Clinical Trials Register

Summary
EudraCT Number:	2011-005399-40
Sponsor's Protocol Code Number:	20110233
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-02-26
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

Czechia - SUKL

A.2

EudraCT number

2011-005399-40

A.3

Full title of the trial

A two part, Phase 2/3 Study to Assess the Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia
Part A - Open-label, Single-arm, Multicenter Pilot Study to Evaluate Safety, Tolerability, and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia
Part B - Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia

Klinické hodnocení fáze 2/3 složené ze dvou částí, posuzující bezpečnost, snášenlivost a účinnost přípravku AMG 145 u pacientů s homozygotní familiární hypercholesterolémií. Část A – otevřené, jednoramenné, multicentrické, pilotní klinické hodnocení hodnotící bezpečnost, snášenlivost a účinnost přípravku AMG 145 u pacientů s homozygotní familiární hypercholesterolémií. Část B – dvojitě zaslepené, randomizované, placebem kontrolované, multicentrické klinické hodnocení hodnotící bezpečnost, snášenlivost a účinnost přípravku AMG 145 u pacientů s homozygotní familiární hypercholesterolémií.

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, tolerability and efficacy of AMG 145 in subjects with homozygous familial hypercholesterolemia

A.4.1

Sponsor's protocol code number

20110233

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 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.3.9.2	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	140
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	Yes
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

Homozygous familial hypercholesterolaemia

E.1.1.1

Medical condition in easily understood language

Hypercholesterolemia (high cholesterol), familial

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10057100
E.1.2	Term	Homozygous familial hypercholesterolaemia
E.1.2	System Organ Class	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

Part A: To characterize the effect of 12 weeks of subcutaneous (SC) AMG 145 on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygous familial hypercholesterolemia (HoFH)
Part B: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145 compared with placebo on percent change from baseline in LDL-C in subjects with HoFH

E.2.2

Secondary objectives of the trial

Part A:
- To evaluate the safety and tolerability of AMG 145 SC in subjects with HoFH
- To assess the effects of 12 weeks of AMG 145 SC on absolute change in LDL-C, and percent change in 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 HoFH
- To evaluate AMG 145 pharmacokinetics and absolute change in PCSK9 in subjects with HoFH
Part B:
-To assess the effects of 12 weeks of AMG 145 SC, compared with placebo, on percent change from baseline in apolipoprotein B (ApoB) and lipoprotein (a) [Lp(a)] in subjects with homozygous familial hypercholesterolemia
- Please refer to page 17 of the protocol for the exploratory objectives for Part B

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

Pharmacogenetic sub-study.
This sub-study will investigate potential correlations of study data including the subject response to AMG 145 with genetic variation in markers of proprotein convertase subtilisin/kexin type 9 (PCSK9) signaling, low-density lipoprotein receptor (LDLR) turnover, cholesterol metabolism, inflammation, and plaque stability.

E.3

Principal inclusion criteria

• Subject has provided informed consent.
• Male or female ≥ 12 to ≤ 80 years of age
• Diagnosis of homozygous familial hypercholesterolemia by 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.
• 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

• LDL or plasma apheresis within 8 weeks prior to enrollment
• Use of Mipomersen or Lomitapide 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 enrollment
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to enrollment
• 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 1 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 enrollment
• Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the subject (eg, alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis)
• 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)
• Female subject of childbearing potential who is not willing to inform
her sexual partner of her participation in this clinical study and who
is not willing to use an acceptable method(s) of birth control during
treatment with Investigational product (AMG 145 or placebo) and for
an additional 15 weeks after the last dose of Investigational Product
(AMG 145 or placebo) unless subject is sterilized or postmenopausal.
Male subject with a female partner of childbearing potential not wiling to agree to inform his partner of his participation in this clinical study.
• Subject is pregnant or breast feeding, planning to become pregnant or planning to breastfeed during treatment with Investigational Product (AMG 145 or placebo) and/or within 15 weeks after the last dose of Investigational Product (AMG 145 or placebo).
• 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
• Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge.
• Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures.

E.5 End points

E.5.1

Primary end point(s)

Part A: The percent change LDL-C from baseline to week 12.
Part B: Percent change from baseline in LDL-C at week 12

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A:
From baseline to week 12
Part B:
Week 12

E.5.2

Secondary end point(s)

Part A:
- Change from baseline in LDL-C at week 12
- Percent change from baseline in non-HDL-C at week 12
- Percent change from baseline in ApoB at week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12
- Response rate of subjects with 15% or greater reduction in LDL-C from baseline to Week 12
- Change from baseline in PCSK9 at week 12

Part B:
Secondary Endpoint:
• Mean percent change from baseline in LDL-C at weeks 6 and 12
• Percent change from baseline in ApoB at week 12
• Mean percent change from baseline in ApoB at weeks 6 and 12
• Percent change from baseline in Lp(a) at week 12
• Mean percent change from baseline in Lp(a) at weeks 6 and 12

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A:
- Baseline to week 12
- Percent change from baseline to week 12
- Percent change from baseline in ApoB at week 12: from baseline to week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12: from baseline to week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12: from baseline to week 12
- Response rate of subjects with 15% or greater reduction in LDL-C from baseline to Week 12 (Part A only): from baseline to week 12
- Change in PCSK9 at week 12 (Part A and Part B)
Part B:
• Mean percent change from baseline at weeks 6 and 12
• Percent change from baseline to week 12
• Mean percent change from baseline to weeks 6 and 12
• Percent change from baseline to week 12
• Mean percent change from baseline to weeks 6 and 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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

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

Yes

E.8.1.7.1

Other trial design description

Part A - Open label, single blind; Part B - double blind, parallel group

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

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

Belgium

Canada

France

Italy

Netherlands

New Zealand

Brazil

Czech Republic

Hong Kong

Lebanon

Malaysia

Spain

South Africa

Turkey

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

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)

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)

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)

The plans for treatment or care after the subject has ended participation in the trial are not different from the expected normal treatment of this condition.

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

2013-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-01-31

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