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    Summary
    EudraCT Number:2013-000935-29
    Sponsor's Protocol Code Number:20120332
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-02-24
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-000935-29
    A.3Full title of the trial
    A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects
    Studio multicentrico, randomizzato in doppio cieco per valutare la sicurezza e l’efficacia di AMG 145, rispetto a ezetimibe, in soggetti con ipercolesterolemia che non sono in grado di tollerare una dose efficace di un inibitore della HMG-CoA reduttasi a causa degli effetti indesiderati di tipo muscolare
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study designed to evaluate the safety and efficacy of AMG 145 compared with Ezetimibe treatment, in people with high cholesterol who have experienced side effects whilst taking existing statin treatment
    Studio per valutare l’efficacia e la sicurezza di AMG 145 rispetto rispetto al trattamento con ezetimibe, in soggetti con elevati livelli di colesterolo che hanno avuto effetti indesiderati durante il trattamento con statine
    A.3.2Name or abbreviated title of the trial where available
    GAUSS-3
    A.4.1Sponsor's protocol code number20120332
    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.3.8INN - Proposed INNNA
    D.3.9.2Current sponsor codeAMG 145
    D.3.9.3Other descriptive nameAMG 145
    D.3.9.4EV Substance CodeSUB32500
    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 Yes
    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.IMP: 2
    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 Yes
    D.2.1.1.1Trade name Atorvastatin calcium
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAtorvastatin
    D.3.2Product code C10AA05
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATORVASTATIN
    D.3.9.1CAS number 134523-00-5
    D.3.9.3Other descriptive nameatorvastatin
    D.3.9.4EV Substance CodeSUB05600MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name ZETIA® (ezetimibe) Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMerck & Co Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameezetimibe
    D.3.2Product code C10A X09
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.1CAS number 163222-33-1
    D.3.9.2Current sponsor codeEZETIMIBE
    D.3.9.3Other descriptive nameEZETIMIBE
    D.3.9.4EV Substance CodeSUB16430MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 4
    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 cartridge
    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.3.8INN - Proposed INNNA
    D.3.9.2Current sponsor codeAMG 145
    D.3.9.3Other descriptive nameAMG 145
    D.3.9.4EV Substance CodeSUB32500
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 Yes
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypercholesterolemia
    Ipercolesterolemia
    E.1.1.1Medical condition in easily understood language
    High Low-density lipoprotein Cholesterol (LDL-C) levels in the blood
    Elevati livelli di LDL-C nel sangue
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10020604
    E.1.2Term Hypercholesterolemia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of AMG 145 administered subcutaneously (SC) once every month (QM) compared with ezetimibe (Part B), on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects who are unable to
    tolerate an effective dose of a statin due to muscle related side effects (MRSE).
    valutare gli effetti di 24 settimane di trattamento con AMG 145 somministrato per via sottocutanea (SC) ogni mese (QM), rispetto a ezetimibe (Parte B), sulla variazione percentuale dei valori di colesterolo LDL (lipoproteine a bassa densità) rispetto al basale in soggetti ipercolesterolemici che non sono in grado di tollerare una dose efficace di una statina a causa degli effetti indesiderati di tipo muscolare (MRSE), come confermato dalla risomministrazione (rechallenge) iniziale in doppio cieco, controllata verso placebo e in crossover di una statina (Parte A).
    E.2.2Secondary objectives of the trial
    • To evaluate the safety and tolerability of SC AMG 145 QM, compared with ezetimibe, in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
    • To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on change from baseline in LDL-C, and percent change from baseline in total
    cholesterol, 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, HDL-C, and VLDL-C in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
    • To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on percent of subjects attaining LDL-C < 70 mg/dL (1.81 mmol/L) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
     Valutare la sicurezza e la tollerabilità di AMG 145 SC QM, rispetto a ezetimibe, in soggetti ipercolesterolemici che non sono in grado di tollerare una dose efficace di statina
     Valutare gli effetti di 24 settimane di trattamento con AMG 145 sc QM, rispetto a ezetimibe, sulla variazione dei valori di LDL-C rispetto al basale e sulla variazione percentuale dei valori di colesterolo totale, colesterolo non HDL (non HDL-C), apolipoproteina B (ApoB), rapporto colesterolo totale/HDL-C, rapporto ApoB/Apolipoproteina A1 (ApoA1), lipoproteina(a) [Lp(a)], trigliceridi, HDL-C e VLDL-C rispetto al basale in soggetti ipercolesterolemici che non sono in grado di tollerare una dose efficace di statina
     Valutare gli effetti di 24 settimane di trattamento con AMG 145 SC QM, rispetto a ezetimibe, sulla percentuale di soggetti che raggiungono valori di LDL-C <70 mg/dL (1,81 mmol/L) in soggetti ipercolesterolemici che non sono in grado di tollerare una dose efficace di statina
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenetic Study:
    All subjects will be invited to consent to pharmacogenetic analyses, where approved by the independent ethics committee and/or institutional review board (IEC/IRB), applicable regulatory and other authorities. If the subject consents to the optional pharmacogenetic portion of this study, DNA analyses may be performed in accordance with schedule of assessments described in the current protocol.

