Clinical trial NCT02733367
Conditions: Adrenal Insufficiency
Sponsor: Neurocrine UK Limited
Start date: 2016-03-04; Completion date: 2018-08-10
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 3, open-label, single-group, non-randomised, observational study of the safety and biochemical disease control of Infacort® in neonates, infants and children with adrenal insufficiency and congenital adrenal hyperplasia who had completed study Infacort 003. All subjects who had satisfactorily completed study Infacort 003 were offered the opportunity to take part in Infacort 004.

Detailed description:
A Phase 3, open-label, single-group, non-randomised, observational study of the safety and biochemical disease control of Infacort® in neonates, infants and children with AI who had completed study Infacort 003 (EudraCT number 2014-002265-30). All subjects who had satisfactorily completed study Infacort 003 wiere offered the opportunity to participate in study Infacort 004 at or after their final visit of study Infacort 003. Subjects received the usual clinically-appropriate dose (since bioequivalence has been demonstrated with conventional hydrocortisone), as determined by the Investigator, which was administered according to usual clinical practice - generally 3 or 4 times a day. Subjects could continue to be treated in this study until they met the study withdrawal criteria, until Infacort® was commercially available locally (which has now been achieved), or until the Sponsor decided to discontinue the study.

Arms: arm 1: Infacort® granules
Interventions: intervention 1: Infacort®
Intervention descriptions: intervention 1: Infacort® is a dry granule formulation of hydrocortisone stored in capsules available in different strengths (0.5, 1.0, 2.0 and 5.0 mg).

Protocol documents:
Prot_000.pdf: 
















Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 9 of 65 
Version: Final 4.0, 20 July 2017 
1. Protocol Synopsis 
 
PROTOCOL TITLE: 
Open-label, long-term follow-up of safety and biochemical 
disease control of Infacort® in neonates, infants and children with 
congenital adrenal hyperplasia and adrenal insufficiency 
previously enrolled in the Infacort 003 study 
PROTOCOL No: 
Infacort 004 
EudraCT No.: 2015-000458-40 
PRINCIPAL 
INVESTIGATOR: 
 
 
 
 
 
 
 
DEPUTIES OF THE 
INVESTIGATOR AND 
SUB-INVESTIGATORS: 
 
 
 
 
 
 
SPONSOR: 
Diurnal Limited 
Cardiff Medicentre 
Heath Park 
Cardiff, CF14 4UJ 
United Kingdom 
REPRESENTATIVE OF THE 
SPONSOR: 
 
 
 
 
 
INVESTIGATIONAL 
PRODUCT: 
Infacort® granules   
PHASE OF DEVELOPMENT: 
Phase 3 
INDICATION AND 
RATIONALE: 
Indication: Treatment of adrenal insufficiency (AI) in children. 
Rationale: This protocol is based on a Paediatric Investigation 
Plan (PIP) that has been agreed by the EMA (EMEA-001283-
PIP01-12). 
AI in children is most commonly congenital, either primary due 
to congenital adrenal failure or secondary due to congenital 
hypopituitarism. All causes result in cortisol deficiency and the 
commonest cause of primary adrenal failure is congenital adrenal 
hyperplasia (CAH), usually caused by 21-hydroxylase 
deficiency, which results in cortisol deficiency and androgen 
excess, with or without aldosterone deficiency. Treatment for all 
causes of AI is with hydrocortisone administered 3 to 4 times 
daily. Current standard treatment in neonates is unsatisfactory, 
as unlicensed adult dosage formulations (hydrocortisone tablets, 
10 mg) are used which are crushed and an approximate dose 
created prior to administration. There is thus no standard for 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 10 of 65 
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formulation, the dose administered is unpredictable, the 
preparations have a bitter taste and are difficult to administer. 
Crushing tablets and administration of doses of 0.5 to 5.0 mg in 
neonates and infants is therefore inaccurate. Recent analysis of 
prescribed hydrocortisone for infants and neonates undertaken in 
Germany showed that 30% of studied crushed tablet batches 
missed the acceptance criteria for precision of mass and/or 
content of the European Pharmacopeia (Kauzor et al., 2014). 
Infacort® is a newly developed paediatric and neonatal 
formulation of immediate release hydrocortisone that is provided 
in appropriate unit dosage (0.5 mg, 1.0 mg, 2.0 mg and 5 mg). It 
has good bioavailability and stability, taste masking and 
predictable pharmacokinetics. The Infacort® development 
program is underpinned by a detailed Phase 1 study in normal, 
healthy adult volunteers which demonstrated bioequivalence to 
licensed hydrocortisone 10 mg tablets and dose linearity from 
0.5 to 10 mg. 
The present protocol is designed to allow subjects who have 
taken part in study Infacort 003 (EudraCT number 2014-002265-
30) an opportunity to receive Infacort® on a continuing basis 
until a regulatory decision has been taken regarding a marketing 
authorisation. 
STUDY DESIGN AND 
SUMMARY OF 
PROCEDURES: 
This is a Phase 3, open-label, single-group, non-randomised, 
observational study of the safety and biochemical disease control 
of Infacort® in neonates, infants and children with AI who have 
completed study Infacort 003. All subjects who have 
satisfactorily completed study Infacort 003 will be offered the 
opportunity to take part in Infacort 004.  
Setting: Specialist endocrine centres which treat children with 
AI.  
The protocol for follow-up will include: 
 
An initial visit 
 
Monthly visits for the first 2 months of treatment 
 
Thereafter visits every 3 months  
 
Final visit 
The study will be conducted in up to 24 subjects from the  
Infacort 003 study requiring replacement therapy for AI due to 
either CAH, primary adrenal failure or hypopituitarism. The 
primary site will be Charité-Universitätsmedizin Berlin, CVK. 
However, some subjects participating in Infacort 003 were 
enrolled at remote sites. Should their parents/carers consent to 
participation in Infacort 004, additional study centres will be 
involved or, if agreeable, the subjects may be cared for at Charité 
Universitätsmedizin Berlin for the purposes of the study, either 
having their visits conducted at Charité-Universitätsmedizin 
Berlin or having the Investigator at Charité-Universitätsmedizin 
Berlin visiting the subject at their local hospital. Parents/carers 
will be provided with the informed consent document at least 
24 hours prior to enrolment of their child in the study. Children 
aged over 3 years old will be informed about their involvement 
in the study in the presence of their parents/carers.  
At each visit the following measures will be collected: 
 
Height/length and weight 
 
Heart rate 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 11 of 65 
Version: Final 4.0, 20 July 2017 
 
Blood pressure (if possible) 
 
Metabolic parameters including cortisol (all subjects) 
and androgens (17-hydroxyprogesterone [17-OHP], 
androstenedione [A4] and testosterone) in CAH subjects 
only, from dried blood spot analysis (every month for 
the first 2 months of the study, then every 6 months  
unless required after 3 months) 
 
Blood sampling for electrolytes, renin, haematocrit, and 
any additional cortisol data (where collected for routine 
care) 
 
Dose of Infacort® (except at final visit) 
 
Other drug treatment  
 
Tanner development stage 
 
Problems associated with dosing (e.g., choking) 
 
Serious and non-serious adverse events (SAEs and AEs), 
including application of sick day rules and adrenal crises 
 
For each visit, care will be taken to note the time of blood 
sampling, and the time and dose of the previous administration 
of glucocorticoid. Subjects will also receive all their standard 
treatments during the study.  
 
Initial Visit: 
Date of birth, gender, race/ethnicity, and medical history will be 
retrieved from Infacort 003 data. Other assessments at this visit 
include: 
 
Informed consent 
 
Changes in medical history/current medical status since 
enrolment in the Infacort 003 study 
 
Physical examination 
 
Height/length 
 
Weight 
 
Body mass index (BMI) and body surface area (BSA) 
(derived) 
 
Vital signs 
o Blood pressure (if possible) 
o Heart rate 
o Temperature 
 
Compliance with inclusion/exclusion criteria 
 
Previous and concomitant medications (including 
current adrenal replacement therapy) 
 
Infacort® administration education for parents/carers  
 
Infacort® administration by the parent/carer in the 
presence of the Investigator.  
 
Problems associated with administration/dosing - entire 
or incomplete dosing will be recorded in the case report 
form (CRF) 
 
Dried blood spot sampling (cortisol [all subjects], and 
17-OHP, A4, testosterone [CAH subjects only])  
 
Blood sampling (electrolytes, renin, haematocrit and any 
additional cortisol data) if taken as part of routine 
clinical care  
 
Tanner development stage 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 12 of 65 
Version: Final 4.0, 20 July 2017 
Interim Visits: 
 
Physical examination 
 
Height/length 
 
Weight 
 
BMI and BSA (derived) 
 
Vital signs 
o Blood pressure (if possible) 
o Heart rate 
o Temperature 
 
Concomitant medication 
 
Dose of Infacort®  
 
Problems associated with administration/dosing  
 
SAEs and AEs, including application of sick day rules 
and adrenal crises 
 
Dried blood spot sampling (cortisol [all subjects], and 
17-OHP, A4, testosterone [CAH subjects only]) every 
month for the first 2 months of the study, then every 6 
months, unless required after 3 months 
 
Blood sampling (electrolytes, renin, haematocrit and any 
additional cortisol data) where taken as part of routine 
clinical care (normally once a year) 
 
Tanner development stage 
 
Final Visit: 
 
Physical examination 
 
Height/length 
 
Weight 
 
BMI and BSA (derived) 
 
Vital signs 
o Blood pressure (if possible) 
o Heart rate 
o Temperature 
 
Concomitant medication 
 
Problems associated with administration/dosing 
 
SAEs and AEs, including application of sick day rules 
and adrenal crises 
 
Dried blood spot sampling (cortisol [all subjects], and 
17-OHP, A4, testosterone [CAH subjects only]) 
 
Blood sampling (electrolytes, renin, haematocrit and any 
additional cortisol data) if taken as part of routine 
clinical care 
 
Tanner development stage 
 
End of study information  
OBJECTIVES: 
Primary objective: 
 
To gather data on the long-term safety of Infacort® in 
subjects completing study Infacort 003 
Secondary objectives:  
 
To gather data on the effects of Infacort® 
ENDPOINTS: 
Primary endpoint:  
 
Nature and occurrence of SAEs and AEs observed 
throughout the study 
 
 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 13 of 65 
Version: Final 4.0, 20 July 2017 
Secondary endpoints:  
 
Standard deviation score (SDS) for height and weight  
 
Cortisol (all subjects) and adrenal androgen levels 
(17-OHP, A4, testosterone) in CAH subjects only  
METHODOLOGY 
NUMBER OF SUBJECTS 
(PLANNED): 
Maximum of 24 subjects 
SUBJECTS: 
Children who have successfully completed study Infacort 003 
PRINCIPAL INCLUSION 
CRITERIA 
Subjects successfully completing study Infacort 003, whose 
inclusion criteria were: 
1. Male and female children less than 6 years of age.  
2. A diagnosis of AI as confirmed by an inappropriately low 
cortisol usually with other supporting tests.  
3. 
Receiving appropriate adrenocortical replacement therapy 
(hydrocortisone with/without fludrocortisone). 
4. 
Adequately hydrated and nourished. 
In addition, the parents/carers must be able to understand and 
give written Informed Consent (according to AMG §40 (1) 3b) 
for this extension study. 
PRINCIPAL EXCLUSION 
CRITERIA:  
1. Clinically evident acute AI (adrenal crisis) (Note: the subject 
can be re-evaluated for eligibility once the episode is over) 
2. Inability of the child to take oral therapy 
3. Subjects with clinical signs of acute infection or fever on 
inclusion (Note: the subject can be re-evaluated for 
eligibility once the episode is over) 
4. Any surgical or medical condition that in the opinion of the 
Investigator may place the subject at higher risk from his/her 
participation in the study 
5. Parents/carers of subjects unwilling to consent to saving and 
propagation of pseudonymised medical data for study 
reasons 
6. Subjects who are in a dependent relationship with the 
Investigator or the Sponsor 
WITHDRAWAL CRITERIA: 
Subjects may be withdrawn from the study for any reason and 
without prejudice to further treatment in the following instances: 
1. Withdrawal of consent (by the parent/carer) 
2. New medical conditions that may compromise the safety of 
the subject 
3. Decision of the Investigator if he/she considers the subject’s 
health may be compromised by remaining in the study 
The study may be terminated at any time in the event of: 
1. Emerging data from the study suggests an unfavourable risk-
benefit analysis 
2. New scientific evidence provided during the study that could 
affect the subject’s safety (benefit-risk analysis no longer 
positive) 
3. Request of the Sponsor, the Independent Data Monitoring 
Committee (IDMC) or regulatory agency 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 14 of 65 
Version: Final 4.0, 20 July 2017 
INVESTIGATIONAL PRODUCT 
FORMULATION//DOSE: 
 
Infacort® is a dry granule formulation of hydrocortisone stored 
in capsules that will be available in different strengths (0.5, 1.0, 
2.0 and 5.0 mg). 
The 
clinically-appropriate 
dose, 
based 
on 
standard 
individualised treatment, will be administered according to 
usual clinical practice – usually 3 or 4 times daily.  
ROUTE OF 
ADMINISTRATION: 
Oral  
 
