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    Summary
    EudraCT Number:2012-002563-10
    Sponsor's Protocol Code Number:BAY86-4875/15961
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-04-19
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-002563-10
    A.3Full title of the trial
    Multicenter open-label study to evaluate efficacy of gadobutrol-enhanced cardiac magnetic resonance imaging (CMRI) for detection of significant coronary artery disease (CAD) in subjects with known or suspected CAD by a blinded image analysis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gadobutrol/Gadavist-enhanced cardiac magnetic resonance imaging (CMRI) to detect Coronary Artery Disease (CAD)
    A.3.2Name or abbreviated title of the trial where available
    GadaCAD 1
    A.4.1Sponsor's protocol code numberBAY86-4875/15961
    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 SponsorBayer AG
    B.1.3.4CountryGermany
    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 supportBayer AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team/Ref: "EU CTR" / Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post codeD-13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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 Gadovist® 1.0mmol/ml, solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holderBayer plc
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameGadovist® 1.0 mmol/ml, solution for injection
    D.3.2Product code BAY 86-4875
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGadobutrol
    D.3.9.1CAS number 138071-82-6
    D.3.9.2Current sponsor codeBAY 86-4875
    D.3.9.3Other descriptive nameGADOBUTROL
    D.3.9.4EV Substance CodeSUB07861MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mmol/ml millimole(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects with known or suspected Coronary Artery Disease (CAD)
    E.1.1.1Medical condition in easily understood language
    Known or suspected disease of the coronary arteries
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    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
    The primary efficacy objectives of this study are to demonstrate that sensitivity and specificity of gadobutrol-enhanced CMRI exceed pre-specified minimum performance thresholds (MPT) of 60 and 55%, respectively and to show superior sensitivity over unenhanced wall motion CMRI at vasodilator rest/stress for the detection of significant CAD:
    Primary objectives (i.e. 3 co-primaries) are to
    1) demonstrate that subject-based sensitivity of gadobutrol-enhanced CMRI at vasodilator stress/rest (lower bound of 95% CI) exceeds the predefined minimum performance threshold of 60%;
    2) demonstrate that subject-based specificity of gadobutrol-enhanced CMRI at vasodilator stress/rest (lower bound of 95% CI) exceeds the predefined minimum performance threshold of 55%;
    3) demonstrate subject-based superior sensitivity of gadobutrol-enhanced CMRI over unenhanced wall motion CMRI.
    E.2.2Secondary objectives of the trial
    1) demonstrate that subject-based sensitivity and specificity, of gadobutrol-enhanced CMRI (lower bound of 95% CI) exceed 60% and 55%, respectively.
    2) demonstrate subject-based superior sensitivity of gadobutrol-enhanced CMRI compared to unenhanced wall motion CMRI.
    3) evaluate coronary territory-based sensitivity and specificity of gadobutrol-enhanced CMRI for localization of CAD;
    • for territories LAD and non-LAD;
    • additional localization for RCA and LCX;
    4) evaluate detection and perfusion pattern of subjects with LMS stenosis;
    5) evaluate subject-based sensitivity and specificity of gadobutrol- enhanced CMRI for detection and exclusion of significant CAD separately in 2 subgroups:
    -subjects with single-vessel disease and
    -subjects with multi-(2- or 3)-vessel disease.
    6) assess the confidence of diagnosis for each defined myocardial region for unenhanced wall motion and gadobutrol-enhanced CMRI.
    7) confirm the safety profile of gadobutrol in this indication.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male or female subjects aged ≥18 years
    - Subjects with suspected or known CAD based on signs and/or (typical or atypical) chest pain who have routine CA without intervention or CTA within 4 weeks around gadobutrol-enhanced CMRI
    - Willingness to undergo stress/rest CMRI and to follow directions and complete all study procedures
    - Women of childbearing potential (e.g. age < 60y, no history of surgical sterilization or hysterectomy): use of contraception and a negative pregnancy test
    E.4Principal exclusion criteria
    - Pregnant or nursing (including pumping for storage and feeding)
    - Received any other investigational product or participation in any other interventional clinical study within 15 days prior to enrollment in this study
    - Suspected clinical instability or unpredictability of the clinical course during the study period
    - Any scheduled procedure such as interventional (PCI, stenting) or surgical treatment that may alter/may have altered the cardiac condition regarding myocardial perfusion status and/or stenosis degree between CMRI and CA or CTA.
