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    Clinical Trial Results:
    Multicenter, open-label study to evaluate the safety and efficacy (by blinded reading) of contrast-enhanced magnetic resonance angiography (MRA) after a single intravenous injection of 0.1 mmol/kg gadobutrol in subjects with known or suspected vascular disease of the supra-aortic vessels

    Summary
    EudraCT number
    		 2010-023001-36
    Trial protocol
    		 DE   CZ   SE   FR   IT   PL   AT  
    Global end of trial date
    28 May 2014

    Results information
    Results version number
    		 v1
    This version publication date
    12 Jul 2016
    First version publication date
    13 Jun 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY 86-4875/14607
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01344447
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Scientific contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of gadobutrol-enhanced MRA over two dimensional-Time of Flight (2D-ToF) MRA in subjects with known or suspected vascular disease of the supra-aortic arteries, 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 and - The minimum gadobutrol performance criteria for sensitivity (more than [>] 50 percent [%]) and - The minimum gadobutrol performance criteria for specificity (> 50%) using computed tomographic angiography (CTA) as the standard of reference (SoR) excluding the first objective (structural delineation).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 17
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 60
    Country: Number of subjects enrolled
    Turkey: 15
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Poland: 117
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Italy: 78
    Worldwide total number of subjects
    479
    EEA total number of subjects
    266
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    164
    From 65 to 84 years
    302
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 56 study centers in 14 countries, between 12 May 2011 (first subject first visit) and 28 May 2014 (last subject last visit).

    Pre-assignment
    Screening details
    		 Of 504 subjects screened, 17 did not complete screening; due to screen failure in 6, consent withdrawal in 6 and other reasons in 5 subjects. Of 487 subjects assigned to treatment, 479 received study drug and 8 discontinued prior to medication due to adverse event in 7 subjects, and other reason in 1 subject.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Gadobutrol (Gadavist, BAY 86-4875)
    Arm description
    		 Gadobutrol was administered to all subjects receiving study drug at the standard dose of 0.1 millimole per kilogram (mmol/kg) body weight (BW) by single intravenous (IV) bolus injection. During the course of the study, non-contrast MRA images were obtained before the administration of gadobutrol, and gadobutrol-enhanced MRA images were obtained after injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY 86-4875
    Other name
    Gadovist, Gadavist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Gadobutrol was administered to all subjects receiving study drug at the standard dose of 0.1 mmol/kg BW by single IV bolus injection.

    Number of subjects in period 1
    		Gadobutrol (Gadavist, BAY 86-4875)
    Started
    479
    Completed
    471
    Not completed
    8
         Consent withdrawn by subject
    1
         Physician decision
    1
         Protocol violation
    1
         MRA unsuccessful
    1
         Error of power injector
    1
         Adverse event
    1
         Bolus tracking failed
    1
         The contrast was not seen
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Gadobutrol was administered to all subjects receiving study drug at the standard dose of 0.1 mmol/kg BW by single IV bolus injection. During the course of the study, non-contrast MRA images were obtained before the administration of gadobutrol, and Gadobutrol-enhanced MRA images were obtained after injection.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 479 479
    Age categorical
    Units: Subjects
        <45 years
    		 9 9
        45-64 years
    		 155 155
        >=65 years
    		 315 315
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.2 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    		 167 167
        Male
    		 312 312
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 76 ± 14.5 -

    End points

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    End points reporting groups
    Reporting group title
    Gadobutrol (Gadavist, BAY 86-4875)
    Reporting group description
    		 Gadobutrol was administered to all subjects receiving study drug at the standard dose of 0.1 millimole per kilogram (mmol/kg) body weight (BW) by single intravenous (IV) bolus injection. During the course of the study, non-contrast MRA images were obtained before the administration of gadobutrol, and gadobutrol-enhanced MRA images were obtained after injection.

    Subject analysis set title
    Gadobutrol-Enhanced MRA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Gadobutrol-Enhanced MRA set included those subjects in FAS who showed only gadobutrol-enhanced MRA image sets.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS included all subjects who have both gadobutrol-enhanced and 2D-ToF MRA image sets, and the SoR diagnosis were available (CTA was required to be interpretable and without technical problems).

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF included all subjects who were administered study drug.

    Subject analysis set title
    CTA minus Unenhanced MRA for blinded reading
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with CTA scan images minus unenhanced MRA images for blinded reading included in this set.

