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    Summary
    EudraCT Number:2014-002277-11
    Sponsor's Protocol Code Number:20120123
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-06-10
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2014-002277-11
    A.3Full title of the trial
    Double-blind, Randomized, Multicenter, Placebo-Controlled, Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for Low Density Lipoprotein-Cholesterol (LDL-C) Reduction, as Add-On to Diet and Lipid-Lowering Therapy, in Pediatric Subjects 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH)
    Estudio aleatorizado, doble ciego, multicéntrico, controlado con placebo y de grupos paralelos para describir la eficacia, seguridad y tolerabilidad de evolocumab administrado durante 24 semanas, como tratamiento adyuvante de la dieta y del tratamiento hipolipemiante, en la reducción del colesterol ligado a lipoproteínas de baja densidad (C-LDL) en sujetos pediátricos de 10 a 17 años de edad con hipercolesterolemia familiar heterocigota (HFHe)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the long term safety and efficacy of evolocumab in children aged 10 to 17 years with Heterozygous Familial Hypercholesterolemia
    Estudio para evaluar a largo plazo la seguridad y eficacia de evolocumab en niños de 10 a 17 años de edad con hipercolesterolemia familiar heterocigota.
    A.4.1Sponsor's protocol code number20120123
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/127/2013
    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.5.4Telephone number+34900 850 153
    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 nameEvolocumab
    D.3.2Product code AMG 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 INNEvolocumab
    D.3.9.3Other descriptive nameAMG145
    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 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.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 hypercholesterolaemia
    hipercolesterolemia familiar heterocigota
    E.1.1.1Medical condition in easily understood language
    Increased cholesterol in the blood
    Incremento de Colesterol en Sangre
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    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 24 weeks of subcutaneous (SC) evolocumab compared with placebo, when added to standard of care, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH).
    Evaluar el efecto de añadir evolocumab por vía subcutánea (SC) durante 24 semanas al tratamiento estándar, en comparación con placebo, en el cambio porcentual desde el nivel basal del colesterol ligado a lipoproteínas de baja densidad (C-LDL) en sujetos pediátricos de 10 a 17 años de edad con HFHe
    E.2.2Secondary objectives of the trial
    ? to evaluate the safety of SC evolocumab compared with placebo, when added to standard of care, in pediatric subjects 10 to 17 years of age with HeFH
    ? to assess the effects of SC evolocumab compared with placebo, when added to standard of care, on mean percent change from baseline to weeks 22 and 24 and change from baseline to week 24 in LDL-C, and on percent change from baseline to week 24 in other lipid parameters in
    pediatric subjects 10 to 17 years of age with HeFH
    ? To characterize PK exposure
    - Evaluar la seguridad de añadir evolocumab por vía SC al tratamiento estándar, en comparación con placebo, en sujetos pediátricos de 10 a 17 años de edad con HFHe.
    - Evaluar los efectos de añadir evolocumab por vía SC al tratamiento estándar, en comparación con placebo, en el cambio porcentual medio del C-LDL entre el nivel basal y las semanas 22 y 24, en el cambio del C-LDL entre el nivel basal y la semana 24, y en el cambio porcentual entre el nivel basal y la semana 24 del colesterol ligado a lipoproteínas de no alta densidad (C-no-HDL), la apolipoproteína B (ApoB), la relación colesterol total/C-HDL y la relación ApoB/apolipoproteína A-1 (ApoA1) en sujetos pediátricos de 10 a 17 años de edad con HFHe.
    - Describir la exposición PK.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Subject has provided informed consent or subject assent prior to initiation of any study-specific activities/procedures.
    and/or
    - Subject?s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written subject assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
    - Male or female, ? 10 to ? 17 years of age at time of randomization (includes the year after the subject completes the 17th year after birth but not the day of completing the 18th year after birth).
    -Diagnosis of heterozygous familial hypercholesterolemia by local applicable diagnostic criteria for HeFH (ie, criteria outlined by the Simon Broome Register Group [Scientific Steering Committee, 1991] or the Dutch Lipid Clinic Network [World Health Organization, 1999]) or by genetic testing.
