Clinical Trials Register

Summary
EudraCT Number:	2014-000972-24
Sponsor's Protocol Code Number:	D3561C00004
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:	2014-09-26
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

2014-000972-24

A.3

Full title of the trial

A Randomized, Double blind, Placebo controlled, Multi center, Cross over Study of Rosuvastatin in Children and Adolescents (aged 6 to <18 years) with Homozygous Familial Hypercholesterolemia (HoFH)

A.3.1

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

A study to evaluate the effect of Rosuvastatin on fatty acids in Children and Adolescents with Homozygous Familial Hypercholesterolemia

A.3.2

Name or abbreviated title of the trial where available

HYDRA

A.4.1

Sponsor's protocol code number

D3561C00004

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Centre
B.5.3	Address:
B.5.3.1	Street Address	n/a
B.5.3.2	Town/ city	n/a
B.5.3.3	Post code	n/a
B.5.3.4	Country	United States
B.5.6	E-mail	information.center@astrazeneca.com

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	Yes
D.2.1.1.1	Trade name	Crestor Tablets (calcium rosuvastatin) Film-Coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Crestor
D.3.2	Product code	ZD4522
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Yes
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	calcium rosuvastatin
D.3.9.1	CAS number	147098-20-2
D.3.9.2	Current sponsor code	ZD4522
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.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	Yes
D.2.1.1.1	Trade name	Crestor Tablets (calcium rosuvastatin) Film-Coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Crestor
D.3.2	Product code	ZD4522
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Yes
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	calcium rosuvastatin
D.3.9.1	CAS number	147098-20-2
D.3.9.2	Current sponsor code	ZD4522
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypercholesterolemia - The current trial will study children with Homozygous Familial Hypercholesterolemia (HoFH)

E.1.1.1

Medical condition in easily understood language

The current trial will study the fatty acid levels in children with a genetic disorder causing them to have high blood levels of fatty acids

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10054380
E.1.2	Term	Familial hypercholesterolemia
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 the efficacy of rosuvastatin 20 mg on low density lipoprotein cholesterol (LDL C), compared to placebo, after 6 weeks of treatment in pediatric patients with Homozygous Familial Hypercholesterolemia (HoFH)

E.2.2

Secondary objectives of the trial

To assess the efficacy of rosuvastatin 20 mg on LDL C, compared to placebo, after 6 weeks of treatment in pediatric patients with HoFH not treated with apheresis
To assess the efficacy of rosuvastatin 20 mg on lipid parameters other than LDL C, compared to placebo, after 6 weeks of treatment in pediatric patients with HoFH
To assess the longitudinal profile of LDL C during treatment with rosuvastatin 20 mg
To characterize the trough plasma exposure of rosuvastatin in pediatric patients with HoFH

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Prior to any study related procedures being performed, provision of written informed consent from a parent/both parents or guardian and statement of assent from the child or adolescent (if required by Institutional Review Board [IRB] or Independent Ethics Committee [EC] according to local regulations and guidelines). Communication between the Investigator (a paediatric specialist), patient/guardian and child/adolescent to confirm understanding and required compliance with the requirements of the study;
2.Male and female children and adolescents (aged 6 to <18 years) with at least 1 of the following criteria:
Documentation of genetic testing confirming 2 mutated alleles of the LDL receptor gene locus; and/or
Documented untreated LDL C >500 mg/dL (12.9 mmol/L) (Note: If a patient is receiving apheresis treatments, this blood lipid level must be obtained prior to the apheresis) and triglyceride (TG) <300 mg/dL (3.4 mmol/L) and at least 1 of the following criteria:
oTendinous and/or cutaneous xanthoma prior to 10 years of age; or
oDocumentation of HeFH in both parents by:
 genetic and/or
 clinical criteria;
3.Negative pregnancy test (b human chorionic gonadotropin analysis) prior to baseline in females of child bearing potential:
Female patients of child bearing potential must adhere to a pregnancy prevention method (abstinence, chemical, or mechanical) during the study and 3 months following the last dose;
Male patients should refrain from fathering a child (including sperm donation) during the study and up to 3 months following the last dose; and
4.Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

E.4

Principal exclusion criteria

1.History of statin inducted myopathy or serious hypersensitivity reaction to other HMG CoA reductase inhibitors (statins), including rosuvastatin, at Visit 1;
2.Fasting serum glucose of >9.99 mmol/L (180 mg/dL) or glycosylated hemoglobin >9% at Visit 1 or patients with a history of diabetic ketoacidosis within the past year;
3.Uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH) >1.5 times the upper limit of normal (ULN) at Visit 1 or patients whose thyroid replacement therapy was initiated or modified within the last 3 months prior to Visit 2;
4.Current active liver disease or hepatic dysfunction (except a confirmed diagnosis of Gilbert’s disease) as defined as elevations of 1.5 times the ULN for any age in any of the following liver function tests at Visit 1: ALT, AST, or bilirubin;
5.Definite or suspected personal history or family history of clinically significant adverse drug reactions (ADRs), or hypersensitivity to drugs with a similar chemical structure to rosuvastatin as well as other statins;

E.5 End points

E.5.1

Primary end point(s)

"Describe efficacy in terms of low density lipoprotein cholesterol (LDL C) following 6 weeks rosuvastatin 20 mg or placebo treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

Samples taken Day 42 (week 6), Day 84 (week 12)

E.5.2

Secondary end point(s)

1 Describe efficacy in terms of low density lipoprotein cholesterol (LDL C) following 6 weeks rosuvastatin 20 mg or placebo treatment in patients not treated with Apheresis
2 Describe efficacy in terms of High density lipoprotein cholesterol (HDL C), total cholesterol (TC), triglyceride (TG), non-HDL C, LDL-C/HDL C, TC/HDL C, non-HDL-C/HDL C, apolipoprotein B (ApoB), ApoB/apolipoprotein A 1 (ApoA 1) and ApoA 1 following 6 weeks of treatment with rosuvastatin 20 mg or placebo
3 Describe the longitudinal profile of LDL C as a change in LDL C from end of placebo period to 6, 12, and 18 weeks of therapy with rosuvastatin 20 mg
4, Describe the pharmacokinetic profile in terms of trough concentrations

Safety
Adverse events, including:
• The frequency and severity of adverse events
• Rate of discontinuations due to adverse
events
• Abnormal serum and urine laboratory values,
ECGs, physical examinations, and vital signs
Assessments of growth, including height (linear
growth [cm and standard deviation (SD) score]),
weight, and secondary characteristics of sexual
maturation by Tanner stage performed at the
beginning of the lead-in phase (Visit 2) and at Visit 7

E.5.2.1

Timepoint(s) of evaluation of this end point

1 and 2: Samples taken Day 42 (week 6), Day 84 (week 12)

3. Samples taken Day 42 (week 6), Day 84 (week 12), Day 126 (week 18), Day 168 (week 24)
4. Samples taken Day 126 (week 18), Day 168 (week 24)

Safety
From screeing up to week 24

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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.8.4.1

Number of sites anticipated in 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

Australia

Belgium

Czech Republic

Hong Kong

Israel

Netherlands

Norway

South Africa

Sweden

Taiwan

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

LVLS

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

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 2014-09-26.

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children aged 6-18 will need Informed consent from a parent/both parents or guardian and statement of assent from the child or adolescent (if required by the IRB / EC according to local regulations and guidelines).

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

F.4.2.2

In the whole clinical trial

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)

Patients will have the opportunity to continue treatment in a separate Long term extension (LTE) study expected to extend through 2016.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-09-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-07-02

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