DURATION AND 
FREQUENCY: 
According to usual clinical practice 
REFERENCE THERAPY 
FORMULATION//DOSE: 
None 
CRITERIA FOR EVALUATION 
BIOCHEMICAL DISEASE 
CONTROL ASSESSMENTS 
SDS score for height and weight, cortisol (all subjects), and 
17-OHP, A4 and testosterone (CAH subjects only) 
SAFETY ASSESSMENTS: 
SAEs, AEs, vital signs, and laboratory assessments 
STATISTICAL METHODS: 
No formal sample size calculation is provided for this study since 
only subjects who have previously been treated in study Infacort 
003 can enter this study. Only descriptive statistical methods will 
be used for the evaluation of this study.  
All recorded and derived variables will be presented for each age 
cohort and overall using standard procedures (depending on the 
underlying distribution: for continuous data, sample size, mean, 
standard deviation (SD), minimum, median and maximum; for 
categorical data, sample size, absolute and relative frequency). 
The behaviour over time of continuous and categorical data will 
be analysed by presenting summary statistics for the actual 
values and change from baseline at each visit, if appropriate. 
Graphical presentations of the concentration data over time will 
also be provided. All collected and derived data will be listed. 
Interim data analyses are expected to be required for regulatory 
review as part of any marketing authorisation applications. 
DATA MONITORING 
COMMITTEE: 
Safety data will be reviewed by an IDMC on a regular basis to 
identify any emerging safety issues. An analysis of safety and 
biochemical disease control will be undertaken on a yearly basis, 
which will be overseen by the IDMC (this may be abbreviated in 
the early years when there is insufficient data to undertake a full 
analysis). 
ESTIMATED DATE OF  
FIRST SUBJECT 
ENROLLED: 
August 2015 
ESTIMATED DATE OF LAST 
SUBJECT COMPLETED: 
Subjects can continue to be treated in this study until they meet 
the study withdrawal criteria, Infacort® is granted a marketing 
authorisation (and so is available commercially1), Infacort® is 
                                                 
1 At the time of submission of this amendment (protocol version 4.0), Infacort® is the subject of an ongoing 
Marketing Authorisation Application procedure. For clarity, the end of study visits for each subject will occur 
after Infacort is commercially available. 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 15 of 65 
Version: Final 4.0, 20 July 2017 
refused a marketing authorisation, or the Sponsor decides to 
discontinue the study. 
NUMBER OF STUDY 
CENTRES: 
The main centre and remote sites participating in Infacort 003 
 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 16 of 65 
Version: Final 4.0, 20 July 2017 
2. 
List of Abbreviations 
 
17-OHP 
17-hydroxyprogesterone 
A4 
Androstenedione 
AE 
Adverse event 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
AI 
Adrenal insufficiency 
AUC 
Area under the plasma concentration versus time curve 
AUC0-t  
AUC from the time of dosing to the time of the last observed concentration 
AUC0-inf 
AUC extrapolated to infinity from dosing time, based on the last observed 
concentration 
BMI 
Body mass index 
BSA 
Body surface area 
CAH 
Congenital adrenal hyperplasia 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CRF 
Case report form  
CRH 
Corticotropin-releasing hormone 
CSR 
Clinical study report 
CV 
Coefficient of variation 
EU 
European Union 
GCP 
Good Clinical Practice 
HDPE 
High-density polyethylene 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Millilitre 
NF 
National Formulary 
PIP 
Paediatric Investigation Plan 
PK 
Pharmacokinetics 
PP 
Polypropylene 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Standard deviation score 
SDV 
Source data verification 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 17 of 65 
Version: Final 4.0, 20 July 2017 
t½ 
Half-life 
Tmax  
Time at which Cmax occurs 
UPI 
Unique product identifier 
WHO  
World Health Organisation 
µg  
Microgram 
µL 
Microlitre 
 
 
 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 18 of 65 
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3. 
Table of Contents 
 
1. 
Protocol Synopsis............................................................................................................... 9 
2. 
List of Abbreviations ....................................................................................................... 16 
3. 
Table of Contents ............................................................................................................. 18 
4. 
Investigators and Administrative Structure ..................................................................... 22 
5. 
Introduction ...................................................................................................................... 23 
5.1 
Background on the Disease ....................................................................................... 23 
5.2 
Preclinical Experience ............................................................................................... 23 
5.3 
Clinical Experience ................................................................................................... 24 
5.4 
Rationale.................................................................................................................... 25 
5.5 
Hypothesis ................................................................................................................. 26 
5.6 
Risk/Benefit Assessment ........................................................................................... 26 
6 
Study Objectives .............................................................................................................. 26 
6.1 
Primary Objective ..................................................................................................... 26 
6.2 
Secondary Objectives ................................................................................................ 26 
7 
Study Endpoints ............................................................................................................... 26 
7.1 
Primary Endpoint ...................................................................................................... 26 
7.2 
Secondary Endpoints ................................................................................................. 27 
8 
Study Design .................................................................................................................... 27 
8.1 
Assessments .............................................................................................................. 28 
8.2 
Repeat Evaluation or Additional Assessments.......................................................... 31 
8.3 
Demographics............................................................................................................ 31 
8.4 
Relevant Medical History/Current Medical Status ................................................... 32 
8.5 
Previous and Concomitant Medication/Treatment .................................................... 32 
8.6 
Physical Examination ................................................................................................ 32 
8.7 
Blood sampling ......................................................................................................... 32 
8.8 
Drug Administration Record ..................................................................................... 33 
8.9 
Infacort® Education for Parents/Carers ..................................................................... 33 
8.10 
Tanner Development Stage ................................................................................... 33 
8.11 
End of Study Information ...................................................................................... 33 
8.12 
Safety Assessments................................................................................................ 33 
8.12.1 Vital Signs and Body Measurements ................................................................. 33 
8.12.2 Adverse Events .................................................................................................. 33 
8.13 
Sick Day Rules ...................................................................................................... 34 
8.14 
Assessment Windows ............................................................................................ 34 
8.15 
Estimated Study Duration ...................................................................................... 34 


Investigational product: 
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Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 19 of 65 
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8.16 
Post-Study Management ........................................................................................ 34 
9 
Subject Population ........................................................................................................... 34 
9.1 
Number of Centres .................................................................................................... 34 
9.2 
Number of Subjects ................................................................................................... 35 
9.3 
Inclusion Criteria ....................................................................................................... 35 
9.4 
Exclusion Criteria ...................................................................................................... 35 
9.5 
Justification for the Inclusion of Minors and Persons Unable to Consent ................ 36 
10 Study Medication and Administration ............................................................................. 36 
10.1 
Randomisation, Numbering and Blinding ............................................................. 36 
10.2 
Description and Handling of Infacort® .................................................................. 36 
10.2.1 Formulation ........................................................................................................ 36 
10.2.2 Packaging and Labelling .................................................................................... 37 
10.2.3 Storage ............................................................................................................... 37 
10.2.4 Accountability .................................................................................................... 37 
10.3 
Dosage and Administration of Infacort® ............................................................... 38 
10.4 
Permitted Concomitant Medications/Treatments .................................................. 38 
10.5 
Overdose ................................................................................................................ 39 
11 Subject Withdrawal and Replacement ............................................................................. 39 
11.1 
Early Withdrawal from the Study .......................................................................... 39 
11.2 
Premature Termination of the Clinical Study ........................................................ 39 
11.3 
Replacement of Withdrawn Subjects .................................................................... 39 
11.4 
Intercurrent Illness or Need for Temporary Increase in Dose ............................... 39 
12 Adverse Events and Toxicity Management ..................................................................... 39 
12.1   
Adverse Event Definition ...................................................................................... 40 
12.2  
Adverse Event Collection ...................................................................................... 40 
12.3 
Reporting of Adverse Events ................................................................................. 40 
12.3.1 Diagnoses vs. Signs/Symptoms ......................................................................... 40 
12.3.2 Pre-Existing Conditions ..................................................................................... 40 
12.3.3 Pre-Planned Surgeries or Procedures ................................................................. 41 
12.3.4 Elective Surgeries or Procedures ....................................................................... 41 
12.3.5 Overdose ............................................................................................................ 41 
12.3.6 AEs of Special Interest....................................................................................... 41 
12.4 
Assessment of Adverse Event Severity ................................................................. 41 
12.5 
Assessment of Adverse Event Causality/Relatedness ........................................... 42 
12.6 
Assessment of Adverse Event Expectedness......................................................... 42 
12.7 
Serious Adverse Event Definitions........................................................................ 42 
12.8 
Serious Adverse Event Reporting .......................................................................... 43 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 20 of 65 
Version: Final 4.0, 20 July 2017 
12.9 
Serious Adverse Event Expedited Reporting ........................................................ 44 
12.9.1 Standards for Expedited Reporting .................................................................... 44 
12.9.2 Expedited Reporting Guideline for Other Observations .................................... 44 
12.10 
Sponsor’s Responsibilities ..................................................................................... 44 
12.11 
Independent Data Monitoring Committee ............................................................. 45 
12.12 
Procedures for Reporting Pregnancy Exposure and Birth Events ......................... 45 
13 Statistical Considerations ................................................................................................. 45 
13.1 
General considerations .......................................................................................... 46 
13.2 
Biochemical Disease Control and Safety Variables .............................................. 46 
13.2.1 Primary Variable ................................................................................................ 46 
13.2.2 Secondary Variables .......................................................................................... 46 
13.3 
Methods of Analysis .............................................................................................. 46 
13.3.1 Analysis Populations .......................................................................................... 46 
13.3.2 Statistical Evaluation ......................................................................................... 46 
13.3.3 Analysis of the Conduct of the Study ................................................................ 47 
13.3.4 Demographic and Other Baseline Characteristics ............................................. 47 
13.3.5 Tanner Development Stage ................................................................................ 47 
13.3.6 Sick Days ........................................................................................................... 47 
13.3.7 Safety Analysis .................................................................................................. 47 
13.3.8 End of Study Information .................................................................................. 48 
13.3.9 Miscellaneous .................................................................................................... 48 
13.4 
Power and Sample Size Considerations ................................................................ 48 
13.5 
Ongoing Reviews and Annual Reports ................................................................. 48 
14 Responsibilities ................................................................................................................ 48 
14.1 
Investigator Responsibilities.................................................................................. 48 
14.2 
Ethical Conduct of the Study ................................................................................. 49 
14.3 
Independent Ethics Committee Approval.............................................................. 50 
14.4 
Informed Consent .................................................................................................. 50 
14.5 
Case Report Forms ................................................................................................ 50 
14.6 
Site Monitoring ...................................................................................................... 51 
14.7 
Source Data Verification ....................................................................................... 51 
14.8 
Subject Confidentiality/Data Protection ................................................................ 51 
14.9 
Data Management .................................................................................................. 52 
14.10 
Drug Accountability .............................................................................................. 52 
14.11 
Inspections ............................................................................................................. 53 
14.12 
Sponsor Responsibilities........................................................................................ 53 
14.12.1 
Indemnity and Compensation......................................................................... 53 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
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14.12.2 
Subject Confidentiality ................................................................................... 53 
14.13 
Publication Policy .................................................................................................. 53 
14.14 
Clinical Study Report ............................................................................................ 53 
14.15 
Data Retention and Availability ............................................................................ 54 
14.16 
Study Termination ................................................................................................. 54 
15. References ........................................................................................................................ 54 
16. Bibliography .................................................................................................................... 54 
Appendix 1 – Blood Spot Analysis .......................................................................................... 56 
Appendix 2 – Tanner Development Stages ............................................................................. 57 
Appendix 3 – Sick Day Rules .................................................................................................. 58 
Appendix 4 – Anticipated Events in the Target Population .................................................... 59 
Appendix 5 – Contact Details for Serious Adverse Events ..................................................... 60 
Appendix 6 – Remote Site Guidelines ..................................................................................... 61 
Appendix 7 – Protocol Amendment History ........................................................................... 63 
 
 
 


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
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4. 
Investigators and Administrative Structure 
Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor (Sponsor) 
 
 
 
 
 
 
 
 
 
Project Manager (Sponsor) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Statistical Consultant 
 
 
 
 
 
 
 
Contract Research 
Organisation / Monitors 
 
 
 
 
 
 
 
 
 
 
Laboratory for Blood Spot 
Analysis 
 
 
  


Investigational product: 
 CONFIDENTIAL 
Protocol No.: Infacort 004 
Infacort®  
      
Diurnal Ltd 
 
Page 23 of 65 
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5. 
Introduction 
5.1 
Background on the Disease 
 
Adrenal insufficiency (AI) may be classified as primary (dysfunction of the adrenal gland itself) 
or secondary (when a lack of secretion of corticotropin-releasing hormone [CRH] from the 
hypothalamus or of adrenocorticotropic hormone [ACTH] from the pituitary leads to 
hypofunction of the adrenal cortex). The condition can be further classified as congenital or 
acquired. In the group of 0-6 years of age, congenital primary AI is the most common aetiology. 
It may occur as a result of adrenal hypoplasia or hyperplasia. 
 