    The analyses will focus on inherited genetic variations to evaluate their possible correlation to the disease and/or responsiveness to the therapies used in this study. The objectives of the optional studies include the use of genetic markers (such as those associated with PCSK9 signaling, low-density lipoprotein receptor (LDLR) turnover, cholesterol metabolism, inflammation, and plaque stability) to help in the investigation of primary hyperlipidemia and mixed dyslipidemia and/or to identify subjects who may have positive or negative response to AMG 145.
    Samples will be stored and destroyed in accordance with the current approved protocol.
    - Sottostudio di farmacogenetica (facoltativo): per valutare la possibile correlazione delle variazioni genetiche con la patologia e/o con la risposta alla terapia. E’ previsto l’utilizzo di marcatori genetici per lo studio dell’iperlipidemia primaria e dislipidemia mista e/o per identificare soggetti che possono avere una risposta positiva o negativa a AMG 145. I campioni verranno conservati e distrutti in accordo al protocollo.

    - Sottostudio sulle ricerche future (facoltativo): Tutti i campioni biologici residui di cui alla Tabella 2 del consenso informato principale, inclusi i campioni di sangue e quelli per lo sviluppo dei biomarcatori, ed i dati clinici raccolti potranno essere usati per queste ricerche future. Questi campioni ed i dati clinici saranno usati per approfondire le conoscenze scientifiche sulle malattie cardiovascolari, sulle dislipidemia e sui disordini metabolici o sul meccanismo di azione del farmaco.
    E.3Principal inclusion criteria
    1) Subject who has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
    2) Male or female ≥ 18 to ≤ 80 years of age at signing of informed consent
    3) Subject who is not at LDL-C goal as evidenced by their NCEP ATP III risk category and the following LDL-C levels by central laboratory at screening:
    a) Fasting LDL-C ≥ 100 mg/dL (2.59 mmol/L) for subjects with diagnosed CHD or are CHD risk equivalent or
    b) Fasting LDL-C ≥ 130 mg/dL (3.37 mmol/L) for subjects without diagnosed CHD or risk equivalent and 2 or more risk factors or
    c) Fasting LDL-C ≥ 160 mg/dL (4.14 mmol/L) for subjects without diagnosed CHD or risk equivalent and with 1 or more risk factors or
    d) Fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L) for subjects without diagnosed CHD or risk equivalent and with no risk factors
    4) Subject who has a history of statin intolerance as evidenced by the following:
    a) Unable to tolerate atorvastatin at an average daily dose of 10 mg AND unable to tolerate any other statin at any dose due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
    OR
    b) Unable to tolerate at least three statins: one statin at the lowest starting average daily dose (defined below) AND any other two statins at any dose, due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
    - atorvastatin - 5 mg
    - simvastatin - 10 mg
    - pravastatin - 40 mg
    - lovastatin - 20 mg
    - fluvastatin - 40 mg
    - pitavastatin - 2 mg
    OR
    c) A documented history of CK elevation > 10 x ULN accompanied by muscle symptoms while on statin therapy and documented resolution of both CK elevation and muscle symptoms upon discontinuation of statin therapy;
    AND
    d) Symptoms resolved or improved when statin dose was decreased or discontinued
    5) Lipid lowering therapy has been stable prior to LDL-C screening for at least 4 weeks if currently on a bile-acid sequestering resin and/or stanol; if subject is on statin or ezetimibe at start of screening, statin or ezetimibe must be discontinued for ≥ 4 weeks before LDL-C screening
    6) Fasting triglycerides ≤ 400 mg/dL (4.52 mmol/L) by central laboratory at screening
    1) soggetto che ha fornito il consenso / assenso informato prima di iniziare
    eventuali attività / procedure di studio

