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    Summary
    EudraCT Number:2017-004299-69
    Sponsor's Protocol Code Number:ARCHITECT
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-14
    Trial 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 number2017-004299-69
    A.3Full title of the trial
    Low interventional, open and multicentric clinical trial to evaluate the effect of alirocumab on volume, architecture and composition of atheroma plaque in patients with familial hypercholesterolemia from SAFEHEART registry. ARCHITECT study
    Ensayo clínico de bajo nivel de intervención, abierto y multicéntrico para evaluar el efecto de alirocumab sobre el volumen, la arquitectura y la composición de la placa aterosclerótica en pacientes con Hipercolesterolemia Familiar del Registro SAFEHEART. Estudio ARCHITECT.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Low interventional, open and multicentric clinical trial to evaluate the effect of alirocumab on volume, architecture and composition of atheroma plaque in patients with familial hypercholesterolemia from SAFEHEART registry. ARCHITECT study
    Ensayo clínico de bajo nivel de intervención, abierto y multicéntrico para evaluar el efecto de alirocumab sobre el volumen, la arquitectura y la composición de la placa aterosclerótica en pacientes con Hipercolesterolemia Familiar del Registro SAFEHEART. Estudio ARCHITECT.
    A.3.2Name or abbreviated title of the trial where available
    ARCHITECT
    ARCHITECT
    A.4.1Sponsor's protocol code numberARCHITECT
    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 SponsorFundación Hipercolesterolemia Familiar
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSanofi Aventis
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDynamic Science
    B.5.2Functional name of contact pointDynamic Science
    B.5.3 Address:
    B.5.3.1Street AddressC/Azcona, 31
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28028
    B.5.3.4CountrySpain
    B.5.4Telephone number34914561105
    B.5.5Fax number34914561126
    B.5.6E-mailc.romera@dynasolutions.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 Yes
    D.2.1.1.1Trade name Praluent
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Aventis Groupe
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 namealirocumab
    D.3.4Pharmaceutical form Solution for injection
    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 INNalirocumab
    D.3.9.3Other descriptive nameALIROCUMAB
    D.3.9.4EV Substance CodeSUB170596
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heterozygous familial hypercholesterolemia
    Hipercolesterolemia familiar heterocigota
    E.1.1.1Medical condition in easily understood language
    Familial hypercholesterolemia
    Hipercolesterolemia familiar
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10057099
    E.1.2Term Heterozygous familial hypercholesterolaemia
    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 alirocumab on coronary atherosclerotic burden in terms of the change in percent atheroma volume (PAV) by means of atherosclerotic plaque quantification and virtual histology of the coronary tree based on the analysis of coronary computed tomography (CCTA) on asymptomatic FH patients receiving optimized and stable treatment with maximum tolerated doses of statins in combination or not with other lipid-lowering drugs.
    Evaluar el efecto de alirocumab en la carga de aterosclerosis coronaria, en base al cambio en el porcentaje de volumen de ateroma (PVA) mediante la cuantificación de la placa de ateroma y la histología virtual en todo el árbol coronario basándose en al análisis del AngioTAC coronario (ATC) en sujetos asintomáticos con HF en tratamiento optimizado y estable con las máximas dosis toleradas de estatinas con o sin otros tratamientos hipolipemiantes
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of alirocumab on the change of the normalized atheroma total volume (ATV)
    - To determine the percentage of patients that showed plaque regression
    - To evaluate the effect of alirocumab on the architecture and composition of the coronary wall
    - To evaluate the prevalence of basal aortic valve calcification and progression of calcification along the study
    - To evaluate the changes on lipid profile and Lp(a) levels along the study
    - To evaluate the security profile of alirocumab on daily practice
    - To evaluate the incidence and types of cardiovascular events during alirocumab treatment
    - Evaluar el efecto de alirocumab sobre el cambio en el volumen total del ateroma (VTA) normalizado.
    - Determinar el porcentaje de pacientes que demostraron la regresión de la placa.
    - Evaluar el efecto de alirocumab en la composición y arquitectura de la pared coronaria.
    - Evaluar la prevalencia de la calcificación basal de la válvula aórtica y el progreso de la calcificación durante el estudio.
    - Evaluar el cambio en el perfil lipídico y en los niveles de Lp(a) durante el estudio.
    - Evaluar el perfil de seguridad de alirocumab en condiciones de práctica clínica.
    - Evaluar la incidencia y el tipo de eventos cardiovaculares durante el tratamiento con alirocumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent before the beginning of specific trial procedures
    - ;ail or female patients, aged between 35 and 65 years
    - Patients with molecular diagnostic of Familial Hypercholesterolemia, enrolled on spanish registry SAFEHEART
    - Asymptomatc patients
    - Patients without previous history of clinical cardiovascular events (myocardial acute infarction, stroke, coronary revascularization...)