Congenital adrenal hyperplasia (CAH) is the most common congenital genetic endocrine 
disorder and results from mutations in the cortisol synthesis pathway in the adrenal glands. 
Mutations in the 21-hydroxylase gene, a key enzyme in cortisol and aldosterone synthesis, 
account for 95% of cases. 21-hydroxylase deficiency has an incidence of 1:12,000 live births 
for severe mutations causing classic CAH, which manifests in the neonatal period. In CAH, 
failure in cortisol synthesis results in reduced cortisol feedback and consequently increased 
pituitary ACTH release, which promotes over-secretion of 17-hydroxyprogesterone (17-OHP), 
progesterone and adrenal androgens. This results in androgen excess that clinically manifests 
with disordered sex development in girls, precocious pseudopuberty, and short stature, and in 
adulthood with hirsutism in females and fertility problems in both sexes.  
 
With proper treatment and compliance, patients with cortisol deficiency can live a normal life 
span without limitations. However, the prognosis for an untreated patient is poor. Death is a 
common outcome, usually from hypotension or cardiac arrhythmia secondary to 
hyperkalaemia, unless replacement steroid therapy is begun. Glucocorticoid replacement in 
CAH aims both to replace cortisol and prevent ACTH-driven androgen excess (Dauber et al., 
2010). This is challenging, since therapy aiming to normalise ACTH and reducing androgen 
levels results in excess glucocorticoid exposure with associated complications including short 
stature, obesity, hypertension and an adverse metabolic profile. Striking the balance between 
too much and too little glucocorticoid treatment is especially difficult as currently available 
glucocorticoid formulations cannot replicate the circadian rhythm of cortisol secretion and are 
not formulated for the paediatric population. CAH is a life-long chronic disorder. In childhood, 
treatment focuses on issues of gender assignment, genital surgery, optimisation of growth and 
pubertal development. Priorities change with increasing age, focusing on fertility in early adult 
life and prevention of metabolic syndrome and osteoporosis in middle and older age, 
respectively. 
 
Other causes for AI besides CAH include congenital adrenal hypoplasia, lipoid adrenal 
hyperplasia and hypopituitarism – all of which are extremely rare. 
5.2 
Preclinical Experience 
 
Hydrocortisone is a naturally-occurring glucocorticoid hormone secreted by the healthy adrenal 
cortex and the goal of therapy in AI is to replace this hormone to physiological levels. Such 
replacement therapy has been a routine part of medical care in both adults and children for more 
than 50 years and its safety profile is well understood. 
 
All the excipients used in Infacort® immediate release granules are standard materials normally 
used in pharmaceutical drug products. All are the subject of European Pharmacopeia and/or 


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United States Pharmacopeia/National Formulary (NF) Monographs and have been used in 
pharmaceutical products worldwide over many years. Additional information on these 
materials may be obtained from ‘The Handbook of Pharmaceutical Excipients – 7th Edition’ 
(2012). Therefore no preclinical studies were performed for Infacort®. 
5.3 
Clinical Experience 
 
The pharmacokinetic (PK) profile of Infacort® immediate release granules has been 
characterised in study Infacort 001 (EudraCT number: 2013-000260-28). This randomised, 
crossover study was undertaken in dexamethasone-suppressed healthy male adult subjects to 
determine the bioequivalence of 10 mg Infacort® compared with a 10 mg dose of immediate 
release hydrocortisone and to evaluate the dose-proportionality of Infacort® at doses of 0.5, 2, 
5 and 10 mg. Each dose of investigational medicinal product (IMP) (Infacort® granules 0.5 mg, 
2 mg, 5 mg, 10 mg and hydrocortisone 10 mg tablet) was administered to each of 16 subjects 
in a randomised crossover manner over 5 treatment periods. Each subject received their 
scheduled treatment at approximately 07:00 hours, in a fasted state. They also received 1 mg 
dexamethasone (to suppress endogenous cortisol production) at approximately 22:00 hours on 
the night before, and at approximately 06:00 and 12:00 hours on the day of treatment. PK 
samples were taken to determine serum cortisol levels pre-dose and at regular intervals for up 
to 12 hours post-dose and used to determine the maximum plasma concentration (Cmax), the 
time at which Cmax occurs (Tmax), half-life (t½), the area under the plasma concentration versus 
time curve (AUC) from the time of dosing to the time of the last observed concentration 
(AUC0-t) and the AUC extrapolated to infinity from dosing time, based on the last observed 
concentration (AUC0-inf). To establish bioequivalence, the geometric least square (LS) mean 
90% confidence interval (CI) for the ratios of Cmax, AUC0-t and AUC0-inf were determined for 
Infacort® and hydrocortisone. Bioequivalence was demonstrated for the 10 mg Infacort® 
compared with a 10 mg dose of immediate release hydrocortisone, and over the 0.5 mg to 
10 mg Infacort® dose range, Cmax, AUC0-t and AUC0-inf were shown to increase in a linear 
fashion. 
 
A second study, Infacort 002 (EudraCT number: 2013-000259-42) has been performed in 
dexamethasone-suppressed healthy adults to show the bioequivalence of 20 mg Infacort® 
compared with a 20 mg dose of immediate release hydrocortisone. Each treatment (Infacort® 
20 mg, hydrocortisone tablets 20 mg, and intravenous hydrocortisone 20 mg) was administered 
as a single dose to each of 14 healthy male subjects in a partially randomised crossover manner 
over 5 treatment periods (1 treatment per period). In treatment period 1, no treatment was 
administered and endogenous cortisol production was measured. In subsequent treatment 
periods, each subject also received 1 mg dexamethasone (to suppress endogenous cortisol 
production) at approximately 22:00 hours on Day 1, and at approximately 06:00 hours and 
12:00 hours on Day 2. Preliminary data from this study indicate that oral Infacort® and 
hydrocortisone tablets are, respectively, approximately 87% and 97% bioavailable when 
compared to the reference intravenous hydrocortisone injection. Oral Infacort® and 
hydrocortisone tablets were considered bioequivalent, with geometric LS mean 90% CI for the 
ratios of Cmax, AUC0-t and AUC0-inf falling within 80 - 125. Tmax was also similar between the 
2 formulations, indicating no important differences in the rate of absorption. The preliminary 
data from this study again demonstrates the bioequivalence of Infacort® and hydrocortisone – 
this time at a dose of 20 mg. There were no notable adverse events (AEs), and Infacort® 
appeared palatable. 
 


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At physiological replacement doses there are no major reported side-effects of hydrocortisone 
therapy. The doses of hydrocortisone in the Infacort 001 and Infacort 002 studies produce 
concentrations that encompass the physiological range. Immediate release oral tablets of 
hydrocortisone have been approved and marketed worldwide (including in all European Union 
[EU] countries) for more than 20 years.  
5.4 
Rationale 
 
As the underlying pathology is, in nearly all cases, untreatable, the mainstay of treatment for 
AI in the paediatric population is replacement therapy using hydrocortisone which has been 
practiced since the late 1940s. The major issue is that there is no evidence base for the use of 
current formulations of hydrocortisone in neonates. For neonates and infants there is no 
licensed preparation available that provides the appropriate physiological dose in a formulation 
that can be given to neonates and infants. Currently available hydrocortisone preparations are 
either for intravenous or adult use. Neonatologists and local pharmacists have to grind 
hydrocortisone tablets to powder and estimate the dose to be encapsulated. Parents are then 
supplied with capsules containing crushed tablets. However, there is no formal quality control. 
A recently undertaken analysis in Berlin showed that nearly 25% of the batches failed to meet 
the acceptance criteria of mass and content uniformity based on the European Pharmacopeia 
(Figure 1) (Neumann et al., 2017), possibly explaining poor control of congenital adrenal 
hyperplasia in some small children and neonates (Kauzor et.al., 2014).  
 
 
Figure 1:  Capsules Containing Hydrocortisone, Individually Prepared for a Subject (Note 
Variation in Dose Between Capsules) 
 
Young children and neonates are therefore at risk for under-treatment, resulting in adrenal 
crisis, or over-treatment which may lead to impairment of growth. 
 
Infacort® is a new formulation of hydrocortisone that is available in a wide range of doses to 
meet the dosing needs of neonates and infants suffering from AI. The taste is also masked to 
avoid the bitter characteristic taste of hydrocortisone. The microparticulate formulation is 
especially suitable for young children in need of hydrocortisone replacement therapy. 
 
Study Infacort 003 evaluated PK, safety and tolerability of a single dose of Infacort® according 
to the agreed Paediatric Investigation Plan (PIP). This study Infacort 004 aims to extend the 
observations to look at long-term treatment effects. 


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5.5 
Hypothesis 
 
The administration of Infacort® to infants, neonates and children who have completed study 
Infacort 003 is safe and produces the required effects following long-term administration. 
5.6 
Risk/Benefit Assessment 
 
The IMP used is hydrocortisone, which is a well understood replacement therapy for subjects 
with AI. The safety profile of hydrocortisone is well characterised. This formulation of 
hydrocortisone is produced specifically for young children, for whom there is no licensed 
preparation of oral hydrocortisone. Infacort® has already been assessed in adult healthy 
subjects, and found to be bioequivalent with hydrocortisone tablets, and to have acceptable 
taste properties. Subjects in this study will already have received a single dose of Infacort® in 
study Infacort 003, and this will have been shown to be adequately absorbed. This study 
therefore poses a minimal risk to the involved subjects.  
 
All emerging safety data will be assessed for any signal of safety problems on an ongoing basis. 
An analysis of safety and biochemical disease control will be undertaken and overseen by an 
Independent Data Monitoring Committee (IDMC) on a yearly basis (this may be abbreviated 
in the early years when there is insufficient data to undertake a full analysis). The IDMC terms 
of reference and supplementary charter will be provided as a separate document. 
 
The potential benefits of the new treatment include precise dosing, avoiding the long-term 
consequences of under or over-treatment, or varying treatment efficacy, and palatable treatment 
that is easily swallowed, which outweigh the risks of this study being performed in children. 
6 Study Objectives 
6.1 
Primary Objective 
 
 To gather data on the long-term safety of Infacort® in subjects completing study 
Infacort 003. 
6.2 
Secondary Objectives 
 
 To gather data on the effects of Infacort®. 
7 Study Endpoints 
7.1 
Primary Endpoint 
 
 Nature and occurrence of serious adverse events (SAEs) and AEs observed 
throughout the study. 


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7.2 
Secondary Endpoints 
 
 Standard deviation score (SDS) for height and weight. 
 Cortisol (all subjects) and adrenal androgen levels (17-OHP, androstenedione [A4], 
testosterone) in CAH subjects only. 
8 Study Design 
 
This is a Phase 3, open-label, single-group, non-randomised, observational study of the safety 
and biochemical disease control of Infacort® in neonates, infants and children with AI who 
have completed study Infacort 003 (EudraCT number 2014-002265-30). All subjects who have 
satisfactorily completed study Infacort 003 will be offered the opportunity to participate in 
study Infacort 004 at or after their final visit of study Infacort 003. Subjects will receive the 
usual clinically-appropriate dose (since bioequivalence has been demonstrated with 
conventional hydrocortisone), as determined by the Investigator, which will be administered 
according to usual clinical practice – generally 3 or 4 times a day. Subjects can continue to be 
treated in this study until they meet the study withdrawal criteria (see Section 11), Infacort® is 
granted a marketing authorisation (and so is available commercially2, which is expected within 
2 years of initiation of this study), Infacort® is refused a marketing authorisation, or the Sponsor 
decides to discontinue the study. 
 
The standardised protocol for follow-up will include: 
 
 Initial visit 
 Monthly visits for the first 2 months of treatment 
 Thereafter visits every 3 months  
 Final visit 
 
The study will be conducted in up to 24 subjects from the Infacort 003 study requiring 
replacement therapy for AI due to either CAH, primary adrenal failure or hypopituitarism. The 
primary site will be Charité-Universitätsmedizin Berlin, CVK. However, some subjects 
participating in Infacort 003 may have been transferred from remote sites. Should their 
parents/carers and clinician agree to participation in Infacort 004, the previous remote sites will 
be involved as study centres in this study (or, if agreeable, the subjects may be cared for at 
Charité-Universitätsmedizin Berlin for the purposes of the study). In some agreed cases, whilst 
the subject is cared for by Charité-Universitätsmedizin Berlin for the purposes of the study, it 
may be necessary for the Investigator at Charité-Universitätsmedizin Berlin to conduct the 
study visits at the subject's local hospital. Detailed guidelines to address the process for 
enrolment of such subjects and the performance of study procedures at remote sites are included 
in Appendix 6 and will be submitted to the Independent Ethics Committee (IEC) and the 
German Competent Authority ‘Bundesoberbehörde’ (BfArM). 
 
Parents/carers will be provided with the informed consent document at least 24 hours prior to 
enrolment of their child in the study. Children aged over 3 years old will be informed about 
their involvement in the study in the presence of their parents/carers. For each visit, care will 
                                                 
2 At the time of submission of this amendment (protocol version 4.0), Infacort® is the subject of an ongoing 
Marketing Authorisation Application procedure. For clarity, the end of study visits for each subject will occur 
after Infacort® is commercially available. 