    Subject analysis set title
    Computed Tomographic Angiography (CTA)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    CTA included those subjects in FAS who showed only CTA scan image sets.

    Subject analysis set title
    CTA minus gadobutrol-enhanced MRA for blinded reading
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with CTA scan images minus gadobutrol-enhanced MRA images for blinded reading included in this set.

    Subject analysis set title
    Unenhanced MRA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Unenhanced MRA set included those subjects in FAS who showed only unenhanced MRA image sets.

    Primary: Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 Percentage of Assessable Vascular Segments Using Gadobutrol-Enhanced MRA and Unenhanced MRA [1]
    End point description
    Each vascular segment was visualized using unenhanced MRA and gadobutrol-enhanced MRA, characterized by the on-site clinical investigators (CI), three independent blinded readers (BR) (BR 1, BR 2 and BR 3) and majority readers (the outcome determined by at least two of the blinded readers). A segment was assessable if it was visualized along its entire length and if any region of stenosis, was measured reliably. There were 21 segments of the supra-aortic arteries assessed per subject. This outcome measure was analyzed on a segment basis, in the below table, "n" signifies segments that were evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    Images were taken pre-injection and post-injection
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-adding of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [2]
    457 [3]
    Units: percentage of segments
    number (not applicable)
        Majority reader (n=9597)
    95
    72.7
        Blinded reader 1 (n=9597)
    88.2
    24.4
        Blinded reader 2 (n=9597)
    94.9
    75.3
        Blinded reader 3 (n=9597)
    97.4
    82.4
        Clinical investigators (n=9597)
    97
    78.6
    Attachments
    		 14607_Statistical Analysis_Primary OM_Assessabilit
    Notes
    [2] - FAS
    [3] - FAS
    No statistical analyses for this end point

    Primary: Sensitivity for Detection of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 Sensitivity for Detection of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA [4]
    End point description
    Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the SoR (CTA; blinded readers). This was determined using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded. This outcome measure was analyzed on a segment basis, in the below table, "n/n" signifies those subjects/segments that were evaluable for the specified category of each group.
    End point type
    Primary
    End point timeframe
    Images were taken pre-injection and post-injection
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-adding of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [5]
    457 [6]
    Units: percentage of sensitivity
    number (not applicable)
        Majority reader (n=141/158)
    60.1
    54.4
        Blinded reader 1 (n=141/158)
    59.5
    54.4
        Blinded reader 2 (n=141/158)
    59.5
    54.1
        Blinded reader 3 (n=141/158)
    58.2
    55.7
        Clinical investigators (n=238/297)
    60.9
    39.4
    Attachments
    		 14607_Statistical Analysis_Primary OM_Sensitivity
    Notes
    [5] - FAS
    [6] - FAS
    No statistical analyses for this end point

    Primary: Specificity for Exclusion of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 Specificity for Exclusion of Clinically Significant Disease Using Gadobutrol-Enhanced MRA and Unenhanced MRA [7]
    End point description
    Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded, as assessed by the SoR (CTA; blinded readers). This was determined using the NASCET criteria. For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. In case of multiple stenosis in any one segment, the most severe stenosis in the segment was recorded. This outcome measure was analyzed on a segment basis, in the below table, "n/n" signifies those subjects/segments that were evaluable for the specified category of each group.
    End point type
    Primary
    End point timeframe
    Images were taken pre-injection and post-injection
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-adding of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [8]
    457 [9]
    Units: percentage of specificity
    number (not applicable)
        Majority reader (n=457/9321)
    96.1
    87.3
        Blinded reader 1 (n=457/9321)
    92
    61.7
        Blinded reader 2 (n=457/9321)
    94.7
    85.1
        Blinded reader 3 (n=457/9321)
    96.7
    89.1
        Clinical investigators (n=457/9133)
    98.1
    89.1
    Attachments
    		 14607_Statistical Analysis_Primary OM_Specificity
    Notes
    [8] - FAS
    [9] - FAS
    No statistical analyses for this end point

