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    Summary
    EudraCT Number:2018-002623-42
    Sponsor's Protocol Code Number:66623
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-02-18
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-002623-42
    A.3Full title of the trial
    Vasospastic angina treatment by Endothelin Receptor Antagonism; a proof of concept study
    Vasospastische angina-behandeling door endotheline Receptorantagonisme; een proof of concept-studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    treatment with vasodilator of chest pain caused by spasm in the vessels of the heart
    Behandeling met een vasodilatator van pijn op de borst veroorzaakt door spasmen in de bloedvaten van het
    A.3.2Name or abbreviated title of the trial where available
    VERA
    VERA
    A.4.1Sponsor's protocol code number66623
    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 SponsorAcademic Medical Center
    B.1.3.4CountryNetherlands
    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 supportAcademic Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Mecical Center
    B.5.2Functional name of contact pointLead investigator
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.a.beijk@amc.uva.nl
    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 Opsumit (macitentan)
    D.2.1.1.2Name of the Marketing Authorisation holderActelion Registration Limited
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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) 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Vasospastic angina, i.e. epicardial vasospasm or microvascular coronary dysfunction.
    Vasospastische angina pectoris, d.w.z. epicardiale vasospasm en microvasculaire coronaire disfunctie
    E.1.1.1Medical condition in easily understood language
    Patients diagnosed with chest pain caused by spasm of the vessels of the heart.
    Patienten met pijn op de borst veroorzaakt door vaatspasme van de kransslagaders
    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 PT
    E.1.2Classification code 10002383
    E.1.2Term Angina pectoris
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to determine whether treatment with the novel ERA macitentan on top of background antianginal therapy reduces the frequency and severity of anginal complaints in patients with VSA.
    De ernst van angina pectoris, berekend als:
    1. de duur (in minuten) * ernst (op een VAS-schaal 1-10) tijdens de onderzoeksperiode tot 2 weken na het staken van de onderzoeksmedicatie;
    2. de frequentie van angina-aanvallen * ernst (op een VAS-schaal van 1-10) tijdens de onderzoeksperiode tot 2 weken na het staken van de onderzoeksmedicatie.
    E.2.2Secondary objectives of the trial
    Secondary Objective:
    1. Determination of side effects (symptoms or laboratory measurement changes) related to treatment with macitentan in patients with VSA.
    2. Difference in the occurrence of adverse events (i.e. hospitalization for anginal symptoms and/or myocardial infarction) during the study period up to 2 weeks after discontinuation of the study medication.
    3. Difference of WHO functional class
    4. Difference in Seattle Angina Questionnaire score
    Effectiviteits-eindpunt:
    • Incidentie en ernst van angina pectoris zoals verkregen door de Seattle Angina-vragenlijst tijdens de onderzoeksperiode tot 2 weken na het stopzetten van de studiemedicatie.

    Veiligheids-eindpunten:
    • Nadelige veranderingen in fysische, laboratorium- of ECG-parameters tijdens de onderzoeksperiode tot 2 weken na het staken van de studiemedicatie.
    • Het optreden van bijwerkingen (dat wil zeggen ziekenhuisopname voor angina-symptomen en / of hartinfarct) gedurende de onderzoeksperiode tot 2 weken na stopzetting van de studiemedicatie.
    Alle mogelijke bijwerkingen zullen worden geregistreerd tijdens de onderzoeksperiode tot 2 weken na stopzetting van de studiemedicatie.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following inclusion criteria:
    • Male and female patients ≥ 18 and <75 years old;
    • Patients with a high frequency (>3 times per week) and duration of anginal complaints, presumed to be caused by VSA;
    • Absence of significant obstructive coronary artery disease (defined as stenosis > 50% in an epicardial coronary artery) documented by invasive coronary angiography;
    • Supporting evidence of myocardial ischemia or spasm, defined as either:
    (a) documented dynamic ECG abnormalities during an episode of angina, or
    (b) documented troponin rise during an episode of angina, or
    (c) documented coronary spasm during invasive coronary angiography with or without acetylcholine provocation testing;
    • Anginal complaints for at least 3 months despite optimal anti-anginal treatment, which is at the discretion of the treating cardiologist.
    • Signed informed consent
    Om in aanmerking te komen voor deelname aan deze studie, moet een patient aan alle onderstaande inclusiecriteria voldoen:
    • Mannelijke en vrouwelijke patiënten ≥ 18 en <75 jaar oud;
    • Patiënten met een hoge frequentie (> 3 keer per week) en de duur van angina-klachten, vermoedelijk veroorzaakt door VSA;
    • Afwezigheid van significante obstructieve coronaire hartziekte (gedefinieerd als stenose> 50% in een epicardiale kransslagader) gedocumenteerd door invasieve coronaire angiografie;
    • Ondersteunend bewijs van myocardischemie of spasmen, gedefinieerd als:
    (a) gedocumenteerde dynamische ECG-afwijkingen tijdens een angina-episode, of
    (b) gedocumenteerde troponine-stijging tijdens een angina-episode, of
    (c) gedocumenteerde coronaire spasmen gedurende invasieve coronaire angiografie met of zonder acetylcholine provocatietesten;
    • Anginaire klachten gedurende ten minste 3 maanden, ondanks optimale anti-anginale behandeling, die ter beoordeling van de behandelende cardioloog is.
    • Ondertekende informed consent
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    • Patients who are pregnant or nursing and those who plan pregnancy in the period up to 1 months after the study;
    • Women of childbearing potential not using contraception;
    • Patients with a limited life expectancy less than one year;
    • Patients unable to provide written informed consent, or are otherwise not suitable for inclusion according to the investigator.

