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    Summary
    EudraCT Number:2019-003360-45
    Sponsor's Protocol Code Number:38RC19.186
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-12-04
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-003360-45
    A.3Full title of the trial
    Effect of impact of PCSK9 inhibitor on coronary microvascular dysfunction in patients with atherosclerotic cardiovascular disease proved by myocardial ischemia and needing coronarography.
    Évaluation de l’impact des anticorps monoclonaux anti--proprotéine convertase subtilisine/kexine de type 9 (PCSK9), sur le dysfonctionnement microvasculaire coronarien chez les patients atteints d’une maladie cardiovasculaire athérosclérotique, prouvée par une ischémie myocardique nécessitant une coronarographie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of impact of PCSK9 inhibitor on coronary microvascular dysfunction in patients with atherosclerotic cardiovascular disease proved by myocardial ischemia and needing coronarography.
    Évaluation de l’impact des anticorps monoclonaux anti--proprotéine convertase subtilisine/kexine de type 9 (PCSK9), sur le dysfonctionnement microvasculaire coronarien chez les patients atteints d’une maladie cardiovasculaire athérosclérotique, prouvée par une ischémie myocardique nécessitant une coronarographie.
    A.3.2Name or abbreviated title of the trial where available
    MICROPROTECT
    MICROPROTECT
    A.4.1Sponsor's protocol code number38RC19.186
    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 SponsorUniversity Hospital Grenoble
    B.1.3.4CountryFrance
    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 supportSociété française de Cardiologie
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Grenoble
    B.5.2Functional name of contact pointTinaig le Costaouec
    B.5.3 Address:
    B.5.3.1Street AddressCS 10217
    B.5.3.2Town/ cityGrenoble
    B.5.3.3Post code38043
    B.5.3.4CountryFrance
    B.5.4Telephone numberFranc+3304 76 76 88 13
    B.5.5Fax numberFranc+3304 76 76 52 21
    B.5.6E-mailarcpromoteur@chu-grenoble.fr
    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 Repatha
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical 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.3.11 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) 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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    atherosclerotic cardiovascular disease
    maladie cardiovasculaire athérosclérotique
    E.1.1.1Medical condition in easily understood language
    coronary artery disease (narrowing and obstruction)
    maladie des artères coronaires (rétrécissement et formation de plaques)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare coronary microvascular dysfunction (CMVD) 4-week after a single administration with evolocumab or without treatment, in patients with atherosclerotic cardiovascular disease proved by myocardial ischemia and needing coronarography.
    Comparer la fonction microvasculaire coronarienne 4 semaines après un traitement par administration unique d’evolocumab ou en l’absence de traitement, chez les patients présentant une ischémie myocardique identifiée par scintigraphie myocardique et nécessitant une coronarographie.
    E.2.2Secondary objectives of the trial
    - To analyse the impact of a PCSK9 inhibitor treatment on soluble VE-cadherin rate (sVE).
    - To analyse the impact of a PCSK9 inhibitor treatment on brachial hyperemia (HB).
    - To compare the rate of periprocedural myocardial infarction (MI) in the evolocumab and no treatment groups.
    - To analyze the correlations between invasive and non-invasive (myocardial scintigraphy - myocardial perfusion entropy (MPE), concentration of sVE, HB) measurements of coronary microvascular dysfunction.
    - To analyze the correlations between the cardiovascular risk on the one hand, and the concentration of sVE and MPE on the other hand.
    - Evaluer l’impact d’un traitement par anti-PCSK9 sur le taux de VE cadhérine soluble (sVE).
    - Evaluer l’impact d’un traitement par anti-PCSK9 sur l’hyperhémie brachiale (HB).
    - Comparer le taux de souffrance myocardique péri-procédurale dans les groupes évolocumab et sans traitement.
    La souffrance myocardique péri-procédurale sera définie comme un niveau de troponine post-angioplastie 10 fois supérieur au 99e percentile de la troponine I car il a été démontré que ces seuils avaient une importance pronostique dans des études antérieures .
    - Analyser les corrélations entre la mesure de fonction microvasculaire coronarienne par mesure invasive et par mesure non-invasive (scintigraphique -hétérogénéité de perfusion myocardique-, concentration de sVE et HB).