    - On an approved statin with stable dose for ? 4 weeks before LDL-C screening and, in the opinion of the investigator, not requiring up-titration.
    - El sujeto ha proporcionado el consentimiento informado o el asentimiento del sujeto antes de iniciar cualquier procedimiento/actividad específico del estudio.
    y/o
    - El representante legal autorizado del sujeto ha dado su consentimiento informado cuando el sujeto es legalmente demasiado joven para dar su consentimiento informado y el sujeto ha proporcionado su asentimiento por escrito de acuerdo con las normativas y/o directrices locales antes de iniciar cualquier actividad/procedimiento específico del estudio.
    - Hombre o mujer de ? 10 a ? 17 años de edad en el momento de la aleatorización (incluye el año después de que el sujeto cumpla los 17 años, pero no el día que cumple los 18 años).
    - Diagnóstico de hipercolesterolemia familiar heterozigota según los criterios diagnósticos locales aplicables para la HFHe (es decir, los criterios descritos por el Simon Broome Register Group [Scientific Steering Committee, 1991] o la Dutch Lipid Clinic Network [World Health Organization, 1999]) o mediante pruebas genéticas.
    - En tratamiento con una estatina aprobada a dosis estables durante ? 4 semanas antes de la determinación del C-LDL de selección y que a criterio del investigador no necesita ajuste ascendente de la dosis.
    - Si está recibiendo cualquier otro tratamiento hipolipemiante (p. ej., ezetimiba, resinas secuestradoras de ácidos biliares, ácidos grasos omega 3 o niacina), este tratamiento no debe cambiarse durante ? 4 semanas antes de la determinación del C-LDL de selección; los fibratos deben mantenerse estables durante al menos 6 semanas antes de la selección.
    - C-LDL en ayunas en la selección ? 130 mg/dL (3,4 mmol/L), determinado en el laboratorio central.
    - Triglicéridos en ayunas ? 400 mg/dL (4,5 mmol/L), determinados en el laboratorio central en la selección.
    E.4Principal exclusion criteria
    - Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%) or newly diagnosed impaired glucose tolerance (within 3 months of randomization).
    - Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at screening.
    - Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening, confirmed by a repeat measurement at least 1 week apart.
    - Persistent 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, confirmed by a repeat measurement at least 1 week apart.
    - Diabetes tipo 1, o diabetes de tipo 2 recién diagnosticada (en los 3 meses anteriores a la aleatorización) o mal controlada (HbA1c > 8,5%), o intolerancia a la glucosa recientemente diagnosticada (en los 3 meses anteriores a la aleatorización).
    - Hipertiroidismo o hipotiroidismo no tratados o no tratados adecuadamente, definidos como hormona estimulante del tiroides (TSH) < al límite inferior de la normalidad (LIN) o > 1,5 veces el límite superior de la normalidad (LSN), respectivamente, y niveles de tiroxina (T4) libre fuera del límite normal en la selección.
    - Insuficiencia renal grave o moderada, definida como una tasa de filtración glomerular estimada (TFGe) < 30 mL/min/1,73 m2 en la selección, confirmada mediante mediciones repetidas con 1 semana de separación como mínimo.
    - Enfermedad hepática activa persistente o disfunción hepática, definida por aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) > 2,0 veces el límite superior de la normalidad, determinadas mediante análisis en el laboratorio central en la selección y confirmadas mediante mediciones repetidas con 1 semana de separación como mínimo.
    - CK > 3 veces el LSN en la selección, confirmada mediante mediciones repetidas con 1 semana de separación como mínimo.
    - Infección activa conocida o disfunción importante hematológica, renal, metabólica, gastrointestinal o endocrina a criterio del investigador.
    - Falta de fiabilidad como participante del estudio según los conocimientos del investigador (o persona designada) sobre el sujeto (por ejemplo, abuso de alcohol y otras drogas en el último año, incapacidad o falta de voluntad de seguir el protocolo, o psicosis).
