Clinical Trials Register

Summary
EudraCT Number:	2013-002644-87
Sponsor's Protocol Code Number:	B1481021
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-02
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

Norway - NOMA

A.2

EudraCT number

2013-002644-87

A.3

Full title of the trial

A 52 WEEK, PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED,PARALLEL-GROUP STUDY TO ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF PF-04950615 IN SUBJECTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

A.3.1

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

A phase 3 study investigating the efficacy, safety and tolerability of PF-04950615 in patients with elevated levels of cholesterol in the blood caused by a defective gene

A.4.1

Sponsor's protocol code number

B1481021

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	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
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	Pfizer 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	Pfizer Inc
B.5.2	Functional name of contact point	Clinical Trials.gov Call Centre
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 800 718 1021
B.5.5	Fax number	+1303 739 1119
B.5.6	E-mail	ClinicalTrials.gov.CallCentre@pfizer.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.3.2	Product code	PF-04950615
D.3.4	Pharmaceutical form	Suspension for injection
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.3.9.1	CAS number	1407435-02-6
D.3.9.2	Current sponsor code	PF-04950615
D.3.9.3	Other descriptive name	RN316
D.3.9.4	EV Substance Code	SUB31542
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	Yes
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	Solution for injection
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

High Cholesterol

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10020604
E.1.2	Term	Hypercholesterolemia
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate a superior LDL-C lowering effect of PF-04950615 150 mg administered by the SC route Q2wks compared to placebo, in subjects with heterozygous familial hypercholesterolemia (HeFH) and at high and very high risk of CV events receiving a maximally tolerated dose of statin therapy and whose LDL-C is ≥70 mg/dL (1.81mmol/L)

E.2.2

Secondary objectives of the trial

To demonstrate a superior effect of PF-04950615 150 mg administered by the SC route Q2wks compared to placebo, in subjects with HeFH and at high and very high risk of CV events receiving maximally tolerated dose of statin therapy and whose LDL-C is ≥70 mg/dL(1.81 mmol/L) on:
- Total cholesterol (TC), HDL-C, Triglycerides (TG), and non HDL-C;
-Other lipid parameters, including Apolipoprotein B (ApoB), Apolipoprotein A-I (ApoAI), Apolipoprotein A-II (ApoA-II), lipoprotein (a)[Lp(a)];
- To compare the safety and tolerability of PF-04950615 150mg administered by the SC
route Q2wks to placebo, in subjects with HeFH and at high and very high risk of CV
events receiving maximally tolerated dose of statin therapy and whose LDL-C is ≥70
mg/dL (1.81 mmol/L);
-To assess the immunogenicity of PF-04950615;
-To assess the exposure of PF-04950615.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3.Males and females ≥18 years of age.
4.With previously diagnosed HeFH phenotype as defined according to the Simon Broome criteria, described in Appendix 2 or a genetic diagnosis of HeFH.
5.Subjects are required to be treated with atorvastatin, simvastatin, or rosuvastatin at the highest locally approved dose. If at a lower dose, there must be documentation that the subject is receiving a maximally tolerated dose of the aforementioned statins; and no dose should be lower than atorvastatin 20 mg, rosuvastatin 20 mg, or simvastatin 40 mg.
•Subjects on simvastatin 80 mg must have been on this dose for >1 year before screening.
•All subjects must be on a stable dose at least 6 weeks prior to screening. There should be no plans at the time of screening and randomization to modify the dose of statin for the duration of the trial.
•Source records and case report form (CRF) must show documentation of the requirements shown above.
6.Subjects should be at high or very high risk of incurring a CV event, defined as:
•Known history of CVD based on any one of the below:
•Coronary heart disease: history of acute myocardial infarction, evidence of silent myocardial infarction or myocardial ischemia, history of unstable angina and stable angina pectoris, and history of coronary procedures (coronary angioplasty and coronary artery surgery);
•Other clinical atherosclerotic diseases: peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (symptomatic [eg, transient ischemic attack or stroke of carotid origin] or >50 percent stenosis on angiography or ultrasound), and likely other forms of clinical atherosclerotic disease (eg, renal artery disease).
OR
•Type 2 or Type 1 diabetes, or;
•Chronic kidney disease (CKD), defined as glomerular filtration rate (GFR) calculated by Modification of Diet in Renal Disease (MDRD) formula between 30 and 60 mL/min/1.73m2 (inclusive).
7.Lipids should meet the following criteria on a background treatment with a statin at the 2 screening visits:
•Subjects at the highest approved dose of statins described in 5, above:
•Fasting LDL C ≥70 mg/dL (1.81 mmol/L) at both screening visits and the value at the second screening visit within 7 days of randomization must not be lower or higher than 20% of this initial value, as described in Section 7.1 of the protocol.
•Subjects not at the highest approved dose of statins described in 5, above:
•Fasting LDL C ≥77 mg/dL (1.99 mmol/L) at both screening visits and the value at the second screening visit within 7 days of randomization must not be lower or higher than 20% of this initial value, as described in Section 7.1.
•Fasting TG ≤ 400 mg/dL (4.5 mmol/L) at the second screening visit within 7 days of randomization.
8.Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 63 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active (Section 4.4.2).
Female subjects who are not of childbearing potential (ie, meet at least one of the following criteria):
•Have undergone a documented hysterectomy or bilateral oophorectomy;
•Have medically confirmed ovarian failure; or
•Achieved post menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicule stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females.