    2) Maschio o femmina di età ≥ 18 a ≤ 80 anni al momento della firma del consenso informato

    3) Soggetto che non è vicino al target di LDL – C, come provato dalla sua categoria di rischio NCEP ATP III e dai livelli di LDL -C:
    a) LDL-C ≥ 100 mg / dL ( 2,59 mmol / L) per i soggetti con CHD diagnosticato o a rischio CHD equivalente o
    b ) LDL-C ≥ 130 mg / dL ( 3,37 mmol / L) per i soggetti senza CHD
    diagnosticato o rischio equivalente e 2 o più fattori di rischio o
    c ) LDL-C ≥ 160 mg / dL ( 4,14 mmol / L) per i soggetti senza CHD
    diagnosticato o rischio equivalente e con 1fattore di rischio o
    d ) LDL-C ≥ 190 mg / dL ( 4,9 mmol / L) per i soggetti senza CHD
    diagnosticato o rischio equivalente e senza fattori di rischio

    4) Soggetti che hanno una storia di intolleranza a statine come dimostrato di seguito:
    a) non tollerano atorvastatina alla dose media giornaliera di 10 mg e non
    in grado di tollerare qualsiasi altra statina a qualsiasi dose a causa di sintomi correlati al sistema muscolo scheletrico (ad esempio dolore, debolezza o crampi )
    O
    b ) Incapacità di sopportare almeno tre statine: una statina alla minima
    dose media iniziale giornaliera (definita di seguito) ed altre due statine a
    qualsiasi dose, a causa di sintomi correlati al sistema muscolo scheletrico (ad esempio dolore, debolezza o crampi)
    - Atorvastatina - 5 mg
    - Simvastatina - 10 mg
    - Pravastatina - 40 mg
    - Lovastatina - 20 mg
    - Fluvastatina - 40 mg
    - Pitavastatina - 2 mg
    O
    c ) una storia documentata di CK > 10 x ULN accompagnato da
    sintomi muscolari durante la terapia con statine e documentata risoluzione di elevazione di CK e sintomi muscolari dopo la sospensione di statine
    E
    d ) I sintomi risolti o migliorati, quando la dose di statine è stata ridotta o
    interrotta

    5) La terapia ipolipemizzante è stata stabile prima dello screening per LDL- C per
    almeno 4 settimane se attualmente trattato con statina e/o resina sequestrante acidi biliari e / o stanoli , se il soggetto è in statina o ezetimibe all'inizio dello screening,
    statina o ezetimibe deve essere interrotto per ≥ 4 settimane prima di LDL- C
    proiezione

    6) trigliceridi a digiuno ≤ 400 mg / dL ( 4,52 mmol / l) allo screening
    E.4Principal exclusion criteria
    1) History of haemorrahagic stroke
    2) Personal or family history of hereditary muscular disorders
    3) NYHA III or IV heart failure, or last known left ventricular ejection fraction (LVEF) < 30%
    4) 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
    5) Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
    6) Planned cardiac surgery or revascularization
    7) 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 serum glucose ≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%) without prior diagnosis of diabetes
    8) Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
    9) Subject who has taken in the last 4 weeks prior to LDL C screening red yeast rice, > 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and derivatives, statins or, ezetimibe) other than bile-acid sequestering resin, or stanols and stanol esters
    10) Subject who has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib.
    11) 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)
    12) Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) < 1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening. Potential subjects with TSH < 1.0 time the lower limit of normal due to thyroid replacement therapy is not considered an exclusion
    13) Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
    14) Active 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
    15) Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
    16) Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization
    17) 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)
    18) 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)
    19) Female subject who has either (1) not used at least 1 highly effective method of contraception 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 or postmenopausal;
    a) 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 (FSH) 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
    b) highly effective methods of birth control include: not having intercourse or using birth control methods that work at least 99% of the time when used correctly and include: birth control pills, shots, implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide

    For the rest of the exclusion criteria (20 to 29) please refer to the current protocol
    1) storia di ictus emorragico
    2) Storia personale o familiare di malattie muscolari ereditarie
    3) NYHA III o IV, insufficienza cardiaca , o l'ultima nota di frazione di eiezione ventricolare sinistra ( FEVS ) <30 %
    4) grave aritmia cardiaca non controllata definita come ricorrente e
    tachicardia ventricolare altamente sintomatica , fibrillazione atriale con rapida
    risposta ventricolare o tachicardia sopraventricolare che non sono
    controllati da farmaci , negli ultimi 3 mesi prima della randomizzazione
    5) infarto del miocardio, angina instabile, intervento coronarico percutaneo
    (PCI ), intervento di bypass coronarico (CABG ) o ictus entro 3 mesi prima della randomizzazione
    6) chirurgia cardiaca o rivascolarizzazione
    7) Il diabete di tipo 1, tipo 2 diabete scarsamente controllato ( HbA1c > 8,5% ),
    diabete di tipo 2 di nuova diagnosi (entro 6 mesi dalla randomizzazione) , o
    prove di laboratorio del diabete durante lo screening (glicemia a digiuno
    ≥ 126 mg / dl [ 7,0 mmol / L] o HbA1c ≥ 6,5 % ) senza la previa diagnosi di
    diabete
    8) l'ipertensione non controllata definita come pressione arteriosa sistolica seduta
    (SBP) > 160 mmHg o pressione diastolica (DBP) > 100 mmHg
    9) Soggetto che ha preso nelle ultime 4 settimane prima dello screening di LDL- C
    lievito di riso rosso , > 200 mg / die niacina , o prescrizione lipidi - disciplinare
    farmaci (ad esempio , fibrati e derivati ) diversi dalle statine , l'ezetimibe , bileacid
    resina sequestrante , o stanoli e esteri di stanoli
    10) Soggetto che ha preso una proteina di trasferimento cholesterylester (CETP)
    inibitore negli ultimi 12 mesi precedenti lo screening di LDL- C , come ad esempio:
    anacetrapib , dalcetrapib o evacetrapib .
    11) Il trattamento negli ultimi 3 mesi precedenti lo screening di LDL- C con qualsiasi
    dei seguenti farmaci: ciclosporina sistemica, steroidi sistemici (ad esempio IV,
    intramuscolare o PO ) ( Nota [ IM ]: la terapia ormonale sostitutiva è consentita), derivati della vitamina A e retinolo derivati per il trattamento di condizioni dermatologiche (es. Accutane); (Nota: vitamina A in preparato multivitaminico è consentita)
    12) ipotiroidismo o ipertiroidismo non controllato come definito dall’
    ormone stimolante la tiroide ( TSH ) < 1,0 volta il limite inferiore del normale
    o > 1,5 volte il limite superiore normale allo screening. I potenziali soggetti con
    TSH < 1.0 volta rispetto al normale a causa della sostituzione della tiroide
    non sono considerati in esclusione.
    13) da moderata a grave disfunzione renale, definita come una stima di
    velocità di filtrazione glomerulare ( eGFR ) <30 ml/min/1.73m2 allo screening
    14) Malattie del fegato attiva o disfunzione epatica , definita come aspartato
    aminotransferasi ( AST ) e alanina aminotransferasi ( ALT) > 2 volte rispetto a
    ULN come determinato da analisi di laboratorio centrale allo screening
    15) infezione attiva nota o disfunzioni maggiori ematologiche, renali , metaboliche,
    disfunzioni gastrointestinali o endocrine a giudizio dello sperimentatore
    16) La diagnosi di trombosi venosa profonda o embolia polmonare entro 3
    mesi precedenti la randomizzazione
    17) Inaffidabilità come partecipante allo studio in base alla conoscenza dello sperimentatore ricercatore (ad esempio alcool o droghe, incapacità o mancanza di volontà di aderire al protocollo, psicosi )
    18) attualmente iscritti in un altro studio sperimentale farmacologico o con dispositivi medici, o meno di 30 giorni dalla conclusione di un altro studio, o l’assunzione di un altro agente sperimentale.
    19) soggetto femminile che ha o (1) non utilizzato almeno 1
    metodo contraccettivo altamente efficace per almeno 1 mese prima dello screening
    o ( 2 ) non è disposto ad utilizzare tale metodo durante il trattamento e per
    ulteriori 15 settimane dopo la fine del trattamento, a meno che il soggetto sia
    sterilizzato o in post-menopausa;
    a) menopausa è definita come: 12 mesi di spontanea e continua amenorrea in donne ≥ 55 anni o 12 mesi di spontanea e continua amenorrea con un livello di ormone follicolo-stimolante (FSH) > 40 IU / L (o secondo la definizione di "range postmenopausale " per
    il laboratorio coinvolto) in una femmina < 55 anni a meno che il soggetto
    sia stato sottoposto ad ovariectomia bilaterale
    b ) metodi altamente efficaci di controllo delle nascite sono: non avere
    rapporti sessuali o usare metodi anticoncezionali che funzionano almeno il 99 % del
    tempo se usati correttamente e comprendono: pillola anticoncezionale, impianti
    o patch , dispositivi intrauterini (IUD) , legatura delle tube / occlusione , attività sessuali con un partner di sesso maschile che ha avuto una vasectomia, preservativo o
    cappuccio occlusivo (diaframma o cappucci cervicali / vault) utilizzato con spermicida
    Per il resto dei criteri di esclusione ( 20 a 29 ) si rimanda al attuale protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Coprimary endpoints are:
    1) Mean percent change from baseline in LDL-C at Weeks 22 and 24 of Part B
    2) Percent change from baseline in LDL-C at Weeks 24 of Part B
     Variazione percentuale media rispetto al basale dei valori di LDL-C alle Settimane 22 e 24 della Parte B
     Variazione percentuale rispetto al basale dei valori di LDL-C alla Settimana 24 della Parte B
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Week 22 and Week 24 of Part B of the study design
    2) Week 24 of Part B
    1) settimana 22 e 24 della parte B dello studio
    2) settimana 24 della parte B
    E.5.2Secondary end point(s)
    Co-secondary endpoints of the means at Weeks 22 and 24 of Part B and at Week 24 of Part B for:
    Tier 1 endpoints
    • Change from baseline in LDL-C
    • LDL-C response (LDL-C < 70 mg/dL [1.81 mmol/L])
    • Percent change from baseline in total cholesterol
    • Percent change from baseline in non-HDL-C
    • Percent change from baseline in ApoB
    • Percent change from baseline in the total cholesterol/HDL-C ratio
    • Percent change from baseline in ApoB/ApoA1 ratio