    Primary: Minimum Gadobutrol Performance for Sensitivity: Sensitivity > 50%

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    End point title
    		 Minimum Gadobutrol Performance for Sensitivity: Sensitivity > 50% [10]
    End point description
    Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter. This outcome measure was analyzed on a segment basis, in the below table, "n/n" signifies those subjects/segments that were evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    Images were taken pre-injection and post-injection
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-adding of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Gadobutrol-Enhanced MRA
    Number of subjects analysed
    457 [11]
    Units: percentage of sensitivity
    number (not applicable)
        Majority reader (n=135/149)
    61.7
        Blinded reader 1 (n=132/146)
    60.3
        Blinded reader 2 (n=139/156)
    59.6
        Blinded reader 3 (n=140/155)
    58.7
        Clinical investigators (n=230 /283)
    61.5
    Attachments
    		 14607_Statistical Analysis_Primary OM_Sensitivity_
    Notes
    [11] - FAS
    No statistical analyses for this end point

    Primary: Minimum Gadobutrol Performance for Specificity: Specificity > 50%

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    End point title
    		 Minimum Gadobutrol Performance for Specificity: Specificity > 50% [12]
    End point description
    Clinically significant disease was defined as 70 to 99% stenosis of a segment, but not occluded as assessed by the SoR (CTA; blinded readers). For each segment, the most severe stenosis/narrowing was identified and considered for the evaluation of clinically significant disease. Gadobutrol minimum performance criteria was based on a stenosis of 50% calculated from the native vessel diameter. This outcome measure was analyzed on a segment basis, in the below table, "n/n" signifies those subjects/segments that were evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    Images were taken pre-injection and post-injection
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-adding of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Gadobutrol-Enhanced MRA
    Number of subjects analysed
    457 [13]
    Units: percentage of specificity
    number (not applicable)
        Majority reader (n=457/8805)
    98
        Blinded reader 1 (n=444/8225)
    97.6
        Blinded reader 2 (n=457/8844)
    97.2
        Blinded reader 3 (n=457/9079)
    98
        Clinical investigators (n=457/8926)
    99.2
    Attachments
    		 14607_Statistical Analysis_Primary OM_Specificity_
    Notes
    [13] - FAS
    No statistical analyses for this end point

    Secondary: Mean Difference in Vessel Diameter (millimeter [mm]) at Normal Point and Narrowest point in Gadobutrol-Enhanced and Unenhanced Images Compared to CTA by Blinded Readers and the Clinical Investigators

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    End point title
    		 Mean Difference in Vessel Diameter (millimeter [mm]) at Normal Point and Narrowest point in Gadobutrol-Enhanced and Unenhanced Images Compared to CTA by Blinded Readers and the Clinical Investigators
    End point description
    The segment reduction in diameter of greater than 10% was considered abnormal and measured. The diameter of each of these abnormal segments was measured using electronic calipers (perpendicular to the long axis of the vessel) at the point of most severe stenosis within each segment. Mean of vessel diameters was calculated by segment separately for CTA and MRA readers. Number of subjects/segments analyzed in below ordered categories (Normal-BRs; Narrowest-BRs; Normal-CIs; Narrowest-CIs) in CTA minus Unenhanced MRA group was 425/2063, 425/2063, 352/816, 352/804 respectively; and was 436/2683, 436/2683, 410/1184, 410/1175 for same categories in CTA minus enhanced MRA group respectively.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 CTA minus Unenhanced MRA for blinded reading CTA minus gadobutrol-enhanced MRA for blinded reading
    Number of subjects analysed
    457 [14]
    457 [15]
    Units: millimeter(s) (mm)
    arithmetic mean (standard deviation)
        Vessel diameter at normal point: BR
    0.21 ± 0.8
    0 ± 0.79
        Vessel diameter at narrowest point: BR
    0.29 ± 0.87
    0.01 ± 0.8
        Vessel diameter at normal point: CI
    0.48 ± 0.98
    0.33 ± 1.01
        Vessel diameter at narrowest point: CI
    0.02 ± 0.81
    0.11 ± 0.79
    Notes
    [14] - Evaluable subjects in FAS.
    [15] - Evaluable subjects in FAS.
    No statistical analyses for this end point

    Secondary: The Percentage of Segments With Artifacts Presence

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    End point title
    		 The Percentage of Segments With Artifacts Presence
    End point description
    Artifacts were collected for the MRA images on a segmental basis.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [16]
    457 [17]
    Units: percentage of segments
    number (not applicable)
        Blinded reader 1
    46.6
    97.1
        Blinded reader 2
    14
    54.9
        Blinded reader 3
    16.2
    41.2
    Notes
    [16] - FAS
    [17] - FAS
    No statistical analyses for this end point

