Clinical Trials Register

Summary
EudraCT Number:	2014-001917-20
Sponsor's Protocol Code Number:	R727-CL-1216.03
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-11-25
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 - PEI

A.2

EudraCT number

2014-001917-20

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia Undergoing Lipid Apheresis Therapy

A.3.1

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

A study to explore the safety and efficacy of alirocumab in patients that require Apheresis to control their blood lipid levels

A.3.2

Name or abbreviated title of the trial where available

ODYSSEY ESCAPE

A.4.1

Sponsor's protocol code number

R727-CL-1216.03

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	Regeneron Pharmaceuticals, Inc.
B.1.3.4	Country	United States
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	Regeneron Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Regeneron Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Garen Manvelian
B.5.3	Address:
B.5.3.1	Street Address	777 Old Saw Mill River Road
B.5.3.2	Town/ city	Tarrytown
B.5.3.3	Post code	NY 10591
B.5.3.4	Country	United States
B.5.6	E-mail	garen.manvelian@regeneron.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	No
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	Alirocumab
D.3.2	Product code	SAR236553/REGN727
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Alirocumab
D.3.9.1	CAS number	1245916-14-6
D.3.9.2	Current sponsor code	Alirocumab/SAR236553/REGN727
D.3.9.3	Other descriptive name	ALIROCUMAB
D.3.9.4	EV Substance Code	SUB74847
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for injection in pre-filled pen
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heterozygous Familial Hypercholesterolemia

E.1.1.1

Medical condition in easily understood language

Hereditary abnormal (high) cholesterol level that cannot be treated with standard medicines therapy

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10057079
E.1.2	Term	Heterozygous familial hypercholesterolemia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to evaluate the effect of alirocumab 150 mg every 2 weeks (Q2W) in comparison with placebo on the frequency of low-density lipoprotein (LDL) apheresis treatments in patients with heterozygous familial hypercholesterolemia (HeFH) undergoing weekly or bi-weekly LDL apheresis therapy.

E.2.2

Secondary objectives of the trial

The secondary objectives are:
• To evaluate the effect of alirocumab 150 mg Q2W on LDL-C levels in patients with HeFH undergoing LDL apheresis therapy
• To evaluate the effect of alirocumab 150 mg Q2W on the following lipid parameters: ApoB, non-HDL-C, total cholesterol, Lp(a), HDL-C, TGs, and ApoA-1 in patients with HeFH undergoing LDL apheresis therapy during the study
• To evaluate the safety and tolerability of alirocumab 150 mg Q2W in patients with HeFH undergoing LDL apheresis therapy
• To assess the PK of alirocumab 150 mg Q2W in patients with HeFH undergoing LDL apheresis therapy (QW versus Q2W)
• To evaluate the development of anti-alirocumab antibodies
• To evaluate PCSK9 levels in response to alirocumab therapy as well as pre and post-apheresis
• To evaluate QOL in patients

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

An optional genomic sub-study will be conducted to identify genetic associations with clinical or biomarker response to PCSK9 inhibition, hyperlipidemia, or CVD. Samples may also be used to identify markers associated with toxicity.

E.3

Principal inclusion criteria

A patient must meet the following criteria to be eligible for inclusion in the study:
1. Men and women ≥18 years of age at the time of the screening visit
2. Diagnosis of HeFH
3. Currently undergoing LDL apheresis therapy QW for at least 4 weeks, or Q2W for at least 8 weeks prior to the screening visit (week -2) and have initiated apheresis treatment for at least 5 months prior to that
Note: A stable apheresis schedule is considered as 4 apheresis procedures performed during a 4-week period, approximately 1 week apart, or 4 apheresis procedures performed during an
8-week period, approximately 2 weeks apart.