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be taken to note the time of any blood sampling, and the time and dose of the previous 
administration of glucocorticoid. 
8.1 
Assessments 
 
Subjects successfully completing study Infacort 003 are eligible to enter this Infacort 004 study. 
The study procedures to be conducted for each subject enrolled into the Infacort 004 study are 
detailed in Table 1: 
 
 
 


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Table 1:  Schedule of Study Assessments 
 
 
Initial Visit 
Interim Visits1 
Final Visit 
Written informed consent2 
X 
 
 
Medical history/current 
medical status3 
X 
 
 
Physical examination 
X 
X 
X 
Height/length 
X 
X 
X 
Weight 
X 
X 
X 
Vital signs4 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
Previous/concomitant 
medication5 
X 
X 
X 
Infacort® administration 
X6 
X 
 
Infacort® education for 
parents/carers 
X 
 
 
Problems associated with 
administration/dosing 
X 
X 
X 
Tanner development stage 
X 
X 
X 
SAEs and AEs7 
 
X 
X 
Blood sampling8 
(electrolytes, renin, 
haematocrit and any 
additional cortisol data) 
X 
X 
X 
Dried blood spot sampling9 
X 
X10 
X 
Incidence of adrenal crisis 
 
X 
X 
Incidence of sick day rules 
 
X 
X 
End of study information11 
 
 
X 
1 Interim visits monthly for the first 2 months of treatment then every 3 months. 
2 Written informed consent must be provided at least 24 hours prior to enrolment. 
3 Medical history from Infacort 003 will be used, plus any changes since the subject was enrolled in the Infacort 
003 study. 
4 Blood pressure (where possible), heart rate and temperature. 
5 To include current adrenal replacement therapy at the initial visit 
6 First dose administered by the parent/carer in the presence of the Investigator at the initial visit. 
7 AEs will be recorded from the time of the first intake of Infacort® in this study until the final visit. SAEs will be 
recorded from the time of the first intake of Infacort® in this study until 7 days after the last dose of Infacort®. Any 
SAEs experienced after this 7-day period should only be reported if the Investigator suspects a causal relationship 
to Infacort®. 
8 Where taken as part of routine clinical care (normally once a year). The time of the blood sampling and the time 
of the last glucocorticoid dose will be recorded.  
9 The time of blood sampling will be noted, as well as the time and dose of the previous administration of 
glucocorticoid. Where possible the blood spot sample should be taken in the morning. 
10 For the first 2 months of treatment and then 6-monthly therafter unless required after 3 months. 
11 At final visit or at withdrawal from the study. 
 
 
 


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Initial Visit: 
The primary site will be Charité-Universitätsmedizin Berlin, CVK. However, some subjects 
participating in Infacort 003 may have been transferred from remote sites. Should their 
parents/carers and clinician agree to participation in Infacort 004, the previous remote sites will 
be involved as study centres in this study (or, if agreeable, the subjects may be cared for at 
Charité-Universitätsmedizin Berlin, for the purposes of the study). In some agreed cases, whilst 
the subject is cared for by Charité-Universitätsmedizin Berlin for the purposes of the study, it 
may be necessary for the Investigator at Charité-Universitätsmedizin Berlin to conduct the 
study visits at the subject's local hospital. Detailed guidelines of the processes in such cases are 
included in Appendix 6. 
 
On completion of Visit 4 of study Infacort 003, subjects can undergo the initial visit for this 
Infacort 004 study. Date of birth, gender, race/ethnicity, and medical history will be retrieved 
from Infacort 003 data. Other assessments at this visit include: 
 
 
Informed consent (parents/carers will be provided with the informed consent document at 
least 24 hours prior to enrolment of their child in this study) 
 
Changes in medical history/current medical status since enrolment in the Infacort 003 study 
 
Physical examination 
 
Height/length 
 
Weight 
 
Body mass index (BMI) and body surface area (BSA) (derived) 
 
Vital signs 
o Blood pressure (if possible) 
o Heart rate 
o Temperature 
   Compliance with inclusion/exclusion criteria 
 
Tanner development stage 
 
Previous and concomitant medication (including current adrenal replacement therapy) 
 
Dried blood spot sampling (cortisol [all subjects], and 17-OHP, A4, testosterone [CAH 
subjects only]). Where possible the blood spot sample should be taken in the morning. The 
time of blood sampling and the time and dose of the previous glucocorticoid administration 
will be recorded.  
 
Blood sampling (electrolytes, renin, haematocrit, and any additional cortisol data) if taken 
as part of routine clinical care (the time of blood sampling and the time of the last 
glucocorticoid dose will be recorded). 
 
Infacort® administration education for parents/carers 
 
First dose of Infacort® administration given by the parent/carer in the presence of the 
Investigator. Details of the dose and time of eating will be recorded in the case report form 
(CRF) 
 
Problems associated with administration/dosing - entire or incomplete dosing will be 
recorded in the CRF  
 
Interim Visits: 
 Physical examination 
 Height/length 
 Weight 
 BMI and BSA (derived) 
 Vital signs 


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o Blood pressure (if possible) 
o Heart rate 
o Temperature 
 Concomitant medication 
 SAEs and AEs, including application of sick day rules and adrenal crises 
 Dried blood spot sampling (cortisol [all subjects], and 17-OHP, A4, testosterone [CAH 
subjects only]) every 6 months following the first 2 months of treatment, unless required 
after 3 months. Where possible the blood spot sample should be taken in the morning. The 
time of blood sampling and the time of the last glucocorticoid dose will be recorded.  
 Blood sampling (electrolytes, renin, haematocrit, and any additional cortisol data) where 
taken as part of routine clinical care (normally once a year). The time of blood sampling 
and the time of the last glucocorticoid dose will be recorded. 
 Tanner development stage 
 Dose of Infacort® 
 Problems associated with administration/dosing  
 
Final Visit: 
 
Physical examination 
 
Height/length 
 
Weight 
 
BMI and BSA (derived) 
 
Vital signs 
o Blood pressure (if possible) 
o Heart rate  
o Temperature 
 
Concomitant medication 
 
Problems associated with administration/dosing 
 
SAEs and AEs, including application of sick day rules and adrenal crises 
 
Dried blood spot sampling (cortisol [all subjects], and 17-OHP, A4, testosterone [CAH 
subjects only]). Where possible the blood spot sample should be taken in the morning. The 
time of blood sampling and the time of the last glucocorticoid dose will be recorded. 
 
Blood sampling (electrolytes, renin, haematocrit, and any additional cortisol data) if taken 
as part of routine clinical care (the time of blood sampling and the time of the last 
glucocorticoid dose will be recorded) 
 
Tanner development stage 
 
End of study information (completion/withdrawal status etc.).   
8.2 
Repeat Evaluation or Additional Assessments 
 
Should it become necessary to repeat an evaluation (e.g., vital signs), the results of the original 
and the repeat evaluation will be captured. The additional assessment should be entered in the 
‘Unscheduled Visit’ page provided in the CRF. 
8.3 
Demographics 
 
These include date of birth, gender, race, height/length and weight. Date of birth, gender and 
race will be retrieved from the Infacort 003 data. 


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8.4 
Relevant Medical History/Current Medical Status 
 
Relevant medical history and current medical conditions will be recorded in the CRF at the 
initial visit. Information on medical history can be used from the Infacort 003 study, but any 
changes since enrolment in the Infacort 003 study must be noted. 
8.5 
Previous and Concomitant Medication/Treatment  
 
At the initial visit, the Investigator will record any medications and significant non-drug 
therapies the child took before the first intake of Infacort® in this study as well as any 
medications that are currently being taken (i.e. concomitant medications). Any changes in 
concomitant medications will be recorded, with other adrenal replacement therapies being 
recorded separately in the CRF. Medication entries should specify the generic name, the single 
dose and unit, the frequency and route of administration, the start and discontinuation date and 
the reason for therapy. 
8.6 
Physical Examination 
 
This evaluation will include an examination of skin, nose and throat region, lungs, heart, 
abdomen, back, genital status and basic nervous system evaluation. Information about the 
physical examination must be present in the source documentation at the study site. Significant 
findings that are present prior to the start of Infacort® treatment must be included in the 
relevant medical history/current medical status section of the CRF. Significant findings made 
after the start of Infacort® treatment which meet the definition of an AE must be recorded in 
the Adverse Event CRF summary page. 
8.7 
Blood sampling  
 
A dried blood spot sample will be collected at the initial and final visits, every month for the 
first 2 months of treatment and thereafter every 6 months, unless required after 3 months. Where 
possible the blood spot sample should be taken in the morning but the exact time of the sample 
should be recorded. The dried blood spots will be analysed for multi-steroids, including cortisol 
(all subjects), and 17-OHP, A4, and testosterone (CAH subjects only), by the laboratory at 
Charité-Universitätsmedizin Berlin (details of collection methodology and analytes to be tested 
are provided in Appendix 1). Electrolytes, renin, haematocrit, and any additional cortisol data 
will also be collected where collected routinely by the local laboratory as part of the routine 
clinical care (normally once a year). The results of all these analyses will be included in the 
database. These data may be merged with that collected in the Infacort 003 study for population 
PK analyses. The amount of blood collected at each visit will be approximately 2 mL. Blood 
sampling performed for the purpose of the study and not as part of routine clinical care (e.g. 
dried blood spot samples) requires 75 – 80 µl of blood for each additional sample. The 
additional blood volumes pose no health risk for the subjects. Blood spots will be collected 
from either venous or capillary sampling.  
 
The taking of venous blood samples poses no additional health risk for the subjects and does 
not provide any additional burden for the subject as study related venous sampling is limited to 
routinely performed venous punctures in the management of the subject’s condition. Where 
venous blood samples are taken as part of routine clinical care the blood spot will also be 
collected from venous sampling. 


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8.8 
Drug Administration Record 
 
The dose of Infacort® prescribed and dispensed to the subject and all changes during the study 
must be recorded on the dosage administration record section of the CRF. A diary card will be 
provided so that parent/carer can record any missed doses etc. between visits. Any problems 
associated with administration or dosing (e.g. capsule spilt etc.) should also be recorded.  
8.9 
Infacort® Education for Parents/Carers 
 
Since the parents/carers will be administering the Infacort® to the subjects at home, they will 
be trained how to administer the study medication by the Investigator or Study Nurse during 
their initial visit. They will also be given an instruction sheet to take home with them for 
reference, which will include written instructions on the dose to be taken from the clinician. 
They will also be instructed how to complete the diary card, and they will be asked to bring 
this along to all visits. 
8.10 Tanner Development Stage 
 
The Tanner Development Stages are shown in Appendix 2. At each visit the Investigator will 
record the development of the subject using this scale.  
8.11 End of Study Information 
 
Information on subject completion or withdrawal from the study and the reason for withdrawal 
from the study will be recorded on the Study Completion CRF page. Study completion 
evaluations must also be performed when a subject prematurely withdraws from the study for 
whatever reason. In the case of death, the cause of death must be recorded.  
8.12 Safety Assessments  
8.12.1 Vital Signs and Body Measurements 
 
Body height/length (cm) and body weight (kg to 1 decimal place) will be obtained at each visit. 
Systolic and diastolic blood pressure (mmHg) (if possible), heart rate (beats/min) and body 
temperature (°C) will also be assessed at each visit. Blood pressure should be assessed using 
the same arm and the same measurement conditions for each time of determination. 
8.12.2 Adverse Events 
 
The collection of AEs is described in Section 12. 
 
AEs will be recorded from the time of the first intake of Infacort® until the final visit. A diary 
card will be provided so that parents/carers can record any relevant events between visits. In 
particular, events associated with dosing (e.g. choking) should be noted. These diary cards will 
be discussed with the Investigator at each visit and any relevant information will be transferred 
into the CRF.  


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8.13 Sick Day Rules  
 
All subjects will be supplied with “Sick day rules” (an example is provided in Appendix 3). 
When these rules are implemented for a subject, the number of days they are used must be 
documented.  
8.14 Assessment Windows 
 
Windows for the following assessment times are acceptable based on logistical and operational 
considerations: 
 
 Interim visit (± 10 days) 
 Final visit (± 10 days) 
 
If a visit needs to be postponed for more than 10 days (i.e. holidays), then the subject should 
attend for the visit before the period of absence for safety and drug supply reasons. Subsequent 
visits will then be scheduled at regular intervals from the revised early visit date. 
8.15 Estimated Study Duration 
 
Subjects will enter this study following completion of the Infacort 003 study. Parents/carers 
will be provided with the informed consent document at least 24 hours prior to enrolment of 
their child in the study. The start of the study will be considered as the date of the signed 
informed consent of the first subject in this study. Subjects can continue to be treated in this 
study until they meet the study withdrawal criteria (see Section 11), Infacort® is granted a 
marketing authorisation (and so is available commercially, which expected within 2 years of 
initiation of this study), Infacort® is refused a marketing authorisation, or the Sponsor decides 
to discontinue the study.  
8.16 Post-Study Management 
 
The conclusion of the study is defined as the last visit of the last subject. Each subject’s study 
participation ends when all planned study procedures have been completed (after the final visit). 
The subjects may continue their usual therapy with hydrocortisone after the last intake of 
Infacort® or with Infacort® if commercially available. 
9 Subject Population 
9.1 
Number of Centres 
 
The primary site will be Charité-Universitätsmedizin Berlin, CVK, since this site enrolled all 
of the subjects into the Infacort 003 study. However, some subjects participating in Infacort 
003 may have been transferred from remote sites. If the parents/carers and clinician of these 
subjects agree to participation in Infacort 004, the previous remote sites will be involved as 
study centres in this study (or, if agreeable, the subjects may be cared for at Charité-
Universitätsmedizin Berlin for the purposes of the study). In some agreed cases, whilst the 
subject is cared for by Charité-Universitätsmedizin Berlin for the purposes of the study, it may 
be necessary for the Investigator at Charité-Universitätsmedizin Berlin to conduct the study 
visits at the subject's local hospital. The procedure for this is detailed in Appendix 6. 