    Secondary: Types of Artifacts on a Segment Basis by Blinded Reader 1

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    End point title
    		 Types of Artifacts on a Segment Basis by Blinded Reader 1
    End point description
    The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [18]
    457 [19]
    Units: percentage of segments
    number (not applicable)
        Motion artifact
    18.6
    41.9
        Venous opacification
    9.8
    0.8
        Saturation artifact
    21.6
    38.2
        Susceptibility artifacts
    0.1
    0.2
        Ringing artifact
    0.5
    29.3
        Bolus timing error
    4.3
    4
        Other
    9.3
    48
    Notes
    [18] - FAS
    [19] - FAS
    No statistical analyses for this end point

    Secondary: Types of Artifacts on a Segment Basis by Blinded Reader 2

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    End point title
    		 Types of Artifacts on a Segment Basis by Blinded Reader 2
    End point description
    The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [20]
    457 [21]
    Units: percentage of segments
    number (not applicable)
        Motion artifact
    5.6
    39.8
        Venous opacification
    5.7
    0.3
        Saturation artifact
    2
    24.5
        Susceptibility artifacts
    0.8
    3.7
        Ringing artifact
    0.2
    0
        Bolus timing error
    1.1
    0
        Other
    0.5
    0.3
    Notes
    [20] - FAS
    [21] - FAS
    No statistical analyses for this end point

    Secondary: Types of Artifacts on a Segment Basis by Blinded Reader 3

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    End point title
    		 Types of Artifacts on a Segment Basis by Blinded Reader 3
    End point description
    The following types of artifacts were considered: Motion artifact (including pulsatility, breathing, swallowing), venous opacification, saturation artifact (for example [eg], in-plane flow, turbulence, dephasing, saturation band), susceptibility artifacts (including devices, eg, stents), ringing artifact (eg, bands), bolus timing error, and other (artifact not specified above or no artifact).
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [22]
    457 [23]
    Units: percentage of segments
    number (not applicable)
        Motion artifact
    0.6
    13.2
        Venous opacification
    1.7
    0.1
        Saturation artifact
    13.8
    39.4
        Susceptibility artifacts
    0.2
    0.5
        Ringing artifact
    0.6
    6.4
        Bolus timing error
    1.6
    0.4
        Other
    0.4
    0.1
    Notes
    [22] - FAS
    [23] - FAS
    No statistical analyses for this end point

    Secondary: The Percentage of Location of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 The Percentage of Location of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA
    End point description
    Location within a segment was based on the point of greatest stenosis and was recorded for stenosis >=70% (including occlusions) as: - At the bifurcation or proximal origin of a segment (occlusion proximal to the origin of the segment) - Within 5 mm of the bifurcation or proximal origin of a segment - Beyond 5 mm from the bifurcation or proximal origin of a segment. In the below table, "n" signifies location of stenosis which were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [24]
    457 [25]
    Units: pecentage of location
    number (not applicable)
        At the bifurcation: BR 1 (n=353,89)
    50.4
    59.6
        At the bifurcation: BR 2 (n=429,429)
    52.2
    58.7
        At the bifurcation: BR 3 (n=525,559)
    44
    54.2
        Within 5 mm of the bifurcation: BR 1 (n=353,89)
    16.7
    12.4
        Within 5 mm of the bifurcation: BR 2 (n=429,429)
    14.7
    10.7
        Within 5 mm of the bifurcation: BR 3 (n=525,559)
    34.7
    27
        Beyond 5 mm of the bifurcation: BR 1 (n=353,89)
    32.9
    28.1
        Beyond 5 mm of the bifurcation: BR 2 (n=429,429)
    33.1
    30.5
        Beyond 5 mm of the bifurcation: BR 3 (n=525,559)
    21.3
    18.8
    Notes
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Secondary: Length of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 Length of Stenosis (>=70%) in the Proximal Segments Assessed by Gadobutrol-Enhanced MRA and Unenhanced MRA
    End point description
    The length of stenosis was based on the most proximal (first point) in a segment where a stenosis exceeded 10% and the most distal point (last point) in the segment where a stenosis exceeded 10%. If a stenosis spanned more than one segment then the measurement was only included to the beginning or end (boundary) of the segment being evaluated. If there was no stenosis of >=70% in a segment then the length was designated as 0. In the below table, "n" signifies location of stenosis which were evaluable for the specified parameter for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [26]
    457 [27]
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Reader 1 (n=290,66)
    11.26 ± 11.77
    13.36 ± 11.47
        Reader 2 (n=315,281)
    6.25 ± 6.99
    7.18 ± 6.07
        Reader 3 (n=277,268)
    4.89 ± 4.69
    5.36 ± 3.76
    Notes
    [26] - FAS
    [27] - FAS
    No statistical analyses for this end point