    - Patiens receiving optimized and stable treatment with maximum tolerated doses of statins in combination or not with other lipid-lowering drugs during at least three months, with inappropiate control, defined by cLDL>100mg/dl
    - Patiens with PAV > 30% on basal coronary ACT, carried out on the last three months before basal visit
    - Patients with indication of alirocumab 150 mg/ml treatment, according to patient's characteristics and technical data sheet
    - Haber otorgado voluntariamente el consentimiento informado antes de la realización de los procedimientos específicos del ensayo.
    - Pacientes de ambos sexos, con edades comprendidas entre los 35 y los 65 años
    - Pacientes con diagnóstico molecular de Hipercolesterolemia Familiar heterocigota incluidos en le registro español SAFEHEART
    - Pacientes asintomáticos
    - Pacientes sin historia previa de acontecimientos cardiovasculares clínicos (infarto agudo de miocardio, ictus, revascularización coronaria...)
    - Pacientes en tratamiento optimizado y estable con dosis máximas toleradas de una estatina con o sin otras terapias hipolipemiantes, durante al menos 3 meses, con un control inadecuado, definido por un nivel de cLDL>100 mg/dl
    - Pacientes con PVA >30% en el ATC coronario basal, realizado en los 3 últimos meses antes de la visita basal
    - Pacientes en los que está indicado el tratamento con alirocumab 150mg/ml, de acuerdo con las características del paciente y la ficha técnica de Praluent
    E.4Principal exclusion criteria
    - Class >II cardiac insufficiency according to NYHA scale (New York Heart Association)
    - Cardiac Rhythm different to normal sinus rhythm (regular CF betwen 60-100 beat per min)
    - Previous history of myocardial acute infarction, peripheral arterial thrombosis, stroke or transient ischemic attack
    - Uncontrolled Hypertension, defined as systolic pressure value at rest >180mmHg at basal visit
    - Fast triglycerides >250 mg/dl at baseline
    - Type 1 or type 2 diabetes poorly controlled (HB1A>9%)
    - History of hereditary muscular disorders
    - Thyroid disease or thyroid hormone replacement therapy
    - Glomerular filtration rate < 60 ml/min/1,73m2 at baseline
    - High levels of AST and/or ALT (>3 ULN levels at baseline)
    - High levels of creatinine kinase (>3 ULN at baseline)
    - Patients that have been treated previously with IPCSK9, CETP inhibitors, mipomersen and/or lomitapide
    - Statin-intolerant patients
    - Active cancer disease or previous history of cancer
    - Active clinically relevant infections or significative hematologycal, metabolic, gastrointestinal, endocrine or kidney dysfunction
    - Availability of coronary angioCT at baseline that does not fulfill technical requisites for being processed with QAngio CT software
    - Patients enrolled in clinical trials, except in case that study treatment has been discontinued more than 6 months before the beginning of the study
    - Pregnant or lactating women, or fertile women that are not willing to use an appropiate anticonceptive method
    • Insuficiencia cardiaca de clase >II de acuerdo a la clasificación funcional de la escala NYHA (de sus siglas en inglés de New York Heart Association).
    • Ritmo cardiaco diferente al ritmo sinusal normal (FC regular entre 60-100 lpm).
    • Historia previa de IAM, angina, trombosis arterial periférica, ictus o accidente isquémico transitorio (AIT).
    • Hipertensión no controlada definida como un valor de presión arterial sistólica en reposo >180 mmHg en la visita basal.
    • Niveles de triglicéridos en ayuno >250 mg/dl en la visita basal.
    • Diabetes tipo 1 o diabetes tipo 2 insuficientemente controlada (HbA1 >9%).
    • Historia personal o familiar de trastornos musculares hereditarios.
    • Enfermedad tiroidea conocida o terapia de sustitución tiroidea.
    • Tasa de filtrado glomerular <60 ml/min/1,73 m2 en la visita basal.
    • Niveles de ALT y/o AST elevados (>3 veces el LSN en la visita basal).
    • Niveles de creatinina kinasa elevados (>3 veces el LSN en la visita basal).
    • Pacientes que hayan recibido previamente iPCSK9, inhibidores de la CETP (proteína transportadora de ésteres de colesterol), mipomersen y/o lomitapide.
    • Pacientes con intolerancia a estatinas.
    • Cancer activo o historia previa de cáncer.
    • Infección clínicamente relevante activa o disfunción hematológica, renal, metabólica, gastrointestinal o endocrina clínicamente significativa.
    • Disponibilidad de un ACT coronario basal que no reúna los requisitos técnicos necesarios para que las imágenes sean procesadas adecuadamente mediante el software QAngio CT.
    • Paciente en tratamiento con cualquier medicamento/producto en investigación o que se encuentre participando en un ensayo clínico que utilice un producto en investigación, con la excepción de estudios en los que el tratamiento de estudio haya finalizado hace más de 6 meses.
