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    Summary
    EudraCT Number:2012-001365-32
    Sponsor's Protocol Code Number:20110117
    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:2012-10-16
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2012-001365-32
    A.3Full title of the trial
    A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Subjects with Heterozygous Familial Hypercholesterolemia
    RUTHERFORD-2
    Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the tolerability and efficacy of AMG 145 in patients with
    heterozygous familial hypercholesterolemia
    A.4.1Sponsor's protocol code number20110117
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmgen Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAmgen Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ Medical Info - Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post code(CH-)6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAMG 145
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAMG 145
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled pen
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heterozygous Familial Hypercholesterolemia
    E.1.1.1Medical condition in easily understood language
    Hypercholesterolemia (high cholesterol)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level LLT
    E.1.2Classification code 10057079
    E.1.2Term Heterozygous familial hypercholesterolemia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145 every-2-weeks (Q2W) and monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia.
    E.2.2Secondary objectives of the trial
    • To evaluate the safety and tolerability of SC AMG 145 Q2W and QM, compared with placebo, in subjects with heterozygous familial hypercholesterolemia
    • To assess the effects of 12 weeks of SC AMG 145 Q2W and QM, compared with placebo, on change from baseline in LDL-C, and percent change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total
    cholesterol/HDL-C ratio, ApoB/Apolipoprotein A1 (ApoA1) ratio, Lipoprotein (a) [Lp(a)], triglycerides, very low-density lipoprotein cholesterol (VLDL-C), and HDL-C in subjects with heterozygous familial hypercholesterolemia
    • To assess the effects of 12 weeks SC AMG 145 Q2W and QM, compared with placebo, on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in subjects with heterozygous familial hypercholesterolemia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Subject has provided informed consent.
    •Male or female ≥ 18 to ≤ 80 years of age
    •Diagnosis of heterozygous familial hypercholesterolemia by having met the diagnostic criteria outlined by the Simon Broome Register Group (Scientific Steering Committee, 1991) as defined by the documentation of one of the following in the patient’s past medical record:
    1. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL
    (> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND tendinous xanthomas in the patient or first- or second-degree relative
    2. Deoxyribonucleic acid (DNA)-based evidence of mutation in the LDLR, ApoB, or PCSK9 gene
    3. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL (> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative
    4. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL (> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/ liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of raised total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in a first or second-degree adult relative or > 260 mg/dL (> 6.7 mmol/liter) in child, brother, or sister aged younger than 16 years
    •On a stable dose of an approved statin, and on stable dose(s) for all allowed (eg, ezetimibe, bile-acid sequestering resin, stanols, or regulatory-approved and marketed niacin (eg, Niaspan or Niacor)) lipidregulating drugs for at least 4 weeks before LDL-C screening and, in the opinion of the investigator, not requiring uptitration.
    •Fasting LDL-C ≥ 100 mg/dL (2.6 mmol/L) by central laboratory at screening
    •Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening

    E.4Principal exclusion criteria
    •Homozygous familial hypercholesterolemia
    •LDL or plasma apheresis within 4 months prior to randomization
    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
    •Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c > 8.5%), newly diagnosed type 2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting plasma glucose ≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%) without prior diagnosis of diabetes
    •Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
    •Subject requires uptitration of their current statin dose (these subjects can be uptitrated and rescreened one month later)
    •Subject has taken in the last 6 weeks prior to LDL-C screening red yeast rice, omega-3 fatty acids ([eg, DHA and EPA combined] [> 1000 mg/day]) or prescription lipid-regulating drugs (eg, fibrates and derivatives) other than statins, ezetimibe, bile-acid sequestering resin, stanols, or regulatory approved and marketed niacin (eg, Niaspan or Niacor)
    •Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib.Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids (eg, IV, intramuscular [IM], or PO) (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is permitted)
    •Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) < 1.0 time the lower limit of normal (LLN) or >1.5 times the upper limit of normal (ULN), respectively, at screening
    •Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screeningActive liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by central laboratory analysis at screening
    •CK > 3 times the ULN at screening
    •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
    •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 who has either (1) not used at least 1 highly effective method of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment unless the subject is sterilized orpostmenopausal;
    (Please refer to page 38 of Protocol for further details)
    •Subject is pregnant or breast feeding, or planning to become pregnant during treatment and/or within 15 weeks after the end of treatment
    •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 PCSK9
    •Known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose
    •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.5.1Primary end point(s)
    Co-Primary Endpoints
    • Mean percent change from baseline in LDL-C at weeks 10 and 12
    • Percent change from baseline in LDL-C at week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Mean percent change from baseline in LDL-C at weeks 10 and 12
    • Percent change from baseline in LDL-C at week 12
    E.5.2Secondary end point(s)
    Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for:
    Tier 1 endpoints
    • Change from baseline in LDL-C at week 12
    • LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) 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
    Tier 2 endpoints
    • Percent change from baseline in Lp(a) at week 12
    • Percent change from baseline in triglycerides at week 12
    • Percent change from baseline in HDL-C at week 12
    • Percent change from baseline in VLDL-C
    E.5.2.1Timepoint(s) of evaluation of this end point
    Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for:
    Tier 1 endpoints
    • Change from baseline in LDL-C at week 12
    • LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) 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
    Tier 2 endpoints
    • Percent change from baseline in Lp(a) at week 12
    • Percent change from baseline in triglycerides at week 12
    • Percent change from baseline in HDL-C at week 12
    • Percent change from baseline in VLDL-C
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    biomarker development
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    France
    Germany
    Hong Kong
    Japan
    Netherlands
    New Zealand
    Norway
    Singapore
    South Africa
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    E.8.7Trial 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
    The end of the study for this trial is defined as the date on which the last randomized subject has had the opportunity to complete their EOS assessment. This will occur at the week 12 assessment for subjects randomized to the QM treatment arm or during the week 14 assessment for subjects randomized to the Q2W treatment arm.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 214
    F.4.2.2In 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)
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-10-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-12-11
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