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9.2 
Number of Subjects 
 
The subjects included in this clinical trial will not be selected with regard to their sex, since no 
gender specific differences concerning efficacy and safety of the IMP are expected (see GCP-
V § 7 (2) No. 12).There are no gender related effects of hydrocortisone which could influence 
the outcome of the study. 
 
A maximum of 24 subjects will be enrolled in study Infacort 004. The number of subjects in 
this study will be determined by the number wanting to continue to receive Infacort® after they 
complete study Infacort 003 (which will recruit up to a maximum of 24 subjects). The 
Investigator in the Infacort 003 study will ensure that all subjects treated in study Infacort 003 
are invited to participate in this Infacort 004 study. No additional exclusions to those detailed 
in Section 9.4 will be applied by the Investigator. 
 
Subject selection is to be established by checking through all inclusion/exclusion criteria at the 
initial visit. A record of this check (e.g. inclusion/exclusion checklist) must be stored with the 
source documentation at the study site. Deviation from any entry criterion excludes a subject 
from enrolment into the study unless it is temporary – then subjects may be entered when the 
temporary exclusion criterion resolves. 
9.3 
Inclusion Criteria 
 
Subjects successfully completing study Infacort 003, whose inclusion criteria were: 
 
1. Male and female children less than 6 years of age.  
2. A diagnosis of AI as confirmed by an inappropriately low cortisol usually with other 
supporting tests.  
3. Receiving appropriate adrenocortical replacement therapy (hydrocortisone with/without 
fludrocortisone). 
4. Adequately hydrated and nourished. 
 
In addition, the parents/carers must be able to understand and give written Informed Consent 
(according to AMG §40 (1) 3b) for this extension study. 
9.4 
Exclusion Criteria 
 
1. Clinically evident acute AI (adrenal crisis) (Note: the subject can be re-evaluated for 
elibility once the episode is over). 
2. Inability of the child to take oral therapy. 
3. Subjects with clinical signs of acute infection or fever on inclusion (Note: the subject can 
be re-evaluated for elibility once the episode is over). 
4. Any surgical or medical condition that in the opinion of the Investigator may place the 
subject at higher risk from his/her participation in the study. 
5. Parents/carers of subjects unwilling to consent to saving and propagation of pseudonymised 
medical data for study reasons 
6. Subjects who are in a dependent relationship with the Investigator or the Sponsor  


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9.5 
Justification for the Inclusion of Minors and Persons Unable to
 
Consent  
 
Although children <6 years of age, infants and neonates with AI are currently treated with 
crushed hydrocortisone tablets, no cortisol replacement therapy has ever been officially 
licensed for these age groups. Whilst hydrocortisone is universally accepted as an appropriate 
replacement therapy in AI, the availability of current oral products only as solid tablets 
significantly impairs its usefulness in neonates, infants and young children. Crushed tablets are 
currently used, leading to imprecise dosing and poor palatability due to the bitter taste of 
hydrocortisone. We are therefore developing an age-appropriate oral formulation of 
hydrocortisone which will allow for optimising therapy in the proposed age-group, since a 
range of microparticulate doses will be available, which will be suitably taste masked.  
10 
Study Medication and Administration 
10.1 Randomisation, Numbering and Blinding 
 
This is an open-label, single-group, non-randomised, observational study and therefore no 
blinding or un-blinding procedures are required. Each subject is uniquely identified in the study 
by the subject number allocated to them in study Infacort 003. This subject number is the unique 
identifier throughout the study and will not be reused.  
10.2 Description and Handling of Infacort® 
10.2.1 
Formulation 
 
Infacort® is formulated as immediate release multiparticulate granules filled in a hard capsule. 
The capsule contents (multiparticulate granules) are either administered directly onto the top, 
and towards the back, of the child’s tongue or the granules can be sprinkled onto a spoonful of 
yoghurt, fruit purees (e.g. apple sauce) or fruit mousses immediately before being administered 
to the child. The granules can also be washed down with water, breast milk, formula milk or 
whole milk following administration. The hard capsule itself is a carrier and not for 
consumption. Infacort® is available in dose strengths of 0.5, 1.0, 2.0 and 5.0 mg hydrocortisone 
and presented in size 00el hard capsules. 
 
All excipients used in Infacort® immediate release granules are the subject of European 
Pharmacopeia and/or United States Pharmacopeia/NF Monographs, and have been used in 
pharmaceutical products worldwide over many years. Infacort® immediate release granules 
have been assigned the unique product identifier (UPI) of 997249. 


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10.2.2 
Packaging and Labelling 
 
Infacort® is supplied as 0.5, 1.0, 2.0 and 5.0 mg dose strengths. Infacort® 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 and 10 blister packs are packaged in a cardboard carton 
to produce a 100-count pack of each dose strength. Each bottle contains 40 capsules of the same 
dose strength. The Sponsor will supply the pharmacy at the study sites with cardboard cartons 
or bottles of each dose strength for dispensing according to the appropriate dose determined by 
the Investigator (see Section 10.3). 
 
Infacort® will be appropriately labelled in accordance with Annex 13, Rev 1 (manufacture of 
IMPs) of the EC guide to Good Manufacturing Practice.  
 
All supplies of Infacort® will be labelled with a minimum of the protocol number, subject 
number, pharmaceutical dosage form (including product name, strength and quantity of dosage 
units), directions for use, storage conditions, expiry date, batch number, the statements ‘For 
clinical trial use only’, Investigator name and the Sponsor’s name and address information.  
 
The documentation supplied with the Infacort® IMP will make it possible to retrace the 
composition and pharmaceutical quality of the product. 
10.2.3 
Storage 
 
Infacort® will be stored in a secure, temperature-controlled pharmacy at a temperature not 
exceeding 25°C. Infacort® does not require cold chain transportation, and the drug product has 
an established stability profile that demonstrates the drug product remains stable at ambient 
storage conditions and is stable at an accelerated temperature of 40°C over 1  month. However, 
Infacort® will always be shipped at a controlled temperature not exceeding 25°C. Temperature 
monitors, included with the Infacort® shipments, will be downloaded by the pharmacist and 
provided to the Sponsor to confirm that the transportation conditions are acceptable, i.e. to 
ensure that the Infacort® is maintained within the established temperature range in accordance 
with the labelled storage conditions. Parent/carer should be instructed to ensure that Infacort® 
is stored in accordance with the labelled storage conditions. The Sponsor must be notified of 
any known temperature excursion during the clinical trial in order to assess the impact and 
provide supportive documentation as necessary. Note: see Appendix 6 for shipment of IMP to 
remote sites. 
10.2.4 
Accountability  
 
All used (empty blister packs/bottles) and unused Infacort® will be returned to the pharmacy, 
where the amount dispensed and the amount returned will be recorded. Following the Sponsor’s 
approval, any unused Infacort® will either be returned to the supplier or to the Charité Pharmacy 
(where it will be destroyed on site and a certificate of destruction provided). 


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10.3 Dosage and Administration of Infacort® 
 
Infacort® is supplied as 0.5, 1.0. 2.0 and 5.0 mg dose strengths. The normal clinically-
appropriate dose, based on standard individualised treatment, will be administered according 
to usual clinical practice (since Infacort® has been shown to be bioequivalent to conventional 
hydrocortisone) – generally 3 or 4 times a day.  
 
The drug is presented in a capsule. The capsule is not to be consumed, it is only a container 
for the drug. 
 
Immediately prior to administration of Infacort®, the capsule will be opened and the entire 
contents (i.e. drug granules) administered. The granules will be administered either: 
1. directly onto the top and towards the back of the child’s tongue and washed down 
immediately with fluid (water, breast milk, formula milk, or whole milk), or 
2. administered onto the top and towards the back of the child’s tongue using a spoon and 
washed down immediately with fluid (water, breast milk, formula milk, or whole milk), 
or  
3. Sprinkled onto a spoonful of yoghurt, fruit purees (e.g. apple sauce) or fruit mousses 
immediately before being administered to the child. The granules can also be washed 
down with water, breast milk, formula milk or whole milk following administration. 
 
Training on administration of the study medication will be given to the parents/carers at the 
initial visit by the Investigator or Study Nurse. The first dose at the initial visit will be 
administered by the parent/carer under the supervision of the Investigator or Study Nurse, with 
subsequent doses administered by the parents/carers at home. Administration of incomplete 
doses (e.g., spilling of granules during administration in excess of 10%) should be recorded by 
the parents/carers in the diary cards and then transcribed into the CRF by the site staff. 
Sufficient drug will be dispensed by the pharmacy in case of spillages prior to administration.  
 
Any case of incomplete administration of the study medication must be recorded in the diary 
card. If it is estimated that >25% of the study medication was not swallowed (i.e. spat out) the 
dose should be repeated, with the repeat administration recorded in the diary card.  
 
If vomiting occurs within 30 minutes of administration of Infacort® the dose should be repeated, 
with the repeat administration recorded in the diary card. Standard care should also be 
implemented. The event should be recorded on the diary card and recorded as an AE, if 
appropriate. In the case of repeated vomiting, the sick day rules apply (an example of which is 
detailed in Appendix 3). 
10.4 Permitted Concomitant Medications/Treatments 
 
Throughout the study the subjects will continue to take all their regular treatments, with the 
exception of hydrocortisone, which will be replaced with Infacort®. All prior and concomitant 
medications must be recorded on the CRF. A diary card will be provided to the parents/carers 
so that any changes to concomitant medications between visits can be recorded. 


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10.5 Overdose 
 
In the event of an overdose, the parent/carer should immediately contact the Investigator or 
Study Nurse for advice. There is no antidote available for Infacort®. 
11 
Subject Withdrawal and Replacement 
11.1 Early Withdrawal from the Study 
 
Individual subjects may be withdrawn from the study for any reasons and without prejudice to 
further treatment including: 
 
 Withdrawal of consent (by the parent/carer) 
 New medical conditions that may compromise the safety of the subject, for example 
any condition that impairs the subject’s ability to swallow, which may preclude oral 
medication. 
 Decision of the Investigator if he/she considers the subject’s health may be 
compromised by remaining in the study. The investigator may consider this if there are 
more than 3 episodes of sick day rules without reasonable explanation (eg infection, 
fever, trauma etc), or two or more episodes of Addisonian Crisis without reasonable 
explanation (eg infection, fever, trauma etc). 
11.2 Premature Termination of the Clinical Study 
 
The study may be terminated at any time in the event of: 
 
 Emerging data from the study suggests an unfavourable risk-benefit analysis. 
 New scientific evidence provided during the study that could affect the subject’s safety 
(benefit-risk analysis no longer positive). 
 Request of the Sponsor, the IDMC or regulatory agency. 
11.3 Replacement of Withdrawn Subjects 
 
Any subject who is withdrawn from the study will not be replaced. 
11.4 Intercurrent Illness or Need for Temporary Increase in Dose 
 
Details of the management of the subject during illness or when a temporary increase in dose 
is needed are provided in Appendix 3.  
12 
Adverse Events and Toxicity Management 
 
The occurrence of AEs events should be sought by indirect questioning of the parents/carers 
and child (if possible) at each visit. AEs may also be detected when they are volunteered by the 
parent/carer or child during or between visits or through diary cards, physical examination, vital 
signs or other assessments. During the study, the parents/carers will be instructed to observe 
their child carefully for any unusual/abnormal signs and symptoms which may constitute an 


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AE. Details must be recorded in the diary card by the parent/carer and will be discussed with 
the Investigator during each visit.  
12.1   Adverse Event Definition 
 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product, which does not necessarily have a causal relationship with the treatment. 
An AE could be any diseases, signs or symptoms (including an abnormal laboratory finding) 
which occurs or worsens after starting the study drug even if the event is not considered to be 
related to study drug. This includes any newly occurring event or previous conditions that have 
increased in severity or frequency since the administration of the study drug. Abnormal 
laboratory values or test results constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
12.2  Adverse Event Collection  
 
AEs will be recorded from the time of first intake of Infacort® until the final visit of the study. 
Clinical events which started before the first intake of Infacort® or that are ongoing AEs from 
study Infacort 003, will be recorded as medical history or concurrent disease. SAEs will be 
recorded from the time of first intake of Infacort® in this study until 7 days following the last 
administration of Infacort®. Any SAEs experienced after this 7-day period will only be reported 
to the Sponsor if the Investigator suspects a causal relationship to Infacort®. If any SAEs are 
ongoing from study Infacort 003, the subject should not start treatment in this extension study 
until the SAE has resolved or stabilised. 
 