E.4

Principal exclusion criteria

Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members directly involved in the conduct of
the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
2. Participation in other studies involving small molecule investigational drug(s)
(Phases 1-4) within 1 month except for cholesteryl ester transfer protein (CETP)
inhibitors (indefinitely), or biological agents within 6 months or 5 half lives, whichever is
longer before the current study begins and/or during study participation (the investigator should refer to documents provided by the subject on the other study to determine the investigational product half life). If the blind has been broken and the Investigator knows (with documentation) that the subject received placebo, he/she can be included.
3. Subjects with prior exposure to PF-04950615 (RN316) or other investigational PCSK9 inhibitors.
4. Subjects who are unable to receive injections, as either a self-injection, or administered by a family member, health care assistant or health care provider.
5. History of a cardiovascular or erebrovascular event or procedure (eg, Myocardial infarction, stroke, transient ischemic attack, angioplasty) during the past 30 days.
6. Congestive heart failure, New York Heart Association (NYHA) functional class IV, or
Left Ventricular Ejection Fraction measured by imaging <25%.
7. Poorly controlled hypertension at any screening visit or at randomization (defined as the average of two systolic blood pressure measurements greater than 160 mm Hg or the average of two diastolic blood pressure measurements greater than 100 mm Hg, even with treatment). Subjects who have hypertension and are controlled on stable dosages of anti hypertensive medications can be included. Subjects may be permitted into the study if in the Principal Investigator’s opinion the assessment(s) are not clinically significant.
Blood pressure (BP) may be repeated up to three times within the hour or at the
completion of the office visit, to confirm a reading.
8. Any history of hemorrhagic stroke.
9. Any history of hypothyroidism or thyroid stimulating hormone (TSH) >1X Upper Limit
of Normal (ULN) at screening.
10. Current history of alcoholism or drug addiction according to the Diagnostic and
Statistical Manual of Mental Disorders (DSM IV) criteria within 12 months prior to
screening. Use of any recreational drugs within 12 months prior to screening.
11. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision).
12. Medical history of positive testing for Human Immunodeficiency Virus (HIV).
13. Any disease or condition that might compromise the hematological, renal, hepatic, pulmonary, endocrine, central nervous, immune, or gastrointestinal systems (unless deemed not clinically significant by the Investigator and/or the Sponsor) or confound the interpretation of the study results. Examples of such conditions include but are not limited to nephrotic syndrome, uncontrolled diabetes, excessive alcohol consumption and
cholestatic liver disease.
14. Use of statins other than atorvastatin, rosuvastatin or simvastatin.
15. Undergoing apheresis or have planned to start apheresis. 16. Initiation of, or change in, non lipid lowering prescription drugs, herbal medicine or supplements within 6 weeks of screening (exception: initiation or change in multivitamins used for general health purposes are acceptable).
17. Subjects on systemic corticosteroids (ie, oral, intravenous (IV), intramuscular [IM], or
intra-articular) at screening. The use of corticosteroids by inhalation is permitted.
18. Subjects taking prescription medications that are contraindicated with the use of statins at screening. Refer to statin product labels for these medications.
19. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibodies (eg, Enbrel® which contains the Fc portion of an antibody or Lucentis® which is a Fab).
20. Subjects who are latex-sensitive (due to potential for exposure to latex or dry rubber in the pre-filled syringe cap during self administration).
21. Any abnormal hematology values, clinical chemistries, urinalysis, or electrocardiograms (ECGs) at screening judged by the Investigator as clinically significant, which could impact on subject safety, were the potential subject to be included in the study or interfere
with interpretation of the study results.
For exclusion conditions 22-30 please refer to the protocol

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline in fasting LDL-C at Week12.

E.5.1.1

Timepoint(s) of evaluation of this end point

at week 12

E.5.2

Secondary end point(s)

-Percent change from baseline in fasting TC, non HDL-C, and ApoB at Week 12;
- Percent change from baseline in Lp(a) at Week 12;
- Percent change from baseline in fasting HDL-C at Week 12.

E.5.2.1

Timepoint(s) of evaluation of this end point

at week 12

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

Yes

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

Yes

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)

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.8.5

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

Bulgaria

Canada

Finland

Italy

Netherlands

Norway

Poland

South Africa

Spain

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

End of Trial in a Member State (MS) of the EU is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment by a MS is not a reason for premature termination but is considered a normal
conclusion to the study in that MS. For all other participating countries it is defined as LSLV.

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:

285

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

135

F.4.2.2

In the whole clinical trial

300

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)

Previous national standard of 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

2013-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-15

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