Clinical Trials Register

Summary
EudraCT Number:	2011-005400-15
Sponsor's Protocol Code Number:	20110271
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-08-09
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

Greece - EOF

A.2

EudraCT number

2011-005400-15

A.3

Full title of the trial

A Multicenter, Single Arm, Open-label Study to Assess the Long-term Safety and Efficacy of AMG 145 on LDL-C in Subjects With Homozygous Familial Hypercholesterolemia or PCSK9 Mutations

Μία Πολυκεντρική, ανοιχτή μελέτη ενός σκέλους για την αξιολόγηση της μακροχρόνιας ασφάλειας και αποτελεσματικότητας του AMG145 στην LDL-C σε ασθενείς με ομόζυγη οικογενή υπερχοληστερολαιμία ή μεταλλάξεις στο γονίδιο PCSK

A.3.1

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

A clinical study to assess the safety and efficacy of AMG 145 on low density cholesterol in subjects with homozygous familial hypercholesterolemia or PCSK9 mutations

Μία Μελέτη για την Αξιολόγηση της Αποτελεσματικότητας και Ασφάλειας του AMG785 σε χαμηλή πυκνότητα χοληστερίνη σε ασθενείς με ομόζυγη οικογενή υπερχοληστερολαιμία ή μεταλλάξεις στο γονίδιο PCSK9 »

A.4.1

Sponsor's protocol code number

20110271

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	Amgen 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	Amgen 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	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ Medical Info - Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	(CH-)6300
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	N/A
B.5.5	Fax number	N/A
B.5.6	E-mail	MedinfoInternational@amgen.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	AMG 145
D.3.2	Product code	AMG 145
D.3.4	Pharmaceutical form	Solution 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.3.9.2	Current sponsor code	AMG 145
D.3.9.3	Other descriptive name	AMG 145
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	70
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
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

Homozygous Familial Hypercholesterolemia

Ομόζυγη Οικογενή Υπερχοληστερολαιμία

E.1.1.1

Medical condition in easily understood language

Hypercholesterolemia (high cholesterol), familial

Υπερχοληστερολαιμία (υψηλή χοληστερόλη), οικογενή

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10057100
E.1.2	Term	Homozygous familial hypercholesterolaemia
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 characterize the safety and tolerability of long-term administration of AMG 145 among patients with severe familial hypercholesterolemia

E.2.2

Secondary objectives of the trial

To characterize the durable efficacy of long-term administration of AMG 145 as assessed by low density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and
ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with severe familial hypercholesterolemia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects have completed study 20110233 or another qualifying Amgen protocol (all scheduled visits) and are still taking investigational product at the end of the study
Or
If the subjects did not complete study 20110233 or another qualifying Amgen protocol they will be eligible if they:
- Have severe familial hypercholesterolemia due to genetic causes (beyond LDL receptor mutations) which were not studied in 20110233, such as PCSK9 gain of function mutations, as evidenced by genetic or functional evidence.
- Have a diagnosis of homozygous familial hypercholesterolemia and are interested in enrolling after 20110233 has closed. As stated in protocol 20110233, the diagnosis of homozygous familial hypercholesterolemia will be based on genetic confirmation or a clinical diagnosis based on a history of an untreated LDL cholesterol concentration greater than 500
mg/dl (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
- Are male or female ≥ 12 to ≤ 65 years of age
- Are on a stable on a low-fat diet and taking pre-existing lipid-lowering therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants or nicotinic acid, or combinations thereof) for at least 4 weeks, with fasting central lab LDL cholesterol concentration >130 (3.4 mmol/L)
- Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening
- Bodyweight of 40 kg or greater at screening

E.4

Principal exclusion criteria

All subjects will be ineligible for the study if they fulfill any of the following criteria:
- Female subject is not willing to use at least one highly effective method of birth control during treatment and for an additional 15 weeks after the end of treatment unless subject is sterilized or postmenopausal;
• Menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone level >40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral oophorectomy”
• Highly effective methods of birth control include abstinence, birth control pills, shots, implants, or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
- Subject is pregnant or breast feeding, or might become pregnant during treatment and/or within 15 weeks after the end of treatment
- Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the subject (eg, inability or unwillingness to adhere to the protocol)
- Experienced a treatment related serious adverse event in the parent study
- Disorder that would interfere with understanding and giving informed consent or compliance with protocol requirements
Have an unstable medical condition, in the judgment of the investigator.
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
If the subjects did not complete study 20110233 or another qualifying Amgen protocol they will be ineligible for this study if they fulfill any of the following criteria:
- Use of Mipomersen within 5 months of screening
- NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%
- Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 3 months prior to randomization
- Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
- Planned cardiac surgery or revascularization within 20 weeks of screening
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg, confirmed with repeat measurement
- Subject requires uptitration of their current statin dose within 4 weeks of screening (these subjects can be uptitrated and rescreened one month later)
- Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
- Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at screening
- Unexplained CK > 5 times the ULN at screening, confirmed by a repeat measurement at least 1 week apart
- Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
- Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization
- Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years
- Subject has previously received AMG 145 or any other investigational therapy to inhibit inhibiting PCSK9
- Known sensitivity to any of the products to be administered during dosing

E.5 End points

E.5.1

Primary end point(s)

Subject incidence of treatment emergent adverse events.

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to week 26 Q4W; quaterly after week 26 until EoS

E.5.2

Secondary end point(s)

• Percent change in LDL-C from Day 1 OL at each 3 month visit
• Percent change in non-HDL-C from Day 1 OL at each 3 month visit
• Percent change in ApoB from Day 1 OL at each 3 month visit
• Percent change in total cholesterol/HDL-C ratio from Day 1 OL at each 3 month visit
• Percent change in ApoB/ApoA1 ratio from Day 1 OL at each 3 month visit

E.5.2.1

Timepoint(s) of evaluation of this end point

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised