH 
Blood 
Blood 
 
OCCBLD 
Occult Blood