Clinical Trials Register

Summary
EudraCT Number:	2015-005448-32
Sponsor's Protocol Code Number:	DIUR-006
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-11-02
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2015-005448-32

A.3

Full title of the trial

A Phase III extension study of efficacy, safety and tolerability of Chronocort® in the treatment of congenital adrenal hyperplasia

Eine Phase III Verlängerungsstudie zur Untersuchung der Wirksamkeit, Sicherheit und Verträglichkeit von Chronocort® bei der Behandlung des adrenogenitalen Syndroms

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The proposed study aims to build on the results of clinical studies DIUR-003 and DIUR-005 and evaluate the long-term safety of Chronocort® and also its long term efficacy.

Eine Verlängerungsstudie, basierend auf den Ergebnissen der klinischen Vorgängerstudien DIUR-003 und DIUR-005, zur Untersuchung der Langzeit-Sicherheit und Langzeit-Wirksamkeit von Chronocort® bei der Behandlung des adrenogenitalen Syndroms

A.4.1

Sponsor's protocol code number

DIUR-006

A.5.4

Other Identifiers

Name:

IND No.

Number:

76485

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Diurnal Ltd
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Diurnal Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Diurnal Ltd
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Cardiff Medicentre, Heath Park
B.5.3.2	Town/ city	Cardiff
B.5.3.3	Post code	CF14 4UJ
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	info@diurnal.co.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/296
D.3 Description of the IMP
D.3.1	Product name	Chronocort® 5 mg
D.3.2	Product code	DIURF-006
D.3.4	Pharmaceutical form	Modified-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HYDROCORTISONE
D.3.9.1	CAS number	50-23-7
D.3.9.3	Other descriptive name	Cortisol
D.3.9.4	EV Substance Code	SUB08065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/296
D.3 Description of the IMP
D.3.1	Product name	Chronocort® 10 mg
D.3.2	Product code	DIURF-006
D.3.4	Pharmaceutical form	Modified-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HYDROCORTISONE
D.3.9.1	CAS number	50-23-7
D.3.9.3	Other descriptive name	Cortisol
D.3.9.4	EV Substance Code	SUB08065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/296
D.3 Description of the IMP
D.3.1	Product name	Chronocort® 20 mg
D.3.2	Product code	DIURF-006
D.3.4	Pharmaceutical form	Modified-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HYDROCORTISONE
D.3.9.1	CAS number	50-23-7
D.3.9.3	Other descriptive name	Cortisol
D.3.9.4	EV Substance Code	SUB08065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Congenital adrenal hyperplasia (CAH); is generally due to 21-hydroxylase deficiency, is a disease of the adrenal cortex characterised by cortisol deficiency with or without aldosterone deficiency, and androgen excess. Subjects with CAH are at risk of developing a number of clinical manifestations, such as obesity in children, insulin resistance, and polycystic ovaries, which may contribute to infertility in women with CAH. Oligomenorrhoea or amenorrhoea may be present in adolescence.

E.1.1.1

Medical condition in easily understood language

CAH is a group of inherited conditions that are present at birth where the body is missing a chemical substance that allows the adrenal glands to release the cortisol hormone.

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10010323
E.1.2	Term	Congenital adrenal hyperplasia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess safety and tolerability of Chronocort® over time, as assessed by signs and symptoms of adrenal insufficiency or over-treatment, use of sick day rules, adrenal crisis, adverse events (AEs), laboratory measures and clinical observation.

E.2.2

Secondary objectives of the trial

The long-term efficacy of Chronocort® will be assessed over time by the
measurement of:
1.Total daily dose in mg/day of hydrocortisone &BSA during the study
and the incidence of dose titrations
2.17-hydroxyprogesterone (17-OHP) and androstenedione (A4) measured at two time points (at 09:00 and 13:00 hours) for:
a.Disease control at each visit as assessed by both 17-OHP and A4 levels in the optimal and normal range &by the proportion of dose given at night.
b.17-OHP and A4 standard deviation scores
c.Change in absolute values compared to pre-Chronocort® baseline
values
3.Changes compared to pre-Chronocort® baseline in:
a.Bone turnover markers - serum C-terminal cross-linked telopeptide,
osteocalcin
b.Testosterone
c.Fasting insulin and blood glucose levels and glycated haemoglobin
d.High sensitivity c-reactive protein and plasma renin activity
e.Body composition (dual energy X-ray absorptiometry)
f.Quality of life – SF-36®, Multidimensional Assessment of Fatigue, EQ-
5D™

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects with congenital adrenal hyperplasia (CAH) who have successfully completed the DIUR-003 or DIUR-005 clinical trials with the current formulation of Chronocort®
2. Provision of signed written informed consent.

E.4

Principal exclusion criteria

1. Co-morbid condition requiring daily administration of a medication (or consumption of any material) that interferes with the metabolism of glucocorticoids
2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or elevated liver function tests (ALT or AST >2 times the ULN)
3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH
4. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study)
5. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study
6. Subjects with a history of bilateral adrenalectomy
7. Subjects unable to comply with the requirements of the protocol.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the safety of Chronocort® over time, assessed using but not limited to the following endpoints throughout the study:
1. Signs and symptoms of adrenal insufficiency or over-treatment
2. Use of sick day rules
3. Occurrence of adrenal crises
4. Occurrence of AEs
5. Change from pre-Chronocort® baseline in safety laboratory assessments at each visit
6. Change from pre-Chronocort® baseline in vital signs, weight, body mass index, and waist circumference at each visit.

E.5.1.1

Timepoint(s) of evaluation of this end point

Each visit throughout the study

E.5.2

Secondary end point(s)

The following secondary endpoints will be assessed (seeking to assess long term efficacy):
1. Total daily dose of Chronocort® in mg/day of hydrocortisone and by
BSA
2. Disease control throughout the study as assessed by both 17-OHP and A4 levels in the optimal and normal range, respectively and by the proportion of dose given at night
3. Change from pre-Chronocort® baseline at each visit in SDS of 17-OHP and A4 and the mean of the two timepoints
4. Change from pre-Chronocort® baseline at each visit in the absolute values of 17-OHP and A4
5. Change from pre-Chronocort® baseline at each visit in:
a. Bone turnover markers - CTX, osteocalcin
b. Testosterone (total)
c. Fasting insulin and blood glucose levels, and HbA1c
d. hsCRP and PRA
g. Body composition (DEXA)(fat mass, lean mass and total bone density)
e. Quality of life – SF-36®, MAF, EQ-5D™
6. Incidence of dose titrations.

E.5.2.1

Timepoint(s) of evaluation of this end point

At all visits:
1. Measurement of 17-OHP and A4 at two time points (the first at 09:00 and the second at 13:00 hours).

At baseline, at each 6-monthly visit and at the final visit:
1. Physical examination, vital signs, weight, BMI and waist circumference.
2. Safety blood tests, serum CTX, osteocalcin, PRA, hsCRP, HbA1c, testosterone,
fasting insulin and blood glucose levels.
3. Quality of life – SF-36®, MAF, EQ-5D™

At yearly intervals:
1. Body composition (DEXA)(fat mass, lean mass and total bone density) (also taken at baseline for subjects entering from study DIUR-003).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Germany

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The final telephone call (30 days after the last visit) of the last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

138

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-11-02.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

136

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects will continue in the study for a maximum of 5.5 years. If after this time point a decision has not been reached concerning a marketing authorisation for Chronocort®, a further extension of the study through a protocol amendment may be considered.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-07-13

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