    Contraindication for macitentan
    • Patients with active liver disease or severe liver dysfunction with ASAT and/or ALAT >3x upper limit of normal (ULM);
    • Patients with known renal impairment (GFR<60 ml/min);
    • Patients with anemia;
    • Use of potent CYP3A4 inducers (rifampicin, St. John's wort, carbamazepine, phenytoin) due to reduced efficacy of macitentan.
    • Use of potent CYP3A4 inhibitors (itraconazole, ketoconazole, voriconazole, clarithromycin, ritonavir, saquinavir).
    Een potentiële proefpersoon die aan een van de volgende criteria voldoet, wordt uitgesloten van deelname aan deze studie:
    • Patiënten die zwanger zijn of borstvoeding geven en diegenen die een zwangerschap plannen in de periode tot 1 maand na het onderzoek;
    • Vrouwen die zwanger kunnen worden en geen anticonceptie gebruiken;
    • Patiënten met een beperkte levensverwachting van minder dan een jaar;
    • Patiënten die geen schriftelijke geïnformeerde toestemming kunnen geven, of anderszins niet geschikt zijn om te worden opgenomen volgens de onderzoeker.

    Contra-indicatie voor macitentan
    • Patiënten met actieve leverziekte of ernstige leverstoornissen met ASAT en / of ALAT> 3x bovengrens van normaal (ULM);
    • Patiënten met een bekende nierfunctiestoornis (GFR <60 ml / min);
    • Patiënten met bloedarmoede;
    • Gebruik van krachtige CYP3A4-inductoren (rifampicine, sint-janskruid, carbamazepine, fenytoïne) vanwege verminderde werkzaamheid van macitentan.
    • Gebruik van krachtige CYP3A4-remmers (itraconazol, ketoconazol, voriconazol, claritromycine, ritonavir, saquinavir).
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this study is to determine whether the endothelin receptor antagonist macitentan reduces the burden of anginal complaints, calculated as:
    1. the duration (in minutes) * severity (on a VAS scale 1-10) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication;
    2. the frequency angina attacks * severity (on a VAS scale 1-10) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication;
    Het primaire doel van deze studie is om te bepalen of de endothelinereceptorantagonist macitentan de last van angina-klachten vermindert, berekend als:
    1. de duur (in minuten) * ernst (op een VAS-schaal 1-10) tijdens medicijngebruik (macitentan of placebo) tot 2 weken na het staken van de onderzoeksmedicatie;
    2. de frequentie angina-aanvallen * ernst (op een VAS-schaal 1-10) tijdens gebruik van medicatie (macitentan of placebo) tot 2 weken na stopzetting van de studiemedicatie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 4 months
    4 weken
    E.5.2Secondary end point(s)
    Efficacy endpoint:
    • Incidence and severity of angina complaints as obtained on a weekly basis by the Seattle Angina Questionnaire during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication.
    • Patients will be asked to keep a diary to record frequency, duration, and severity (on a VAS scale 1-10) of anginal episodes, as well as circumstances of the complaints and use of sublingual nitroglycerin tablets or sprays.

    Safety endpoints:
    • Detrimental changes in physical, laboratory or ECG parameters during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication.
    • The occurrence of adverse events (i.e. hospitalization for anginal symptoms and/or myocardial infarction) during the study period.
    • All possible side effects will be recorded during the study period.
    Effectiviteit eindpunt:
    • Incidentie en ernst van angina pectoris zoals verkregen door de Seattle Angina-vragenlijst tijdens de onderzoeksperiode tot 2 weken na het stopzetten van de studiemedicatie.

    Veiligheids-eindpunten:
    • Nadelige veranderingen in fysische, laboratorium- of ECG-parameters tijdens de onderzoeksperiode tot 2 weken na het staken van de studiemedicatie.
    • Het optreden van bijwerkingen (dat wil zeggen ziekenhuisopname voor angina-symptomen en / of hartinfarct) gedurende de onderzoeksperiode tot 2 weken na stopzetting van de studiemedicatie.
    Alle mogelijke bijwerkingen zullen worden geregistreerd tijdens de onderzoeksperiode tot 2 weken na stopzetting van de studiemedicatie.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 4 months
    4 maanden
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    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 concerned2
    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
    LVLS
    laatste bezoek van laatste 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 months8
    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: 30
    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 state30
    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)
    continue normal treatment
    doorgaan met reguliere behandeling
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
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