    - Analyser les corrélations entre le risque cardiovasculaire d’une part, et la concentration de sVE et l’hétérogénéité de perfusion myocardique d’autre part.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male or female patient, aged 40 to 85,
    - More than 50 kilograms
    - Defined at high cardiovascular risk according to European guidelines
    - LDL-C level ≥ 0.7 g / L (biological assessment of less than 6 months)
    - Having benefited from myocardial scintigraphy
    - For which coronarography is indicated according to European guidelines
    - Affiliated with social security,
    - Signed informed consent form
    - Patient de sexe masculin ou féminin, âgé de 40 à 85 ans,
    - Pesant plus de 50kg
    - Défini à haut risque cardiovasculaire selon les recommandations européennes,
    - Ayant un taux de LDL-C ≥ 0.7 g/L (bilan biologique de moins de 6 mois)
    - Ayant bénéficié d’une scintigraphie myocardique
    - Pour lequel la réalisation d’une coronarographie est indiquée selon les recommandations européennes
    - Affilié à la sécurité sociale,
    - Ayant donné leur consentement écrit pour participer à l’étude.
    E.4Principal exclusion criteria
    - Clinical presentation of unstable angina
    - Patient whose state of physical or psychological health could compromise the obtaining of his informed consent and his compliance with the requirements of the protocol, with the study evaluation, procedures or completion.
    - End stage disease (estimated survival of less than one year)
    - Severe renal dysfunction, defined as an estimated creatinine clearance (MDRD) < 30 mL/min at screening
    - Contra-indication to adenosin : hypersensitivity to active active substance or to any of the excipients, type II or III atrioventricular block or atrial disease (except for pacemaker users), long QT syndrome, severe arterial hypotension, acute heart failure, asthma and severe chronic obstructive pulmonary disease, unstable angina unstabilized by drug therapy, taking dipyridamole, aminophylline, theophylline or other xanthine base within 24 hours prior to adenosine administration
    - Contra-indication to heparin: hypersensitivity to active substance or to any of the excipients, past heparin induced thrombopenia type II, haemorrhage.
    - Prior CABG
    - Prior myocardial infarction in the territory of ischemia
    - NYHA class III or IV, or last known left ventricular ejection fraction < 30%
    - Known hemorrhagic stroke at any time
    - Uncontrolled or recurrent ventricular tachycardia
    - Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg
    - Actual use of PCSK9 inhibitior (evolucumab or others)
    - Untreated or inadequately treated hyperthyroidism or hypothyroidism, controlled by biological assessment if needed, 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
    - Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN at screening
    - Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
    - Personal or family history of hereditary muscular disorders
    - LDL apheresis within 12 months prior to randomization
    - CPK> 5 ULN at screening
    - Active infection or others active disease judge by investigator incompatible with the protocole completion
    - Main known active infection including positive viral serology (HIV, HBV and HCV)
    - Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
    - Known sensitivity to evolocumab or their excipients to be administered during dosing or natural rubber / latex
    - Patient likely to not be available to complete all protocol-required study visits or procedures.
    - Patient in exclusion period of another study
    - Woman able to procreate in the absence of highly effective contraception
    - Persons referred to in Articles L1121-6 to L1121-8 of the French code of public health (this corresponds to all persons protected: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure).