    - El sujeto ha sido tratado con inhibidores de la proteína de transferencia de ésteres de colesterol (CETP) como anacetrapib, dalcetrapib, evacetrapib en los últimos 12 meses, o con mipomersen o lomitapida en los últimos 5 meses previos a la determinación del C-LDL de selección.
    - El sujeto ha recibido previamente evolocumab o cualquier otro tratamiento en investigación para inhibir la PCSK9.
    - Estar recibiendo actualmente tratamiento en otro estudio de un fármaco o dispositivo en investigación o haber transcurrido menos de 30 días desde el fin del tratamiento en otro estudio de un fármaco o dispositivo en investigación. Están excluidos otros procedimientos o tratamientos experimentales durante la participación en este estudio.
    - Las mujeres que han experimentado la menarquia y no están dispuestas a utilizar métodos anticonceptivos aceptables y eficaces durante el tratamiento con el PI (evolocumab o placebo) y durante 15 semanas más después del final del tratamiento con el PI (evolocumab o placebo). Una mujer que ha experimentado la menarquia se considera en edad fértil.
    Los métodos aceptables para prevenir el embarazo incluyen: abstinencia sexual verdadera cuando esto está en consonancia con el estilo de vida preferido y habitual del sujeto (la abstinencia periódica [p. ej., métodos de calendario, ovulación, sintotérmico y posovulación], la declaración de abstinencia durante la duración del estudio y la marcha atrás no son métodos anticonceptivos aceptables), o el uso de métodos anticonceptivos hormonales (oral, implantable, inyectable, transdérmico, intravaginal), dispositivos intrauterinos (DIU), sistema intrauterino (SIU) de liberación hormonal o de dos (2) métodos de barrera (uno para cada miembro de la pareja y al menos uno de los métodos de barrera debe incluir espermicida, a menos que el espermicida no esté aprobado en el país o región; el hombre debe usar un condón y la mujer debe elegir ya sea un diafragma, un capuchón cervical O una esponja anticonceptiva. Nota: no se puede utilizar conjuntamente un preservativo femenino y otro masculino debido al riesgo de rotura de uno de los preservativos.).
    Nota: si se administra medicación adicional durante el tratamiento que puede alterar los requisitos de anticonceptivos (esta medicación adicional puede requerir un aumento del número de métodos anticonceptivos y/o del tiempo de uso de los anticonceptivos después de la última dosis de los tratamientos requeridos por el protocolo) el investigador comentará estos cambios con el sujeto del estudio.
    - Sujeto femenino con una prueba de embarazo positiva.
    - Mujer embarazada o en período de lactancia, o que planee quedarse embarazada o amamantar durante la selección, durante el tratamiento con el PI (evolocumab o placebo) y en las 15 semanas posteriores al fin del tratamiento con el PI (evolocumab o placebo).
    Para resto de Criterios ver Protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Percent change from baseline to week 24 in LDL-C
    Cambio porcentual del C-LDL entre el nivel basal y la semana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and week 24
    Nivel Basal y la semana 24
    E.5.2Secondary end point(s)
    Mean percent change from baseline to weeks 22 and 24 in LDL-C
    Change from baseline to week 24 in LDL-C
    Percent change from baseline to week 24 in the following:
    - non-HDL-C
    - ApoB
    - total cholesterol/HDL-C ratio
    - ApoB/ApoA1 ratio
    Cambio porcentual medio del C-LDL entre el nivel basal y las semanas 22 y 24.
    Cambio del C-LDL entre el nivel basal y la semana 24.
    Cambio porcentual entre el nivel basal y la semana 24 en los siguientes parámetros:
    - C-no-HDL
    - ApoB
    - Relación colesterol total/C-HDL
    - Relación ApoB/ApoA1
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, week 22 and week 24
    Nivel Basal, la semana 22 y la semana 24
    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 No
    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 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 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 trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Brazil
    Canada
    New Zealand
    South Africa
    Turkey
    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
    LVLS
    Última visita, ultimo paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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 Yes
    F.1.1Number of subjects for this age range: 150
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 135
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 150
    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
    Ninguno
    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 Decision2015-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-11-25
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