Details of any AEs will be collected, including details of date of onset, end date, frequency, 
severity, seriousness, relationship to Infacort®, action taken and outcome. Any AE 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 Investigator, subjects will be followed up with appropriate medical 
management until values are considered to be clinically acceptable and no further changes can 
be expected. Referral or collaborative care will be organised if required.  
12.3 Reporting of Adverse Events 
 
All individual AEs should be evaluated by the Investigator and recorded in the CRF.  
12.3.1 Diagnoses vs. Signs/Symptoms 
 
Each AE should be recorded to represent a single diagnosis. Accompanying signs 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. 
12.3.2 Pre-Existing Conditions 
 
Pre-existing conditions that are present before the intake of Infacort® in this study (including 
any ongoing AEs from study Infacort 003) are considered concurrent medical conditions and 
should NOT be recorded as AEs. These findings should be recorded on the current medical 
status CRF page. 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 


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should ensure that the AE term recorded captures the change in the condition (e.g., “worsening 
of….”). 
12.3.3 Pre-Planned Surgeries or Procedures 
 
Pre-planned procedures (surgeries or therapies) that were scheduled prior to the start of the 
study 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. 
12.3.4 Elective Surgeries or Procedures 
 
Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
12.3.5 Overdose 
 
Cases of drug overdose without manifested events are NOT considered AEs, however, such 
events should be noted in the CRF. 
12.3.6 AEs of Special Interest 
 
AEs, whether or not they are considered serious, leading to the application of sick day rules 
and use of sick day medication and which lead to any medical intervention either sought or 
required, such as at a hospital/clinic, are considered to be AEs of special interest and should be 
recorded as such, In addition, any occurrence of adrenal crisis must be recorded as an AE of 
special interest. Similar information to that collected for SAEs will be collected for such events 
(however, the event only needs to be reported as an SAE if it meets the criteria detailed in 
Section 12.7).  
12.4 Assessment of Adverse Event Severity 
 
The following guidelines for rating severity of AEs will 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.  
 
Moderate: 
Discomfort enough to cause interference with usual activities; the study medication may have 
been interrupted.  
 
Severe: 
Incapacitating with inability to 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 


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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: 
 
 Unrelated 
 Related 
 
All AEs judged by the Investigator as being related to an IMP qualify as adverse drug reactions 
(ADRs).  
 
Appendix 4 provides a comprehensive list of events that are anticipated to occur in the targeted 
study entry population of subjects with AI when disease treatment is not optimum.  
 
During the course of the trial, if aggregate analyses indicate that the events are occurring more 
frequently than anticipated, the Sponsor will notify the IDMC and/or 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. 
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: 
 
 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 patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 


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Similar information to that collected for SAEs will be collected if the application of sick day 
rules and the occurrence of adrenal crisis is seen. However, the event only needs to be reported 
as an SAE if they meet the criteria detailed above).  
12.8 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 specific SAE Case Report Form.  
 
In general, if events as listed in Appendix 4 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 Infacort®.  
 
Any SAE that occurs between administration of the last dose of Infacort® until 7 days after the 
dose of Infacort® 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. Contact 
details are provided in Appendix 5. 
 
All SAEs should be monitored until they are resolved or stabilised. Any SAEs experienced 
after this 7-day period should only be reported to the Sponsor if the Investigator suspects a 
causal relationship to Infacort®. 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 IEC with any additional requested information. 
 
The report must be made by telephone, facsimile, or email to the Sponsor/designee. An initial 
report by telephone must be followed up within 24 hours by a faxed or emailed SAE form. 
 
The SAE form requires the following information (at a minimum): 
 
 Subject ID (case number, gender) 
 Trial number 
 Study therapy  
 Concomitant medication (including dose, route, form, regime, start date, if 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). 
 
The Investigator or Sub-investigators are required to sign the form and fax or email it to the 
Sponsor/designee within 24 hours of awareness of the event, even if the required information 
is incomplete or if the Investigator is waiting for laboratory or diagnostic reports. The original 
copy of the SAE Report Form and the fax confirmation sheet or sent email (printed out) must 
be kept with the CRF documentation at the study site. 
 


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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 authorities and IECs all safety updates and 
periodic reports, as required by applicable regulatory requirements. 
12.9 Serious Adverse Event Expedited Reporting 
 
The Sponsor or designee should expedite the reporting to the appropriate regulatory authorities 
and IECs of all ADRs that are both suspected unexpected serious adverse reactions (SUSARs). 
Such expedited reports should comply with the applicable regulatory and IEC requirements. 
12.9.1 Standards for Expedited Reporting 
 
For each SAE, the Investigator and Sponsor (or designee) will independently assess whether 
there is a reasonable possibility that the event may have been caused by the IMP (“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 
German Regulatory Authority (BfArM). SUSARs are required to be reported to BfArM and 
Eudravigilance 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.  
 
SAEs will be reported by the Investigator or designee to the IEC within 7 days for 
life-threatening events and within 15 days for other events.  
12.9.2 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 an SAE that could be associated with the trial 
procedures and which could modify the conduct of the trial 
12.10 Sponsor’s Responsibilities  
 
The Sponsor is responsible for the ongoing safety evaluation of the IMP by the IDMC and a 
medically qualified person. The Sponsor is also responsible for ensuring that expedited reports 
are made to the regulatory authorities 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. The 
Sponsor should submit to the regulatory authority all safety updates and periodic reports, as 
required by applicable regulatory requirements.  
 
The Sponsor is responsible for arranging structures and written standard operating procedures 
(SOPs) to ensure that the necessary quality standards are observed in every step of the case 
documentation, data collection, validation, evaluation, archiving and reporting. 
 
A case number will be assigned by the pharmacovigilance provider for use in all future 
correspondence regarding the event and the case number will be forwarded to Diurnal Ltd 
within 1 working day.  
12.11 Independent Data Monitoring Committee 
 
In this study an IDMC has been established to monitor subject’s safety. The responsibilities of 
the IDMC include the following: 
 
 Review the study protocol, Investigator’s Brochure and plans for data safety and 
monitoring 
 Review the safety data on an ongoing basis for any emerging safety issues 
 Review the annual analysis of safety and biochemical disease control for any issues 
 Consider any other relevant information that may have an impact on the safety of the 
subjects of the study 
 Protect the safety of the study subjects 
 Make recommendations to the Sponsor concerning continuation, termination, or other 
modifications to the study based on the observations of the safety in the study. 
 
The details of composition, responsibilities, data to be reviewed and frequency for reviews are 
laid down in the charter for this IDMC, which will be provided as a separate document. 
 
SAEs will be forwarded immediately to the IDMC for review. All other AE data will be 
reported on a regular basis.  
12.12 Procedures for Reporting Pregnancy Exposure and Birth Events 
 
Not relevant in this study. 
13 Statistical Considerations 
 
Analysis of the data will be under the direction of Diurnal Ltd personnel. Full details of 
procedures for the statistical analysis will be documented in the Statistical Analysis Plan (SAP). 
 
Interim data analyses are expected to be required for regulatory review as part of any marketing 
authorisation applications. 
 
After the completion of the study and when all data have been checked for plausibility, 
corrected to the extent possible and all coding and assessments have been completed, the 
database will be locked. 


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13.1 General considerations 
 
Only descriptive statistical methods will be used for the statistical evaluation of this study (this 
includes CIs). All recorded and derived variables will be presented using standard procedures 
depending on the underlying distribution: for continuous data, sample size, mean, standard 
deviation (SD), minimum, median and maximum; for categorical data, sample size, absolute 
and relative frequency. The behaviour over time of continuous and categorical data will be 
analysed by presenting summary statistics for the actual values and change from baseline at 
each visit, if appropriate. No missing data will be replaced for any secondary variable. 
13.2 Biochemical Disease Control and Safety Variables 
13.2.1 Primary Variable 
 
SAEs and AEs observed throughout the study. 
13.2.2 Secondary Variables 
 
SDS for height and weight, cortisol (all subjects) and adrenal androgen levels (17-OHP, A4, 
testosterone) in CAH subjects only. 
13.3 Methods of Analysis 
13.3.1 Analysis Populations 
 
Protocol Violations/Deviations 
 
Any protocol violations/deviations will be reviewed and classified as either ‘minor’ (unlikely 
to appreciably affect the trial outcomes) or ‘major’ (likely to affect outcomes).  
 
Safety Population 
 
The Safety Population will include all subjects who receive one complete or a partial dose of 
Infacort®. All analyses will be conducted on the Safety Population. 
13.3.2 Statistical Evaluation 
13.3.2.1 
Adverse events 
The analysis of AE data will be described in detail in the SAP. All information obtained on 
AEs will be displayed in listings and subject, including demographic information. The number 
and percentage of subjects with AEs will be tabulated by System Organ Class (SOC) and 
Preferred Term (PT). A subject with multiple AEs within a SOC or PT is only counted once 
towards the total of this SOC or PT.  
 
Further AEs tables, for example by severity, relationship or outcome, will be presented if the 
number of events make such table useful information.  
 
Analyses and detailed listings of AEs with particular relevance for the formulation (such as 
choking, vomiting related to dosing etc.) and to AI (sick days, adrenal crisis etc.) will be 
presented separately. 


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13.3.2.2 
Growth Velocity 
SDS for height and weight will be calculated for each subject using an age- and gender-matched 
German healthy reference cohort. Details will be described in the SAP. 
13.3.2.3 
Adrenal Cortisol and Androgen Levels 
Blood concentrations data taken from dried blood spot samples (cortisol and androgen levels) 
will be listed and presented in summary statistics (sample size, arithmetic mean, geometric 
mean, SD, coefficient of variation (CV), minimum, median and maximum) for each cohort and 
overall. Time-concentration curves will be presented for individual subjects and also for each 
cohort and the subject group as a whole. These data may be merged with that collected in the 
Infacort 003 study for population PK analyses. 
13.3.3 Analysis of the Conduct of the Study 
 
Data concerning the conduct of the study (e.g. inclusion/exclusion criteria, subject 
disposition/withdrawals, and protocol violations) will be listed by subject for the safety 
population. Details will be described in the SAP. 
13.3.4 Demographic and Other Baseline Characteristics 
 
Demographic and other baseline characteristics will be listed and summarised for the safety 
population. BMI and BSA will be derived from the recorded height and weight. Medical history 
and current medical status and previous and concomitant medication/treatment will be listed 
by subject, including an index if the onset was before or after Infacort® intake. Frequency tables 
(n and %) for the coded events will only be provided if the number of events make such a table 
useful information.  
 
Drug administration data will be listed by cohort and subject.  
13.3.5 Tanner Development Stage 
A frequency table for the stages at each visit and shift tables from the initial visit will be 
presented.  
13.3.6 Sick Days 
The number of days will be presented by visit using frequency tables and, if useful, the number 
of subjects with no sick days, up to 7 sick days, and greater than 7 days will also be presented. 
Complete details will be provided in the SAP. 
13.3.7 Safety Analysis 
All vital signs data will be listed by subject, and visit/time and if ranges are available 
abnormalities (and clinically significant changes) will be flagged. Summary statistics will be 
provided overall and by visit/time. All reasons for discontinuation will be listed by subject. All 
physical examination data will be listed by subject. Shift tables comparing screening/baseline 
ratings with the ratings at end of study will be presented for each category. 
Electrolytes, renin, haematocrit, and any additional cortisol data values will be listed and 
presented in summary statistics (sample size, arithmetic mean, geometric mean, SD, CV, 
minimum, median and maximum) for each cohort and overall. Time-concentration curves will 
be presented for individual subjects and also for each cohort and the subject group as a whole. 


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These data may be merged with that collected in the Infacort 003 study for population PK 
analyses. 
13.3.8 End of Study Information 
All end of study data will be listed and a frequency table about completion and reason for 
termination will be provided, if useful.  
13.3.9 Miscellaneous 
All statistical analysis will be performed using the software package SAS version 9.1 or higher 
(SAS Institute Inc., Cary, NC 27513, USA). Missing data will be treated as missing and no 
attempts will be made to impute values for missing data. Any statistical analyses not described 
in the protocol or the SAP will be documented in the study report. 
 
The versions of the following international dictionaries current at the time of study conduct will 
be used for medical coding: 
 
 Diagnoses: 
Medical Dictionary for Regulatory Activities (MedDRA) 
 Medications: 
World Health Organisation (WHO) Drug Dictionary including  
 
 
ATC classification 
 Adverse events: MedDRA 
13.4 Power and Sample Size Considerations 
 
No formal sample size calculation is provided for this study since only subjects who have 
previously been treated in study Infacort 003 can enter this study. Hence the maximum number 
of subjects in this study is 24. 
13.5 Ongoing Reviews and Annual Reports 
 
All emerging safety data will be assessed for any signal of safety problems on an ongoing basis. 
An analysis of safety and biochemical disease control (overseen by the IDMC) will be 
undertaken on a yearly basis (this may be abbreviated in the early years when there is 
insufficient data to undertake a full analysis). Details of the data to be provided at the IDMC 
review meetings will be provided in the SAP. 
14 Responsibilities 
14.1 Investigator Responsibilities 
 
By signing the protocol, the Investigators agree to: 
 
1. 
Conduct the study in accordance with the protocol and make changes only after 
agreement from the Sponsor, except in cases to protect the safety, rights or welfare of 
subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Inform any subjects enrolled in the study that the drug is being used for investigational 
purposes.  
4. 
Ensure that the requirements relating to obtaining informed consent and IEC review and 
approval are met. 


