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    Summary
    EudraCT Number:2012-001583-29
    Sponsor's Protocol Code Number:Er-02-Perf-AD
    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:2012-07-12
    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 ConcernedGermany - BfArM
    A.2EudraCT number2012-001583-29
    A.3Full title of the trial
    Prospective, open-label, two-arm, parallel-group, single center phase IV clinical trial to evaluate the diagnostic value of a Gadobutrol enhanced dynamic susceptibility perfusion MRI (DSC-MRP) and a non contrast arterial spin labeling perfusion MRI (ASL-MRP) in subjects with minor cognitive impairment or minor Alzheimer's disease compared to age matched mentally healthy subjects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DSC-MRP in cognitive decline
    A.4.1Sponsor's protocol code numberEr-02-Perf-AD
    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 Erlangen
    B.1.3.4CountryGermany
    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 supportUniversity of Erlangen, Bayer Healthcare
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Erlangen
    B.5.2Functional name of contact pointProf. Dr. Arnd Dörfler
    B.5.3 Address:
    B.5.3.1Street AddressSchwabachanlage 6
    B.5.3.2Town/ cityErlangen
    B.5.3.3Post code91054
    B.5.3.4CountryGermany
    B.5.4Telephone number49091318539388
    B.5.5Fax number49091318536179
    B.5.6E-mailneuroradiologie@uk-erlangen.de
    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
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Vital GmbH
    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
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous bolus use (Noncurrent)
    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.3.9.3Other descriptive nameGADOBUTROL
    D.3.9.4EV Substance CodeSUB07861MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number604,72
    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 Yes
    D.3.11.13.1Other medicinal product typeparamagnetic contrast media
    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
    Patients with dementing disorders, namely minor alzheimers disease or subjects with mild cognitive impairment and normal controls
    E.1.1.1Medical condition in easily understood language
    dementia in the elderly
    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
    To compare the robustness of Gadobutrol enhanced DSC-MRP with spin-labeling perfusion studies in subjects with MCI and minor Alzheimer´s disease (AD)
    E.2.2Secondary objectives of the trial
    • To assess regional perfusion abnormalities with dynamic susceptibility weighted (DSC-) MR perfusion in subjects with symptoms of mental decline with mentally healthy subjects serving as a reference.
    • To identify areas of reduced perfusion as early marker for a dementing disorder.
    • To compare the technical performance of both DSC-MRP and ASL-MRP in a cohort of subjects with mental decline – in regard of image quality and image artifacts.
    • To assess Gadobutrol as a contrast agent in DSC-MRP in patients with MCI or minor AD.
    • To compare the quantitative results of cerebral blood flow measures in both DSC- and ASL-MRP in an intraindividual comparison.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult subjects, age >45 years
    2. Subjects with symptoms of MCI or minor AD referred for diagnostic work-up with MRI -
    or mentally healtyh control subjects in the same age range.
    3. Willing to undergo all study procedures
    4. Subjects who have completed a neuropsychologic assessment or a MMSE with a score that allows full understanding of the study procedures and ability to give informed consent – for control subjects a normal MMSE is required.
    5. Subject has voluntarily given written informed consent
    E.4Principal exclusion criteria
    1. 1. Having any physical or mental status that interferes with the informed consent procedure including self-signed consent
    2. Having an underlying disease or concomitant medication which may interfere with efficacy or safety evaluations as planned in this study.
    3. GFR <60ml/m²/1.73m² (MDRD) as determined from a serum creatinine value not older than 1 week before MR contrast media injection, or subjects on hemodialysis
    4. Renal or liver transplant subjects, including subjects with scheduled liver transplant are excluded due to the potential risk for nephrogenic systemic fibrosis (NSF)
    5. MR contraindications (pacemaker, magnetic clips, severe claustrophobia)
    6. Known allergy to Gadobutrol
    7. Subjects presenting with a history of anaphylactoid or anaphylactic reaction to any allergen including drugs and contrast medias
    8. Having received any investigational drug within 7 days prior to entering this study.
    9. Not being able to remain lying down for at least 30-45min (e.g. subjects with unstable angina, dyspnea at rest, severe pain at rest, severe back pain)
    10. Close affiliation with the investigational site; e.g. a close relative of the investigator or staff members of the coordinating investigators department.
    11. Having been previously enrolled in this clinical trial.
    12. Women who are pregnant, lactating or who are of childbearing potential and have not had a negative urine pregnancy test the same day as administration of the investigational contrast media. The manufacturer’s instructions for performing the urinary pregnancy test are to be followed.
    E.5 End points
    E.5.1Primary end point(s)
    All images will be evaluated for technical adequacy by on site and off site readers to check their eligibility. A blinded read will be performed off site using appropriate technology and equipment. The preparation of the reading will be adhering to international quality standards and documented accordingly. On site, the MR perfusion source data will be analyzed in a standardized way using the Siemens "MRPerf" software. This software generates color-coded parameter maps of mean transit time (MTT), time to peak (TTP), relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF). Furthermore, a global bolus plot (GBP) is calculated, showing the time course of the global T2* signal. CE-MRA will be reconstructed on site as rotating thick slice maximum intensity projections (MIP). The blinded readers will have access to the source data, as well as the MIPs. For both DSC- and ALS-MRP, the visual (qualitative) image analysis in the blinded read will comprise a dedicated simultaneous matched-pairs assessment from both examinations together. The blinded readers will assess the technical adequacy of the each examination. Images will be rated as

    - 1 = excellent,
    - 2 = adequate (with artefacts but tolerable for assessment)
    - 3 = inadequate (not tolerable for further evaluation).

    As primary efficacy endpoint, an overall assessment of image quality will be performed by the blinded readers for both DSC- and ASL-MRP images combined:

    - “DSC-MRP better than ASL-MRP”
    - “both equal” or
    - “ASL-MRP better than DSC-MRP”
    E.5.1.1Timepoint(s) of evaluation of this end point
    July 2013
    E.5.2Secondary end point(s)
    ROI-Analysis

    To compare the perfusion results both group of patients and normal volunteers will be assessed by a quantitative ROI based analysis. After post-processing of the perfusion data ROIs will be placed in normal appearing white and grey matter on the anatomic images. The ROIs will be relocated to the parameter maps of CBF and CBV and compared accordingly.
    As in ASL MRP only CBF maps are available the quantitative results will only be compared for CBF.
    Based on all available measurements we try to identify perfusion as an early marker for the development of an dementing disorder in the group of MCI subjects. For that MCI subjects will be clinically monitored for at least 12 month after inclusion into the study.

    Technical Assessment – Image Quality - Artifacts

    The technical performance of the two perfusion techniques will be compared in the qualitative assessment in an intraindividual comparision. For both the raw data of perfusion and the generated parameter maps the image quality will be rated on a four point scale:

    • Poor
    • Moderate
    • Good
    • Excellent

    and also as diagnostic or non-diagnostic.


    DSC-MRP As quantitative DSC-MRP parameters highly depend on the current circulation status of the patient, no quantitative assessment will be performed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    July 2013
    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 No
    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 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 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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    non enhanced perfusion technique
    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
    Study ends with the last patient last visit - a blinded read analysis of the data is foreseen.
    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 months
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state50
    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)
    Post-study therapy will follow routine clinical care
    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 Decision2012-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-01-12
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