    - Any contrast agent +/- 24 h prior to or after gadobutrol-enhanced CMRI (i.e. ensure minimum interval of 24 h between the SoR and the CMRI). This does not apply for emergency CA.
    - Contraindication to the cardiac MRI examination (e.g. inability to hold breath; severe arrhythmias preventing gated acquisition; very low cardiac output, severe claustrophobia, defibrillators or other metallic devices not approved for MRI, such as pace makers)
    - History of severe allergic or anaphylactoid reaction to any allergen including drugs and contrast agents according to the investigator’s assessment / judgment
    - Estimated glomerular filtration rate (eGFR) value <30 mL/min/1.73 m2 derived from a serum / blood creatinine result within 2 weeks prior to gadobutrol injection. Any subject on hemodialysis or peritoneal dialysis is excluded from enrollment.
    - Acute renal insufficiency
    - Previous enrollment into this study or any other Bayer-sponsored study using gadobutrol
    - Coronary artery bypass grafting (CABG)
    - Acute myocardial infarction (< 14 days prior to inclusion), unstable angina / acute coronary syndrome, severe congestive heart failure, decompensated heart failure with ejection fraction <35%
    - Irregular heart rhythm
    - Condition that precludes the safe administration of pharmacological stressor according to the respective approved label such as sinus node disease, 2nd or 3rd degree atrioventricular block, obstructive lung disease
    - Uncontrolled and severe hypertension
    - Baseline hypotension
    - Subject has a close affiliation with the investigational site; e.g. a relative of the investigator, or a dependent person.
    E.5 End points
    E.5.1Primary end point(s)
    1. Presence of a myocardial perfusion defect indicating significant CAD [coronary artery disease] per subject on gadobutrol-enhanced CMRI [cardiac magnetic resonance imaging] (based on regional perfusion score), based on the blinded readers’ assessment.
    2. Absence of a myocardial perfusion defect excluding significant CAD per subject on gadobutrol-enhanced CMRI (based on regional perfusion score), based on the blinded readers’ assessment.
    3. Presence of a myocardial perfusion defect indicating significant CAD per subject on gadobutrol-enhanced CMRI versus unenhanced wall motion CMRI images (based on regional perfusion/regional wall motion score), based on the blinded readers’ assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 8 weeks
    E.5.2Secondary end point(s)
    1. Presence of a myocardial perfusion defect indicating significant CAD per subject on gadobutrol-enhanced CMRI (investigator's assessment).
    2. Absence of myocardial perfusion defect excluding significant CAD per subject on gadobutrol-enhanced CMRI (investigator's assessment).
    3. Presence of a myocardial perfusion defect indicating significant CAD per subject on gadobutrol-enhanced CMRI versus unenhanced wall motion CMR images (investigator's assessment).
    4. Localization of a myocardial perfusion defect to a coronary territory, i.e. LAD [left anterior descending artery] and non-LAD, on gadobutrol-enhanced CMRI (blinded readers' and investigator's assessments).
    5. Additional localization of a non-LAD myocardial perfusion defect to RCA [right coronary artery] and LCX [left circumflex artery] territory respectively on gadobutrol-enhanced CMRI (blinded readers' and investigator's assessments).
    6. Detection of subjects with LMS [left main stem] stenosis.
    7. Perfusion pattern of subjects with LMS stenosis.
    8. Presence/absence of a myocardial perfusion defect indicating/excluding significant CAD (per subject), in subjects with multi-vessel versus single vessel disease evaluated on gadobutrol-enhanced CMRI (blinded readers' and investigator's assessments).
    9. Score for confidence of diagnosis for each myocardial region on unenhanced wall motion and gadobutrol-enhanced CMR images (blinded readers' and investigator's assessments).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 8 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 Yes
    E.8.2.3.1Comparator description
    Unenhanced CMRI
    E.8.2.4Number of treatment arms in the trial1
    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
    France
    Germany
    Korea, Republic of
    New Zealand
    Switzerland
    United Kingdom
    United States
    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
    For each participating EU country, the end of the study according to the EU Clinical trial Directive) will be reached when the last visit of the last subject for all centers in the respective country has occurred. As for this study, the primary outcome will be collected after last patient (or subject) last visit (LPLV), the end of the study as a whole will be the date when the clean database is available.
    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 days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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 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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 315
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state67
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 275
    F.4.2.2In the whole clinical trial 450
    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)
    Not applicable for this diagnostic study
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NHIR Comprehensive Clinical Research Network (CCRN)
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-08-10
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