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5. 
Report to the Sponsor any AEs/SAEs that occur during the course of the study, in 
accordance with International Conference on Harmonisation (ICH) guidelines. 
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 and to make those records available for 
inspection with the Sponsor, their designated representative, or any agency authorised 
by law. 
9. 
Ensure that an IEC will be responsible for initial and continuing review and approval 
of the clinical study. 
10. 
Report promptly to the IEC and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments 
and 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. 
 
Protocol adherence 
 
Investigators confirm they will apply due diligence to avoid protocol deviations. If the 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Diurnal 
and approved by the IEC it cannot be implemented. All significant protocol deviations will be 
recorded and reported in the clinical study report (CSR). 
 
Protocol Amendments 
 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Diurnal, Health Authorities where required, and the IEC. Only 
amendments that are required for subject safety may be implemented prior to IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Diurnal should 
be notified of this action and the IEC at the study site should be informed within 10 working 
days. 
14.2 Ethical Conduct of the Study 
 
The study will be conducted according to ICH Good Clinical Practice (GCP), the Declaration 
of Helsinki (1996), and IEC and BfArM requirements. 
 


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14.3 Independent Ethics Committee Approval 
 
The study protocol, subject information and consent form will be presented to the relevant 
IECs. The study will only start at a study site after ethics approval has been granted. The IECs 
will immediately be informed (by the Sponsor) of all changes to the protocol (according to 
GCP-V § 10) and of all events that could affect a subject’s safety. The IECs will also be 
informed of all suspected SUSARs and of regular or premature termination of the study.  
 
The Investigators have to register with the IECs (together with proof of qualification) before 
they enrol any subjects.  
14.4 Informed Consent 
 
The principles of informed consent in the Declaration of Helsinki (1996), in the current 
requirements of GCP published by ICH and local regulation, whichever affords the greater 
subject protection, will be implemented before any protocol-specified procedures or 
interventions are carried out.  
 
Before enrolment every subject (parent/carer) will receive full oral and written information 
about the nature, purpose, expected advantages and possible risks of the trial. The parent/carer 
will agree to participation in the trial by signing the informed consent form. They will be given 
an opportunity to enquire about details of the study. After a sufficient period of time (at least 
24 hours) for the individual’s consideration and decision, comprehension and consent shall be 
documented on the consent form by the dated signature of the subject’s parent/carer and the 
Investigator/treating doctor. 
 
Design of the forms and language will be adjusted to the study site’s needs. The final versions 
of subject information and consent will be presented to the IECs. Both the subject information 
and the subject consent form are prepared in duplicate. One of each form will be retained by 
the Investigator, a duplicate will be given to the subject. 
 
All information sheets and consent forms will be provided in German. 
14.5 Case Report Forms  
 
CRFs will be provided for each subject. Subjects will not be identified by name or initials on 
any study documents (or copies) retrieved from the site (for subject confidentiality). The subject 
identification number entered upon study entry shall identify each subject.  
 
All data on the CRF must be legibly recorded in black or blue ink. Corrections are to be made 
by striking through the incorrect information and writing the revision alongside. All corrections 
must be initialled and dated. All relevant information recorded in the diary cards must be 
transcribed into the CRF by the Investigator or designee. The Investigator must review the 
CRFs for completeness and accuracy and must sign and date the appropriate CRF pages as 
indicated. The Investigator will retain full responsibility for the accuracy and authenticity of all 
data entered on the CRFs. CRFs will be reviewed at the study site during regularly scheduled 
visits by study monitors.  
 
A copy of the CRF with all related corrections and queries should be kept at the study site; the 
original copy (and any other copies) will be collected by the local monitor. 


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All data collected in the CRF will be double entered into a validated computerised clinical data 
management system.  
14.6 Site Monitoring 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Diurnal 
representative will review the protocol and CRFs with the Investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to GCP, the 
progress of enrolment, and to ensure that the IMP is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. 
 
The Investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the subject's file. The Investigator 
must also keep the original informed consent form signed by the subject (a signed copy is given 
to the subject). Note: see Appendix 6 for handling of documents at remote sites. 
 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
AEs and SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed. 
14.7 Source Data Verification 
 
The information in original documents and records (e. g. patient files, laboratory notes, diary 
cards etc.) are defined as source data and will be reviewed by the monitor for source data 
verification (SDV). All data that will be recorded directly in the CRF without prior written or 
electronic record will be described in the protocol and considered to be source data. SDV 
ensures accuracy and credibility of the data obtained. During monitoring visits reported data 
are reviewed with regard to being accurate, complete and verifiable from source documents 
(e.g. subject files, recordings from automated instruments, laboratory notes).  
14.8 Subject Confidentiality/Data Protection 
 
All data forwarded to the Sponsor or designees will be identified only by a subject number. The 
Investigator agrees that representatives of the Sponsor, its designee, representatives of the 
relevant IECs, or representatives of regulatory authorities will be allowed to review that portion 
of the subject’s primary medical records that directly concerns this trial (including, but not 
limited to, laboratory test result reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s trial participation and autopsy reports for deaths 
occurring during the trial). 
 
The subjects’ data will be saved in a pseudonymous form. All regulative requirements applying 
to data protection will be met. Re-identification of a subject’s name will be possible from the 


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subject identification log, which is kept in a locked research office at the trial site where access 
is only possible by the Principal Investigator or persons authorised by the Principal Investigator.  
 
Subjects (parent/carer) will be informed that their disease-related data will be saved for 
scientific purpose (publication, etc.) using a pseudonym. Consenting subjects (parent/carer) 
have got the right to be informed about the data recorded. Subjects (parent/carer) will also be 
informed that their pseudonymised data will be forwarded to BfArM and to the IECs 
responsible, in accordance with legal notification obligation for drug safety. Subjects 
(parent/carer) who disagree with this process of data transfer will not be allowed to participate 
in this study. 
14.9 Data Management 
 
All data collected in the CRF will be transferred via double-data-entry method to a validated 
computerised clinical data management system. The final data management process contains 
the plausibility, consistency and range checks of the entered data. In case of faulty or missing 
data the data manager will generate data management queries and send them to the site. 
Implausible or missing data will be corrected or added after consulting the Investigator. 
Documentation for these corrections will be stored with the CRFs. The data correction in the 
database will be performed with scripts in SAS or directly in the study database.  
 
After all data management steps are finished, the database will be locked and will be available 
for the statistical analysis. 
14.10 Drug Accountability 
 
The monitor will perform drug accountability checks. 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 Sponsor. 
 
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 CRF. 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 by the Charité 
Pharmacy following appropriate drug accountability procedures and authorisation from the 
Sponsor.  


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14.11 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. 
14.12 Sponsor Responsibilities 
14.12.1 
Indemnity and Compensation 
 
For participating subjects, an insurance (
) is in force. The 
insurance is provided by 
, and will cover 
incidents for the study duration (from 1st Feb 2015 for 30 months but will be extended if 
necessary). The insurance is limited to a maximum of 500,000 Euros per subject. 
 
Terms for the provision of indemnity and for the provision and maintenance of insurance will 
be documented in contracts between Diurnal Ltd and the relevant parties. 
14.12.2 
Subject Confidentiality 
 
The Sponsor’s staff or any designees affirm and uphold the subject’s privacy/confidentiality. 
Throughout this trial, all data forwarded to the Sponsor or designees will be identified only by 
a subject number. 
14.13 Publication Policy 
 
The study results will be published irrespective of the study outcome. No confidential subject 
information will be published. 
 
The Sponsor's comments on the proposed publication shall be considered in good faith by the 
authors. Publication of the results will not include confidential information without the 
permission of the Sponsor. 
 
The Sponsor may announce quality assured summary data in order to comply with Financial 
Regulatory Authorities, whilst ensuring that release of such data will not compromise the 
Investigator’s ability to publish the data in appropriate scientific forums. No announcements 
will be made prior to the publication of the Principal Investigator’s manuscript, unless reviewed 
and authorised by the Principal Investigator. 
14.14 Clinical Study Report 
 
The results of the study will be presented in an integrated CSR according to GCP and ICH-E3 
guidance.  


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14.15 Data Retention and Availability 
 
The Investigator is required to maintain all study documentation, including regulatory 
documents, copies of CRFs, signed informed consent forms, and records for the receipt and 
disposition of study medications, for a period of 2 years following approval date of the last 
Marketing Authorisation Application for the drug, or until 15 years after completion of the 
study, whichever is later. 
 
During and after the study, the Investigator must make study data accessible to the Sponsor, 
IECs and appropriate regulatory authorities. A file for each subject must be maintained that 
includes the signed informed consent form 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 CRF was derived. 
14.16 Study Termination 
 
The study may be terminated at any time at the request of the Sponsor, the Investigator, the 
IECs or Regulatory Authorities 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 
 
Dauber A, Kellogg M, Majzoub JA. Monitoring of therapy in congenital adrenal hyperplasia.  
Clin Chem. 2010; 56(8): 1245-51.  
 
Kauzor D, Spielmann S, Brosig H, Ross RJ, Blankenstein O, Kloft C. Medication safety study 
investigating hydrocortisone individually and extemporaneously compounded capsules for 
paediatric use in CAH. Published poster presentation at: ECE, 3 – 7 May 2014, Wroclaw, 
Poland. 
 
Neumann U, Burau D, Spielmann S, Whitaker MJ, Ross RJ, Kloft C, Blanenstein O. Quality 
of compounded hydrocortisone capsules used in the treatment of children. Eur J Endocrinol, 
2017;177(2):239-242. 
 
The Handbook of Pharmaceutical Excipients Editors: Rowe RC, Sheskey PJ and Owen SC – 
7th Edition Pharmaceutical Press and American Pharmacists Association. (2012).  
16. 
Bibliography 
 
Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, 
Ross RJ. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in 
patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2004; 61(3): 367-75. 
 


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Martinez JM,  Bartoli F, Recaldini E, Lavanchy L, Bianchetti MG. A taste comparison of two 
different liquid cholecalciferol (vitamin D3) preparations in healthy newborns and infants. Clin 
Drug Investig; 26 (2006): 663-5. 
 
Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs. 1988; 
14(1): 9-17. 
 
 
 


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Appendix 1 – Blood Spot Analysis 
 
Where possible the blood spot sample should be taken in the morning. Blood spots will be 
collected from either venous or capillary samples using the following procedure: 
 
 All samples will be collected in aseptic conditions (i.e. the area to be sampled will be 
wiped with an antiseptic wipe). 
 Whatman® Protein Saver 903® paper will be used to collect all the samples. 
 If using capillary sampling,the lateral finger pad will be pricked with a sterile lance. 
 The first drop will be used to soak the 5 circles on the blood spot card, with the blood 
being put against one side of each circle and allowed to soak across. Each blood spot is 
approximately 75-80 µL, giving a total blood volume of 375 µL per card. 
 The blood spots will be dried for 2-4 hours at room temperature (kept away from direct 
sun and heat). 
 The dried blood spots will be sent to the laboratory at Charité-Universitätsmedizin 
Berlin on the same day as the samples are taken.  
 The dried blood spots must be transported and stored at room temperature. 
 The dried blood spots will be stored for up to 15 years. 
         
The following analytes will be analysed from the blood spots: 
 
17a-hydroxyprogesterone 
Deoxycorticosterone 
Androstenedione  
Testosterone  
Dihydrotestosterone 
Cortisol  
11-Deoxycortisol 
21-Deoxycortisol 
Corticosterone 
17-Hydroxypregenolone 
Pregnenolone 
Dihydro-Epi-Androstendion 
Progesterone 
Aldosterone 
Cortisone 
 
 
 


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Appendix 2 – Tanner Development Stages 
 
Pubic hair 
PH1 
No pubic hair 
PH2 
Sparse, pigmented hair mainly on labia, at base of penis 
PH3 
Coarser and darker hair spread over mons pubis 
PH4 
Adult type hair but not spreading to medial surface of the thighs 
PH5 
Adult type hair and distribution 
PH6 
Adult type hair and distribution, spreading along linea alba 
 
 
Breast 
B1 
Papilla elevation 
B2 
Palpable breast buds; areola enlargement 
B3 
Areola and breast enlargement; no projection of the areolae  
B4 
Projection of areola and papilla to form secondary mound 
B5 
Mature with projection of papilla only 
 
 
Genitalia 
G1 
Penis size prepubertal, testes <4mL volume, long axis <2.5 cm 
G2 
Early penile and scrotum growth, testes 4-8 mL volume, length 2.5 to 3.3 cm 
G3 
Increase in penile length and width, testes 10-15 mL volume, length 3.4 to 4.0 cm 
G4 
Increase in penile length and width, scrotum pigmenting, testes 15-20 mL 
volume, length 4.1 to 4.5 cm 
G5 
Adult size and shape penis, testes >20 mL volume, length >4.5 cm 
 
 


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Appendix 3 – Sick Day Rules  
 
Each site should follow their own sick day rules, or if these are not available then the following 
rules should be used: 
 
Emergency situation measures to be taken by the parent/carer  
 
Intercurrent illness with: 
 
Fever 
>38°C - double oral hydrocortisone dose as long as body temperature continues to be elevated  
>39°C - triple oral hydrocortisone dose as long as body temperature continues to be elevated 
>40°C - increase oral hydrocortisone dose 5-fold as long as body temperature continues to be 
elevated 
 
Vomiting, diarrhoea   
Triple the oral hydrocortisone dose (starting immediately). In case of repeated vomiting, 
administer prednisone (100 mg) as a suppository. Patient should be seen by a physician without 
delay. If the clinical condition worsens rapidly, call an ambulance (112) or take the child to the 
local emergency room.  
 