    Secondary: The Percentage of Presence of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease

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    End point title
    		 The Percentage of Presence of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease
    End point description
    Each segment was assessed for secondary signs of stenosis for diagnosis of clinically significant disease. The following indicators were considered for the MRA studies: - post-stenotic dilation or ulceration (segmental), - post-stenotic signal dropout, narrowing and intensity reduction, and - thrombus. Each of the three parameters were assessed as present or absent in the region distal to the stenosis. If they were found in any segment distal to the stenosis then they were assessed as present. This end point was analyzed on a segment basis, in the below table, "n" signifies segments that were evaluable for the specified category of each group.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [28]
    457 [29]
    Units: percentage of radiologic indicator
    number (not applicable)
        Reader 1 (n=9203, 9336)
    3.9
    0.7
        Reader 2 (n=9177, 9444)
    2.8
    2
        Reader 3 (n=9009, 9285)
    2.4
    2.7
    Notes
    [28] - FAS
    [29] - FAS
    No statistical analyses for this end point

    Secondary: Type of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease

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    End point title
    		 Type of Secondary Radiologic Indicators for Diagnosis of Clinically Relevant Disease
    End point description
    Each segment was assessed for secondary signs of stenosis for diagnosis of clinically significant disease. The following indicators were considered for the MRA studies: - post-stenotic dilation or ulceration (segmental), - post-stenotic signal dropout, narrowing and intensity reduction, and - thrombus. Each of the three parameters were assessed as present or absent in the region distal to the stenosis. If they were found in any segment distal to the stenosis then they were assessed as present. If there were tandem (serial) stenosis in a vessel then the secondary signs were assigned to the stenosis of >=70% that was proximal and closest in proximity to the secondary sign. This end point was analyzed on a segment basis, in the below table, "n" signifies segments that were evaluable for the specified category of each group.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [30]
    457 [31]
    Units: percentage of segments
    number (not applicable)
        Post-stenotic dilation: BR 1 (n=390,63)
    49.7
    20.6
        Post-stenotic dilation: BR 2 (n=271,188)
    74.2
    56.4
        Post-stenotic dilation: BR 3 (n=236,246)
    7.2
    1.6
        Post-stenotic signal dropout: BR 1 (n=390,63)
    49.5
    77.8
        Post-stenotic signal dropout: BR 2 (n=271,188)
    25.5
    43.6
        Post-stenotic signal dropout: BR 3 (n=236,246)
    92.8
    98.4
        Thrombus: BR 1 (n=390,63)
    0.8
    1.6
        Thrombus: BR 2 (n=271,188)
    0.4
    0
        Thrombus: BR 3 (n=236,246)
    0
    0
    Notes
    [30] - FAS
    [31] - FAS
    No statistical analyses for this end point

    Secondary: Diagnostic Confidence by the Blinded Readers Using Gadobutrol-Enhanced MRA and Unenhanced MRA

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    End point title
    		 Diagnostic Confidence by the Blinded Readers Using Gadobutrol-Enhanced MRA and Unenhanced MRA
    End point description
    Diagnostic confidence was evaluated to determine the level of certainty that the blinded readers assigned to a diagnosis for each segment. This was defined as the degree of confidence that the information on the MRA images represented the true and complete clinical picture of a particular segment. The degree of confidence was rated on a 4-point scale: 1 = Not confident, 2 = Somewhat confident, 3 = Confident, and 4 = Very confident. This outcome measure was analyzed on a segment basis, in the below table, "n" signifies segments that were evaluable for the specified category of each group.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [32]
    456 [33]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Reader 1 (n=9408, 9231)
    3.2 ± 1
    1.3 ± 0.6
        Reader 2 (n=9535, 9301)
    2.9 ± 0.6
    2.2 ± 0.9
        Reader 3 (n=9539, 9302)
    2.8 ± 0.5
    2.4 ± 0.8
    Notes
    [32] - FAS
    [33] - FAS
    No statistical analyses for this end point