    • Mujeres embarazadas o en periodo de lactancia, y mujeres en edad fértil y sexualmente activas que no estén dispuestas a utilizar un método anticonceptivo adecuado (como anticonceptivos orales, dispositivo intrauterino o método de barrera anticonceptivo junto con espermicida o esterilización quirúrgica) durante el estudio. Se definen mujeres en edad fértil como aquellas mujeres que no hayan sido sometidas a procedimientos de infertilidad permanente o que sean amenorreicas desde hace menos de 12 meses.
    E.5 End points
    E.5.1Primary end point(s)
    Change in percent of atheroma volume (PAV) of the coronary tree between baseline (before the initiation of alirocumab) and 18 months after the beginning of alirocumab, based on angio CT images, analyzed with QAngio TC software
    Valoración del cambio en el PVA, en todo el árbol coronario desde la valoración basal (antes del inicio del tratamiento con alirocumab) hasta 18 meses después del inicio del tratamiento con alirocumab, en base a las imágenes del ATC analizadas mediante el software QAngio TC
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baselline and 18 months after the beginning of treatment
    Visita basal y 18 meses tras el inicio del tratamiento
    E.5.2Secondary end point(s)
    - Change on normalized VTA, based on ACT images at baseline and at 18 months after the beginning of alirocumab
    - Percentage of patients presenting atherosclerotic plaque regression 18 months after the beginning of alirocumab, based on percentage of patients showing PAV reduction or any VTA reduction from baseline
    - Changes in composition and architecture of atherosclerotic plaque, based on volume and percentage of fibrotic plaque, fibrofatty plaque, necrotic plaque and calcified plaque, form baseline to 18 months
    - Percentage of patients with aortic valve calcification and changes on calcium score, based on cuantitative measure of calcium in the aortic valve using Agatson method, based on coronary CT images without contrast administration, form baseline to 18 months
    - Change on cLDL and Lp(a) levels from baseline to 18 months after the beginning of alirocumab treatment
    - Safety profile of alirocumab, based on the development of adverse events in patients form baseline to final visit, including anomalous laboratory values, anomalies on examination or clinical AE
    - Incidence and type of cardiovascular events which have taken place during alirocumab treatmen, including death for ischemic cardiopathy, myocardial infarct, stroke, hospitalization for unstable angina or unplanned revascularization
    • Cambio en el VTA normalizado (mm3) medido en base a las imágenes del ATC desde la valoración basal (antes del inicio del tratamiento) hasta 18 meses después del inicio del tratamiento con alirocumab (visita final).
    • Porcentaje de pacientes que presentan regresión de la placa de ateroma a los 18 meses del inicio del tratamiento con alirocumab, en base al porcentaje de pacientes que muestran cualquier reducción de PVA y cualquier reducción de VTA desde la valoración basal.
    • El cambio en la composición y arquitectura de la placa de ateroma se evaluará en función del volumen y el porcentaje de la placa fibrosa, la placa fibro-grasa, la placa necrótica y la placa cálcica desde la valoración basal a los 18 meses (visita final).
    • Porcentaje de pacientes con calcificación de la válvula aórtica y cambio en el score de calcio mediante la valoración cuantitativa del calcio en la válvula aórtica en base al método de Agatston a través de la adquisición previa de imágenes por ATC coronario sin administración de contraste desde la valoración basal (antes del inicio del tratamiento) hasta los 18 meses después del inicio del tratamiento con alirocumab (visita final).
    • Cambio en los niveles de cLDL desde la visita selección/basal hasta los 18 meses después del inicio del tratamiento con alirocumab, y cambio de los niveles de Lp(a) desde la valoración basal a los 18 meses.
    • El perfil de seguridad del tratamiento con alirocumab en condiciones de práctica clínica se evaluará en base los acontecimientos adversos (AAs) que experimenten los pacientes desde el inicio del tratamiento hasta la visita final del paciente, incluyendo valores anómalos de laboratorio, anomalías registradas en la exploración física, y AAs clínicos.
    La seguridad del tratamiento de analizará en función de los siguientes parámetros:
     Incidencia y gravedad de AAs y acontecimientos adversos graves (AAGs) clínicos y de laboratorio.
     Porcentaje de muertes relacionadas o no con el tratamiento.
     Porcentaje de pacientes en los que se discontinúa el tratamiento debido a un AA.
    • Incidencia y tipo de acontecimientos cardiovasculares clínicos que hayan sufrido los pacientes durante el tratamiento con alirocumab, incluyendo muerte por cardiopatía isquémica, infarto de miocardio, ictus isquémico, hospitalización por angina inestable, o revascularización no planificada.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, 3, 12 and 18 months
    Visita basal, 3, 12 y 18 meses
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned25
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 del último 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 months0
    E.8.9.1In the Member State concerned 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: 162
    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 state162
    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 Decision2018-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-11
    P. End of Trial
    P.End of Trial StatusOngoing
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