Emergency measures by trained medical personnel  
 
Shock, severe trauma, coma, emergency surgery: 
 
give i.v. bolus of hydrocortisone:  
o 25 mg at age < 6 months  
o 50 mg at age 6 months to 6 years  
o 100 mg at age > 6 years 
 
Alternatively, any other glucocorticoid available can be given at an equivalent dose, e. g. 
methylprednisolone at 5 mg, 10 mg, and 20 mg, respectively.  
 
This should be followed by a continuous infusion of hydrocortisone 150 mg/m²/24 hours until 
the subjects condition has stabilised.  
 
Initial basic solution for parenteral fluid therapy (all age groups including infants and young 
children): mix 450 mL 0.9% NaCL + 50 mL 40% (or 50%) glucose (adjust total volume and 
infusion rate to the results of continuous monitoring of fluid and electrolyte balance). In 
general, at parentally administered high hydrocortisone doses there is no need for additional 
mineralocorticoids. 
 
 


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Appendix 4 – Anticipated Events in the Target Population 
 
A list of anticipated events in this group of subjects is detailed below: 
 
chronic fatigue 
anorexia 
asthenia 
nausea  
vomiting 
loss of appetite 
weight loss 
recurring abdominal pain  
weakness and a lack of energy 
increased skin pigmentation   
salt craving  
hypoglycaemia 
hypotension 
orthostatic changes in blood pressure and heart rate (pulse)  
altered mental status 
 
 


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Appendix 5 – Contact Details for Serious Adverse Events 
 
All SAEs should be reported to 
: 
 
 
 
 
 
 
 
 


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Appendix 6 – Remote Site Guidelines 
Background 
Subjects participating in Infacort 004 were previously enrolled in Infacort 003. In the third 
cohort of Infacort 003 in which neonates (<28 days) were recruited, some subjects were 
identified in centres outside the Charité Universitätsmedizin Berlin. Two of these subjects 
were enrolled into Infacort 004 and visited the Charité Universitätsmedizin Berlin for the 
purpose of study visits. However, due to the travelling time and consequent associated 
practicalities, one of these subjects, although still having their care transferred to Charité 
Universitätsmedizin Berlin for the remainder of the study, will have their visits conducted by 
the Charité staff at the subject’s local hospital. Thus for the purposes of the study procedures, 
this subject (and any further subjects enrolled into the study on this basis) will be considered 
to be under the care of Charité Universitätsmedizin Berlin. 
 
Establishment of remote sites 
The Charité Investigator will contact the local physician and provide study information, to 
include required supply of study-specific medical supplies and equipment availability. 
The Charité Investigator will provide a treatment agreement for execution, to include 
agreement on the use of the local site’s treatment rooms, study-specific medical supplies and 
equipment, and laboratory facilities. 
 
The local physician will send a request for consultation treatment to the Charité Investigator. 
 
Subject recruitment 
The local physician will remind the parents/carers about the opportunity for their child to 
enrol into the study following completion of participation in study Infacort 003. Where 
parents/carers confirm their interest in participation of their child in the study they will give 
consent for issue of their contact details to the Charité Investigator by their local physician. 
The Charité Investigator will contact the parents/carers informing them about the study and 
confirming continuing interest in participation of their child. The Charité Investigator will 
provide the parents/carers with the Information Sheet and Consent Form to provide adequate 
time for them to consider participation of their child. The Charité Investigator will provide the 
parents/carers with the practical details of their participation in the study at the remote site 
such as the dates for study participation. The Charité Investigator will confirm each of their 
visits to the remote site with the local physician. 
 
IMP 
The Charité Investigator will issue a prescription for Infacort® to the Charité Pharmacy either 
calculated from that dispensed at the previous visit, or from information provided by the local 
physician, and with the necessary overage to allow for both repeated dosing in the case of 
incomplete administration and any increases in dose in the event of the necessity for 
implementation of sick day rules. The Charité Pharmacy will dispense the prescription for 
collection and transport either by courier to the Charité Investigator at the remote site or by 
the Charité Investigator him-/herself. Temperature monitoring during transport to the remote 
site in either event, included with the IMP shipment, will be downloaded by either the courier 
or the Charité Investigator and provided to the Sponsor to confirm that the transportation 
conditions were acceptable prior to administration and supply of the IMP to the subject. 
All unused  medication and empty (used) Infacort® capsules that are returned by the subject’s 
parents/carers at each visit will be sent by the Charité Investigator to the Charité Pharmacy in 
Berlin for the purpose of IMP accountability verification. 


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Completion of study procedures at the remote site 
The Charité Investigator will arrive at the local site in advance of the subject’s arrival. The 
local physician will arrange for a formal handover of their patient to the care of the Charité 
Investigator for the duration of each study visit. The Charité Investigator will perform the 
visit study procedures, including blood sampling, in accordance with the study protocol. The 
additional blood samples for routine clinical care can be taken simultaneously by the local 
physician.  
 
The Charité Investigator will train the parents/carers in how to administer the study 
medication at the initial visit since parents/carers will be administering the Infacort® to the 
subjects at home. Parents/carers will also be given an instruction sheet to take home with 
them for reference by the Charité Investigator, which will include written instructions on the 
dose to be taken. They will also be instructed in how to complete the diary card, and they will 
be asked to bring this along to all visits. 
 
At Visit 1, the Charité Investigator will attend with an emergency case which will include the 
standard contents as required by the Charité Universitätsmedizin Berlin.  
 
After each study visit the Charité Investigator will arrange for a formal handover of the 
subject to the care of the local physician. 
 
Study sampling 
All study samples will be taken in accordance with the study protocol. The collected blood 
spots will be transferred under ambient conditions to Charité Universitätsmedizin Berlin by 
the Investigator for analysis of steroid metabolites.  
 
Electrolytes, renin, haematocrit, and any additional cortisol data will also be collected where 
collected routinely by the local laboratory as part of the routine clinical care (normally once a 
year). The results of all these analyses will be included in the database. 
 
Study Data Management 
All study-specific documentation will remain with the Charité Investigator and be transferred 
to Charité Universitätsmedizin Berlin. Redacted results reports following analysis of 
electrolytes, renin, haematocrit, and any additional cortisol data (where collected for routine 
care) will be provided to the Charité Investigator when available for inclusion in the database.  
Subject selection is to be confirmed by the Charité Investigator by checking through all 
inclusion/exclusion criteria at the initial visit. A record of this check (e.g. inclusion/exclusion 
checklist) will be stored with the source documentation at the remote site. Any change to 
medical history and current disorders, and all concomitant medications since conclusion of 
participation in Infacort 003 will be confirmed by the Charité Investigator through reference 
to the subject’s medical records and included in the CRF by the Charité Investigator. Copies 
of medical records entries will not leave the remote site. The Charité Investigator will record 
all information relevant to the subject’s participation in the study while at the remote site. 
One copy will remain in the local notes (subject’s medical records) and one will return to 
Charité Universitätsmedizin Berlin as the sole source data.  
 
The study monitor will monitor the CRFs and diary cards with associated source document 
verification at Charité Universitätsmedizin Berlin. 
 
 


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Appendix 7 – Protocol Amendment History 
 
Protocol Version 1.0 dated 23 July 2015 
Original protocol. 
 
Protocol Version 2.0 dated 15 September 2015 
The following clarifications were made to the protocol prior to any subjects being enrolled: 
 
1) The early withdrawal criteria of ‘new medical conditions that may impair the safety of the 
subject’ was expanded to provide the example of any condition that impairs the subject’s 
ability to swallow, which may preclude oral medication. 
 
2) The early withdrawal criteria of ‘decision of the Investigator if he/she considers the 
subject’s health may be compromised by remaining in the study’ was expanded to clarify 
that the investigator may consider this if there are more than 3 episodes of sick day rules 
without reasonable explanation (eg infection, fever, trauma etc), or two or more episodes 
of Addisonian Crisis without reasonable explanation (eg infection, fever, trauma etc). 
 
Protocol Version 3.0 dated 25 July 2016 
 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
 
 
2) The telephone number of 
 was added in Appendix 5 and the international 
dialing code added to the fax number. 
 
3) Interim data analyses are expected to be required for regulatory review as part of any 
marketing authorisation applications. As such a statement to this effect was added to the 
statistical methods section of the synopsis and in Section 13. 
 
4) In addition to the Infacort® granules being administered directly onto the top, and towards 
the back, of the child’s tongue, the granules can now also be mixed with yoghurt, fruit 
purees (e.g. apple sauce) or fruit mousses immediately before being administered to the 
child. The granules can also be washed down with water, breast milk, formula milk or 
whole milk following administration. This information was added to Section 10.2.1 of the 
protocol. 
 
5) In Section 8.5 (Previous and Concomitant Medication/Treatment) the protocol incorrectly 
stated that the trade names of the medications should be provided. This was changed to 
specify generic names. 
 
6) The timing of the blood spot samples was clarified to state that these should be taken in 
the morning wherever possible, since this is usually the time of poor control.  
 
7) Section 8 stated that, if agreeable, subjects from remote sites could be cared for at Charité-
Universitätsmedizin Berlin, CVK, for the purposes of the study. For clarity this statement 
was added to the synopsis as well. 
 


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8) Blood spot samples will be taken every month for the first 2 months of the study, then 
every 6 months  unless required after 3 months. The synopsis text was updated for 
clarification. 
 
9) The statistical analysis section was updated to confirm that the change from baseline at 
each visit for continuous and categorical data would only be conducted if appropriate. 
 
10)  The address for 
 at 
was updated.  
 
11)  The Infacort® capsules will now be supplied in both blister packs and bottles. Therefore 
Section 10.2.2 (Packaging and Labelling) was updated. 
 
Protocol Version 4.0 dated 20 July 2017 
 
The following changes were made to the protocol: 
 
1) The Sponsor signatory was changed from 
 
 
2) Confirmed in Section 12.3.6 that AEs, whether or not they are considered serious, 
leading to the application of sick day rules and use of sick day medication and which lead 
to any medical intervention either sought or required, such as at a hospital/clinic, are to 
be considered to be AEs of special interest, In addition, any occurrence of adrenal crisis 
must be recorded as an AE of special interest. 
 
3) In some cases, whilst the subject is cared for by Charité-Universitätsmedizin Berlin for 
the purposes of the study, it may be necessary of the Investigator at 
Charité-Universitätsmedizin Berlin to visit the subject at their local hospital. A detailed 
procedure for this scenario has been added as Appendix 6. 
 
4) In line with the proposed labelling for Infacort®, the wording around administration of 
the granules was amended to say that the granules can be sprinkled onto a spoonful of 
yoghurt, fruit purees (e.g. apple sauce) or fruit mousses rather than using the term 
'mixed'. 
 
5) The protocol currently states that subjects can continue to be treated in this study until 
they meet the study withdrawal criteria, Infacort® is granted a marketing authorisation 
(and so is available commercially), Infacort® is refused a marketing authorisation, or the 
Sponsor decides to discontinue the study. A footnote has been added stating that at the 
time of submission of this amendment (protocol version 4.0), Infacort® is the subject of 
an ongoing Marketing Authorisation Application procedure and that for clarity, the end 
of study visits for each subject will occur after Infacort® is commercially available. 
 
6) Published data are now available on the study conducted at Berlin on the lack of formal 
quality control of crushed tablets so the information has been updated in Section 5.4 
(Rationale) and the formal reference added. 
 
7) Added to Section 8.14 that if a visit needs to be postponed for more than 10 days, then 
the subject should attend for the visit before the period of absence for safety and drug 
supply reasons. Subsequent visits will then be scheduled at regular intervals from the 
revised early visit date. 


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8) Testing of hydrocortisonacetat in the blood spot analyses (Appendix 1) was removed 
since this is no longer analysed by the laboratory. 
 
9) After discussion with the Investigators, it was discovered that no mean and SD for the 
age- and gender-matched German reference population was available. So it was decided 
that the secondary endpoint of growth velocity would not be used, but instead the SDS 
for height and weight would be calculated for each subject using an age- and 
gender-matched healthy German reference cohort. This change was implemented 
throughout the protocol. 

SAP_001.pdf: