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    Summary
    EudraCT Number:2014-004490-17
    Sponsor's Protocol Code Number:72
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-29
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-004490-17
    A.3Full title of the trial
    Effect of ACE-Inhibition on Microvascular Function in Women with Assessed Microvascular Dysfunction and No Obstructive Coronary Artery Disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of ACE-Inhibition treatment on the function of the small vessels in the heart in Women with Assessed Vmall Vessel Dysfunction and No Obstructive Coronary Artery Disease.
    ACE-hæmmer behandlings effekt på funktionen af de små kar i hjertet for kvinder med nedsat funktion af de små kar og ingen forsnævringer af kranspulsårene.
    A.3.2Name or abbreviated title of the trial where available
    ACIM
    A.4.1Sponsor's protocol code number72
    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 SponsorBipebjerg University Hospital
    B.1.3.4CountryDenmark
    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 supportThe Herat Foundation
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportThe University of Copenhagen
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBispebjerg University Hospital
    B.5.2Functional name of contact pointhttps://clinicaltrials.gov
    B.5.3 Address:
    B.5.3.1Street AddressBispebjerg Bakke 23
    B.5.3.2Town/ cityCopenhagen NV
    B.5.3.3Post code2400
    B.5.3.4CountryDenmark
    B.5.6E-mailEva.Irene.Bossano.Prescott@regionh.dk
    D. IMP Identification
    D.IMP: 1
    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 Ramipril
    D.2.1.1.2Name of the Marketing Authorisation holderHexal
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 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 INNRamipril
    D.3.9.1CAS number 87333-19-5
    D.3.9.3Other descriptive nameRAMIPRIL
    D.3.9.4EV Substance CodeSUB10248MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5 to 10
    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 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
    Microvascular dysfunction/microvascular angina
    E.1.1.1Medical condition in easily understood language
    Small vessel disease
    småkarssygdom
    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 10065566
    E.1.2Term Microvascular angina
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this study is to explore effects of long term treatment with ACE-inhibitor on the microvasculature assessed by coronary flow reserve by transthoracic echocardiography in normotensive patients with microvascular dysfunction (CFR<2.2) and Angina Pectoris but no coronary artery disease
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to explore effects of long term treatment with ACE-inhibitor on the endothelial function assessed by flow mediated dilation (FMD), on symptoms and exercise level and on myocardial strain in rest and during stress assessed by echocardiography in normotensive patients with microvascular dysfunction (CFR<2.2) and Angina Pectoris but NO-CAD.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients from the iPower cohort with microvascular dysfunction defined as a TTDE measured CFR < 2.2 with a good quality (quality index > 3) examination who are normotensive will be included in the study. Patients with a CFR <2.0 will be invited before patients with a CFR between 2.0 - 2.2. Normotensive will in this study be defined as patients who have a blood pressure ≤ 150 at last visit in iPower and who are not in treatment for documented hypertension. Patients will be found searching for patients in the iPower database with these criteria.

    The iPower cohort has included women aged 18-80 with angina-like chest discomfort but no obstructive coronary artery disease (Coronary angiography with no significant stenotic lesions (<=50%) of epicardial vessels performed within 1 year of inclusion) since 2012.
    E.4Principal exclusion criteria
    • Current treatment with ACE-inhibitors or Angiotensin II-antagonists
    • Atrial fibrillation
    • Pace-maker
    • Allergy towards Ace-inhibitor, Ramipril ® or tool-medicine: Dipyridamole/adenosine, Nitro-glycerine or rescue medicine: Theophylline
    • Baseline CFR >2.5 when entering ACIM-study.
    • No episodes of chest pain within 6 months before inclusion
    • Coronary angiography with significant stenotic lesions (>/=50%)
    • Other cause of chest discomfort deemed highly likely
    • Left ventricular ejection fraction below 45% assessed by echocardiography at baseline measurement
    • Significant valvular heart disease (Definition: Verified in medical records after echocardiography. If the echocardiographer in this study suspects valvular heart disease, the patient is referred for expert evaluation and excluded from the study until valvular disease has been excluded. All definitions are taken from the guidelines of the Danish Society of Cardiology (DCS).
    o Haemodynamic significant Aortic Stenosis: Valve area < 1 cm2 or <0.6 cm2/m2 body surface area.
    o Severe aorta Regurgitation (AR): Vena contracta > 6 mm, Moderate/severe LV volume load, ERO > 0.3 cm².
    o Mitral Stenosis (MS): Valve area < 2.5 cm2.
    o Severe Mitral Regurgitation (MR): ERO > 0.4 cm², Moderate/severe LV-load, Vena contracta > 6 mm.
    • Congenital heart disease or cardiomyopathy verified in medical records
    • Significant co-morbidity with < 1 year expected survival: decision made by the person responsible for inclusion based on the patient interview and/or medical records.
    • Severe COPD with FEV1<50% of predicted
    • Severe asthma defined as asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (long acting β2 agonist (LABA), leukotriene modifier, theophylline or systemic corticosteroids) to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy."
    • Previous verified myocardial infarction (Definition: verified in medical records, STEMI (ST segment elevation, elevated enzymes) or NSTEMI (elevated enzymes, ECG changes/no ECG changes).
    • Previous revascularization (PCI or CABG)
    • Elevated cardiac biomarkers: Troponin > 50 ng/l (high sensitive) or > 0.03 μg/l (4. generation), CKMB > 4.0 μg/l (women).
    • ECG with verified ST-segment elevation
    • Language- or other barrier to giving informed consent (for example mental ability to understand project)
    • Travel distance: a distance to research hospital requiring more than 3 hours of travel
    • Patient unwilling to participate (Low burden of symptoms, other illnesses, “Lack of energy”, transport problems, anxiety because of the examination, other).
    • No signed informed consent.
    • Other (Pregnancy, significant psychiatric disorder)
    • GFR < 50 mL/min/1,73 m2

    WITHDRAWAL CRITERIA
    Patients who will be withdrawn from participating in the study:
    a) Suspected serious reaction where medication type will be unblinded by the sponsor by calling Glostrup pharmacy (open day and night)
    b) If they do not want to continue with treatment before total up titration of treatment
    c) Sustained side-effects which make the patients unable to take ACE-inhibitor/placebo before total up titration of treatment
    d) Poor compliance defined as less than 70 % of the time not taking ACE-inhibitor/placebo assessed by investigator. Patients will also be excluded with a more than 2 months continuous pause from medication or more than 2 weeks continuous pause up to endpoint measurements.
    e) Patients who do not wish any endpoint measures
    f) GFR < 50 mL/min/1,73 m2 and/or 20 % decrease in GFR during commencement of ramipril treatment

    If a patient wish to withdraw or have sustained side effects after total up titration of treatment but before finishing 12±2 month with more than 70% compliance in the treatment period, endpoint measurements will be performed if patient agree to this and the patient will not be excluded from the study.

    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint: CFR after treatment with ACE-inhibitor/placebo treatment in 6±1.5 months, assessed by a non-invasive Trans-Thoracic Doppler Echocardiography (TTDE).

    E.5.1.1Timepoint(s) of evaluation of this end point
    6±1.5 months
    E.5.2Secondary end point(s)
    Secondary endpoints: 1) Symptoms after 12±2 months of treatment with ACE-inhibitors assessed by Seattle angina questionnaire (annex 3) 2) exercise level assessed by iPAQ (annex 3) 3) strain assessed by speckle tracking echocardiography after 6±1.5 months of treatment with ACE-inhibitor 4) Endothelial function by FMD after treatment with ACE inhibitor in 6±1.5 months, assessed by flow mediated dilation of the brachial artery by ultrasound.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6±1.5 months
    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) 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 Yes
    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 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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    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: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state72
    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)
    After final visit patients will return to normal control at general practitioner
    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 Decision2014-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-04-28
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