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    Summary
    EudraCT Number:2010-023002-13
    Sponsor's Protocol Code Number:BAY86-4875/91759
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-03-31
    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 ConcernedGermany - BfArM
    A.2EudraCT number2010-023002-13
    A.3Full title of the trial
    Multicenter, open-label study to evaluate the safety and efficacy (by blinded reading) of Gadobutrol-enhanced magnetic resonance angiography (MRA) after a single injection of 0.1 mmol/kg of Gadobutrol in subjects with known or suspected renal artery disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Contrast-Enhanced MRI of the renal arteries
    A.3.2Name or abbreviated title of the trial where available
    Gadobutrol-enhanced MRA of the renal arteries (GRAMS)
    A.4.1Sponsor's protocol code numberBAY86-4875/91759
    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 HealthCare 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 Health Care AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer Health Care 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® 1.0 mmol/ml, solution for injection
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.10 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 renal artery disease
    E.1.1.1Medical condition in easily understood language
    Known or suspected renal artery disease
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10038378
    E.1.2Term Renal artery stenosis
    E.1.2System Organ Class 10038359 - Renal and urinary 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 evaluate the efficacy of gadobutrol-enhanced MRA over 2D-ToF MRA in subjects with known or suspected renal artery disease, as verified by

    - superiority for structural delineation,
    - non-inferiority for the detection of clinically significant vascular disease,
    - non-inferiority for the exclusion of clinically significant vascular disease,
    - minimum performance for gadobutrol detection of clinically significant vascular disease, and
    - minimum performance for gadobutrol exclusion of clinically significant vascular disease

    using CTA as the SoR excluding the first objective, structural delineation.
    E.2.2Secondary objectives of the trial
    A further objective of this study is to confirm the safety profile of gadobutrol for this indication.
    Secondary efficacy assessments will include:
    - minimum diameter of the segment
    - location and length of stenotic segment with ≥50 % stenosis
    - aneurysmal dilatation
    - artifacts by type
    - diagnostic confidence (segmental)
    - additional imaging studies recommended (example: non contrast MRA, computed tomography, ultrasound, nuclear medicine study).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The following inclusion criteria must be met at the time of screening unless otherwise specified.

    1. Male or female subjects, aged ≥ 18 years
    2. Known or suspected renal artery disease based on any of the following:
    a. Referred for evaluation of the renal arteries for clinically significant stenosis. In Germany, only subjects who undergo a CTA within 60 days prior to consent or subjects who clinically require a CTA which is ordered by the referring physician as part of the standard clinical routine will be included. Once the German Radiation Protection Authority has approved the conduct of a study-specific CTA, subjects without prior CTA or referral for a clinically indicated CTA can be included and undergo a CTA as part of the study.
    b. follow-up for a metallic stent in a renal artery
    c. prior imaging study (CTA) showing ≥ 50% renal artery stenosis (within 60 days prior to consent)
    If there is inadequate enrollment of subjects with clinically significant disease (based on CTA interpretation made by the investigators) then the enrollment may be restricted to subjects who underwent a CTA (within 60 days prior to consent) or clinically indicated and ordered by the referring physician as part of the standard clinical routine (within 7 days prior to the MRA) showing at least moderate disease (≥ 50%). Once the German Radiation Protection Authority has approved the conduct of a study-specific CTA, subjects without prior CTA or referral for clinically indicated CTA can be included and undergo a CTA as part of the study. This would meet the protocol guidelines as described in Section 8.6.2.

    Note: Any CTA must meet the specifications provided in Section 7.3.4 and will be used as the SoR for this study. If the CTA does not meet the specifications, then the CTA has to be repeated as part of the study or the subject cannot be enrolled.

    3. Willingness to undergo the routine CE MRA examinations with gadobutrol
    4. Willingness and ability to follow directions and complete all study procedures specified in the protocol
    5. Females of childbearing potential only: Negative pregnancy test on the day of the MRA prior to administration of study drug
    6. Written informed consent, including information about the provisions of the Health Insurance Portability and Accountability Act as applicable
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria at the time of screening will be excluded:

    1. Pregnant or nursing (including pumping for storage and feeding)
    2. Received any other investigational product or participation in any other clinical trial within 30 days prior to enrollment in this study
    3. Previous enrollment into this study or any other Bayer sponsored study using gadobutrol
    4. Contraindication to the MRI examination (e.g. inability to hold breath; severe arrhythmias; very low cardiac output, severe claustrophobia, defibrillators, or other metallic devices not approved for MRI)
    5. Contraindications to the use of Gd-containing contrast agents (including subjects who are suspected for or known to have NSF)
    6. History of severe (as judged by the investigator, taking into account the intensity of the event) allergic or anaphylactoid reaction to any allergen including drugs and contrast agents
    7. Received any contrast agent within 72 hours prior to the study MRA, or is scheduled to receive any contrast agent within 72 hours after the study MRA
    (Note: This applies also to a CTA potentially scheduled during the course of the study)
    8. Estimated glomerular filtration rate (eGFR) value < 30 mL/min/1.73 m² derived from a serum creatinine result within 2 weeks prior to gadobutrol injection. Any subject on hemodialysis or peritoneal dialysis is excluded from enrollment.
    (Note: If there are multiple creatinine values, the values obtained prior to and closest to the time of the MRA should be used. The core lab value should not be used if not available prior to the MRA/CTA).
    9. Acute renal insufficiency of any intensity, either due to hepato-renal syndrome or occurring in the perioperative liver transplantation period.
    10. Known history of severe cardiovascular disease (e.g., acute myocardial infarction [< 14 days], unstable angina, congestive heart failure [New York Heart Association Class IV]) or known long QT syndrome
    11. Suspected clinical instability or unpredictability of the clinical course during the study period (e.g., due to previous surgery or acute stroke)
    12. Scheduled or potentially expected for the period between the CTA and gadobutrol MRA:
    a. any procedure that may alter the MRA or CTA interpretation, or
    b. any interventional or surgical procedure involving the renal or abdominal aorta

    In Germany, the investigators additionally have to adhere to guidelines given in the country specific package insert.
    E.5 End points
    E.5.1Primary end point(s)
    The following five co-primary endpoints are based on the proportion of assessable vascular segments, and the sensitivity and specificity of clinically significant disease:
    • Superiority in the proportion of assessable segments with gadobutrol-enhanced MRA compared to non-contrast MRA
    • Non-inferior diagnosis of clinically significant disease based on the sensitivity [≥ 50% stenosis] on a segmental basis
    • Non-inferior diagnosis of clinically significant disease based on the specificity [≥ 50% stenosis] on a segmental basis
    • The two minimum gadobutrol performance criteria (both sensitivity and specificity should exceed 50%)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Approximately 15 months after LPLV
    E.5.2Secondary end point(s)
    The following secondary efficacy variables will be summarized:
    - Length of the right and left renal arteries
    - Narrowest diameter of a segment
    - Location of stenoses in the proximal segments
    - Artifacts by type (segmental)
    - Accessory (duplicate) renal arteries
    - Aneurysmal dilatation (segmental)
    - Diagnosis (subject): FMP vs. arteriosclerosis
    - Diagnostic confidence (segmental)
    - Additional imaging studies recommended (subject)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Approximately 15 months after LPLV
    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 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.8.2.4Number 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Argentina
    Austria
    Brazil
    China
    Colombia
    Czech Republic
    France
    Germany
    Korea, Republic of
    Poland
    Switzerland
    Taiwan
    Turkey
    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 (subject) last visit (LPLV) and the end of the study as a whole will be the date when the clean data base is available.
    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 months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    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.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-03-31. Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the subject is not capable of providing a signature, a verbal statement of consent can also be given in the presence of an impartial witness.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 190
    F.4.2.2In the whole clinical trial 336
    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 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 Not Applicable
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-04-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-07-12
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