E.4

Principal exclusion criteria

A patient who meets any of the following criteria will be excluded from the study:
1. Homozygous FH
2. Background medical LMT (if applicable) that has not been stable for at least 8 weeks prior to the screening visit (week -2)
3. LDL apheresis schedule/apheresis settings that have not been stable for at least 4 weeks prior to the screening visit (week -2) for patients undergoing apheresis weekly and at least 8 weeks prior to the screening visit (week -2) for patients undergoing apheresis bi weekly
4. An LDL apheresis schedule other than QW to Q2W
5. Initiation of a new exercise program or exercise that has not remained stable within 8 weeks prior to the screening visit (week -2)
6. Initiation of a new diet or a diet that has not been stable within 8 weeks prior to the screening visit (week -2)
7. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount that has not been stable for at least 8 weeks prior to the screening visit (week -2), or between the screening and randomization visit
8. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
9. Signs and symptoms of hypothyroidism (thyroid replacement therapy is permitted)
10. History of bariatric surgery within 12 months prior to the screening visit (week -2)
11. Unstable weight (variation >5 kg) within 2 months prior to the screening visit (week -2)
12. Newly diagnosed (within 3 months prior to randomization visit [day 1]) diabetes mellitus or poorly controlled (hemoglobin A1c [HbA1c] >9%) diabetes
13. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization; topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered
as ‘systemic’ and are allowed
14. Use of estrogen or testosterone therapy, unless the regimen has been stable in the past 6 weeks prior to the screening visit (week -2) and no plans to change the regimen during the study
15. Systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg at the
screening visit (week -2) or time of randomization (day 1)
Note: Blood pressure assessment for study eligibility may be obtained at a visit occurring
between these 2 visits in the event that the patient had not taken, or plans not to take,
prescribed hypertensive medications at the screening or randomization visit due to
apheresis schedule.
16. History of a myocardial infarction (MI), unstable angina leading to hospitalization,
coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI),
uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic
attack or carotid revascularization within 3 months prior to the screening visit (week -2),
or endovascular procedure or surgical intervention for peripheral vascular disease within
1 month prior to the screening visit (week -2)
17. History of New York Heart Association Class III or IV heart failure within 12 months prior to the screening visit
18. Known history of a hemorrhagic stroke
19. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
20. Known history of a positive test for human immunodeficiency virus
21. Use of any active investigational drugs within 1 month or 5 half-lives of screening, whichever is longer
22. Patients who have been treated with at least 1 dose of alirocumab or any other anti-PCSK9 monoclonal antibody in any other clinical studies
23. Conditions/situations such as:
- Any clinically significant abnormality identified at the time of screening that, in the judgment of the investigator or any sub-investigator, would preclude safe completion of the study or constrain endpoints assessment; eg, major systemic diseases, patients with short life expectancy
- Considered by the investigator or any sub-investigator as inappropriate for this study for any reason, eg:
- Deemed unable to meet specific protocol requirements, such as scheduled visits
- Deemed unable to tolerate injections, as per the patient or the investigator
- Investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol, etc
- Presence of any other conditions (eg, geographic or social), either actual or anticipated, that the investigator feels would restrict or limit the patient’s participation for the duration of the study
24. Certain laboratory findings during screening period
25. Known hypersensitivity to monoclonal antibody therapeutics or to any component of the drug product
26. Pregnant or breastfeeding women
27. Women of childbearing potential not protected by highly-effective method(s) of birth control and/or who are unwilling or unable to be tested for pregnancy

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the rate of apheresis treatments during the
12-week period from week 7 to week 18, normalized by the number of planned apheresis treatments according to each patient’s established schedule at screening, week -10 to week -2.

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout the duration of the study

E.5.2

Secondary end point(s)

The key secondary endpoints are:
• Percent change from baseline in LDL-C (pre-apheresis) to week 6, regardless of adherence to treatment
• The standardized rate of apheresis treatments during the 4-week period from week 15 to week 18, defined similarly as for the primary efficacy endpoint
• Percent change from baseline in (pre-apheresis): ApoB, non-HDL-C, total cholesterol and ApoA-1to week 6, regardless of adherence to treatment
• Proportion of patients with ≥30% and ≥50% reduction in LDL-C (pre-apheresis) at week 6, regardless of adherence to treatment
• Percent change from baseline in (pre-apheresis): LDL-C, ApoB, non-HDL-C, total cholesterol, in ApoA-1 to week 18, regardless of adherence to treatment
• Proportion of patients with ≥30% and ≥50% reduction in LDL-C (pre-apheresis) at week 18, regardless of adherence to treatment
• Change of W-BQ22 index score from baseline to week 18, regardless of adherence to treatment
• Percent change from baseline in (pre-apheresis): Lp(a), HDL-C and TG levels to week 6, regardless of adherence to treatment
• Percent change from baseline in (pre-apheresis): Lp(a), HDL-C and TG levels to week 18, regardless of adherence to treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the duration of the study

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Added an open-label treatment period

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

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

Last visit of last subject - 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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

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)

After participation in the trial, patients will receive their standard
medical care.

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

2015-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-13

P. End of Trial
P.	End of Trial Status	Completed

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