    - Présentation clinique d’un angor instable
    - Patient dont l’état de santé physique ou psychologique pourrait compromettre l’obtention de son consentement éclairé et sa compliance aux exigences du protocole,
    - Patient en phase terminale d’une maladie grave (survie estimée de moins d’un an),
    - Insuffisance rénale sévère définie par une clairance de la créatinine < 30 ml/min selon la formule MDRD (Modification of the Diet in Renal Disease),
    - Contre-indication à l’adénosine : hypersensibilité à la substance active ou à l’un des excipients, bloc de cœur de 2e ou 3e degré (sans un stimulateur cardiaque), maladie sinusale (sans un stimulateur cardiaque), syndrome du QT long, hypotension grave, insuffisance cardiaque décompensée, asthme et broncho-pneumopathie chronique obstructive sévère, angor instable non stabilisé par un traitement médicamenteux, prise de dipyridamole, d’aminophylline, de théophylline ou d’autre base xanthique dans les 24 heures précédant l’administration de l’adénosine
    - Contre-indication à l’héparine : hypersensibilité à la substance active ou à l’un des excipients, antécédent de thrombopénie grave de type II, hémorragies
    - Revascularisation préalable par pontage coronaire
    - Antécédent d’infarctus du myocarde connu dans le territoire de l’ischémie
    - NYHA classe III ou IV, ou dernière fraction d'éjection ventriculaire gauche connue <30%
    - AVC hémorragique connu à tout moment
    - Tachycardie ventriculaire non contrôlée ou récurrente
    - Hypertension incontrôlée définie comme pression artérielle systolique assise (SBP)> 180 mmHg ou diastolique (DBP)> 110 mmHg
    - Utilisation actuelle d’un traitement anti-PCSK9 (évolocumab ou autre)
    - Hyperthyroïdie connue non traitée ou insuffisamment traitée ou hypothyroïdie, au besoin confirmé par un bilan biologique. Une dysfonction thyroïdienne est définie par la thyroïde stimulating hormone (TSH) < limite inférieure de la normale ou > 1.5 fois la limite supérieure de la normale (LSN), respectivement, et niveau de thyroxine libre (T4L) en dehors des valeurs normales au screening
    - Maladie hépatique évolutive ou dysfonction hépatique, définie comme aspartate aminotransférase (AST) ou alanine aminotransférase (ALT)> 3 LSN au screening
    - Receveur d'une greffe majeure d'organe (p. Ex., Poumon, foie, coeur, moelle osseuse, rein)
    - Antécédents personnels ou familiaux de troubles musculaires héréditaires
    - LDL-aphérèse dans les 12 mois précédant la randomisation
    - CPK> 5 LSN
    - Infection active ou autre pathologie évolutive jugée incompatible avec la réalisation du protocole par l’investigateur
    - Principale infection active connue dont sérologie virale positive (VIH, VHB et VHC)
    - Cancer (sauf les cancers de la peau autres que les mélanomes, les carcinomes cervicaux in situ, les canaux canalaires du sein carcinome in situ ou cancer de la prostate au stade 1) au cours des 10 dernières années
    - Hypersensibilité connue à l'évolocumab ou à ses excipients ou au caoutchouc naturel / latex
    - Patient susceptible de ne pas être disponible pour effectuer toutes les visites ou procédures d'étude requises par le protocole
    - Patient en période d’exclusion d’une autre étude,
    - Femme en capacité de procréer* en l’absence de contraception hautement efficace**
    - Personnes visées aux articles L1121-6 à L1121-8 du CSP (correspond à l’ensemble des personnes protégées : femme enceinte, parturiente, mère qui allaite, personne privée de liberté par décision judiciaire ou administrative, personne faisant l’objet d’une mesure de protection légale).
    E.5 End points
    E.5.1Primary end point(s)
    Index of microcirculatory resistance (IMR), measured during invasive coronary angiography (ICA) (in mmHg.s).
    IMR mesuré au cours de la coronarographie, défini par le produit de la pression distale coronarienne par le temps moyen de transit de repos de 3 ml de solution saline à température ambiante lors d’une hyperémie induite par injection d’adénosine, et exprimé en mm Hg.s
    E.5.1.1Timepoint(s) of evaluation of this end point
    4 weeks
    4 semaines
    E.5.2Secondary end point(s)
    - sVE rate at baseline and four weeks after treatment with evolocumab or without treatment.
    - Variation of the luminal diameter of the humeral artery with baseline and four weeks after treatment with evolocumab or without treatment.
    - Troponin I level after PCI.
    - IMR, MPE, sVE and the variation of the luminal diameter of the humeral artery.
    - Risk score, sVE rate and MPE.
    - Taux de sVE cadhérine à la baseline et quatre semaines après le traitement par evolocumab ou sans traitement.
    - Variation du diamètre luminal de l’artère humérale à la baseline et quatre semaines après le traitement par evolocumab ou sans traitement.
    - Taux de troponine I après PCI.
    - IMR, MPE, sVE et variation du diamètre luminal de l’artère humérale.
    - Score de risques, taux de sVE cadhérine et MPE
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, 4 weeks after treatment with evolocumab or without treatment.
    Baseline, 4 semaines après traitement avec evolocumab ou sans traitement.
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    absence de traitement et mesure de la microcirculation coronarienne lors de la coronographie
    no treatment and measurement of coronary microcirculation during coronography
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    Last Visit Last Subject
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    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: 33
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 33
    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 state66
    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
    aucun
    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 Decision2020-01-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-18
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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