    Tier 2 endpoints
    • Percent change from baseline in Lp(a)
    • Percent change from baseline in triglycerides
    • Percent change from baseline in HDL-C
    • Percent change from baseline in VLDL-C
    Endpoint co-secondari delle medie rilevate alle Settimane 22 e 24 e alla Settimana 24 della Parte B per:

    - Livello 1
    - Variazione rispetto al basale dei valori di LDL-C
    - Risposta delle LDL-C (LDL-C <70 mg/dL [1,81 mmol/L])
    - Variazione percentuale rispetto al basale dei valori di colesterolo totale
    - Variazione percentuale rispetto al basale dei valori di non HDL-C
    - Variazione percentuale rispetto al basale dei valori di ApoB
    - Variazione percentuale rispetto al basale del rapporto colesterolo totale/HDL-C
    - Variazione percentuale rispetto al basale del rapporto ApoB/ApoA1

    Livello 2
    - Variazione percentuale rispetto al basale dei valori di Lp(a)
    - Variazione percentuale rispetto al basale dei valori dei trigliceridi
    - Variazione percentuale rispetto al basale dei valori di HDL-C
    - Variazione percentuale rispetto al basale dei valori di VLDL-C
    E.5.2.1Timepoint(s) of evaluation of this end point
    The means at Weeks 22 and 24 of Part B and at Week 24 of Part B
    La media alla settimana 22 e 24 della parte B e la settimana 24 della parte B
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    This a 3 part study: please refer to the protocol for the design of parts A to C
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Canada
    Denmark
    France
    Italy
    Netherlands
    New Zealand
    Norway
    Australia
    Czech Republic
    Germany
    South Africa
    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
    End of Trial is defined in the protocol as all enrolled subjects in Part C of the study have either completed all the scheduled visits in Part C or have early terminated from the study
    Per fine dello studio si intende il momento in cui tutti i pazienti arruolati nella parte C dello studio hanno completato le visite previste dalla parte C o hanno terminato anticipatamente lo studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 210
    F.4.2.2In the whole clinical trial 500
    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)
    None
    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 Decision2014-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-21
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