    Secondary: The Percentage of Subjects With Additional Imaging Studies Recommended by the Blinded Readers and the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images

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    End point title
    		 The Percentage of Subjects With Additional Imaging Studies Recommended by the Blinded Readers and the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images
    End point description
    A measure of diagnostic value was the reduction in the number of additional diagnostic imaging studies recommended/ordered. The clinical investigators and the blinded readers were asked if they would have recommended an additional imaging study for each subject and was recorded.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    457 [34]
    457 [35]
    Units: percentage of subjects
    number (not applicable)
        Reader 1
    71.1
    100
        Reader 2
    44.2
    98.2
        Reader 3
    22.1
    83.2
        Clinical investigators
    11.2
    43.1
    Notes
    [34] - FAS
    [35] - FAS
    No statistical analyses for this end point

    Secondary: Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 1

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    End point title
    		 Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 1
    End point description
    An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, Digital subtraction catheter angiogram (DSCA), and Nuclear medicine study.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    325 [36]
    457 [37]
    Units: subjects
        Non-contrast MRA
    0
    0
        Contrast-enhanced MRA
    64
    448
        CTA
    124
    4
        Ultrasound
    0
    0
        DSCA
    137
    5
        Nuclear medicine study
    0
    0
    Notes
    [36] - FAS with subjects who were recommended for additional imaging studies.
    [37] - FAS with subjects who were recommended for additional imaging studies.
    No statistical analyses for this end point

    Secondary: Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 2

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    End point title
    		 Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 2
    End point description
    An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, DSCA, and Nuclear medicine study.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    202 [38]
    449 [39]
    Units: subjects
        Non-contrast MRA
    50
    2
        Contrast-enhanced MRA
    30
    415
        CTA
    113
    30
        Ultrasound
    0
    0
        DSCA
    9
    2
        Nuclear medicine study
    0
    0
    Notes
    [38] - FAS with subjects who were recommended for additional imaging studies.
    [39] - FAS with subjects who were recommended for additional imaging studies.
    No statistical analyses for this end point

    Secondary: Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 3

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    End point title
    		 Types of Additional Imaging Studies Recommended by the Blinded Readers After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images – Blinded Reader 3
    End point description
    An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, DSCA, and Nuclear medicine study.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    101 [40]
    380 [41]
    Units: subjects
        Non-contrast MRA
    0
    0
        Contrast-enhanced MRA
    12
    64
        CTA
    88
    316
        Ultrasound
    0
    0
        DSCA
    1
    0
        Nuclear medicine study
    0
    0
    Notes
    [40] - FAS with subjects who were recommended for additional imaging studies.
    [41] - FAS with subjects who were recommended for additional imaging studies.
    No statistical analyses for this end point

    Secondary: Types of Additional Imaging Studies Recommended by the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images

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    End point title
    		 Types of Additional Imaging Studies Recommended by the Clinical Investigator After Evaluation of the Unenhanced and Gadobutrol-Enhanced MRA Images
    End point description
    An additional imaging study recommended was specified from the following list: Non-contrast MRA, Contrast-enhanced MRA, CTA, Ultrasound, DSCA, and Nuclear medicine study.
    End point type
    Secondary
    End point timeframe
    Images were taken pre-injection and post-injection
    End point values
    		 Gadobutrol-Enhanced MRA Unenhanced MRA
    Number of subjects analysed
    51 [42]
    197 [43]
    Units: subjects
        Non-contrast MRA
    1
    0
        Contrast-enhanced MRA
    0
    142
        CTA
    44
    51
        Ultrasound
    1
    0
        DSCA
    5
    4
        Nuclear medicine study
    0
    0
    Notes
    [42] - FAS with subjects who were recommended for additional imaging studies.
    [43] - FAS with subjects who were recommended for additional imaging studies.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From the time the consent was signed until 24 (+/-6) hours follow-up after the study MRA but was continued until completion of the CTA in those subjects who had the CTA performed after the MRA (as part of the study)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Gadobutrol (Gadavist, BAY 86-4875)
    Reporting group description
    		 Gadobutrol was administered to all subjects receiving study drug at the standard dose of 0.1 mmol/kg BW by single IV bolus injection. During the course of the study, non-contrast MRA images were obtained before the administration of gadobutrol, and Gadobutrol-enhanced MRA images were obtained after injection.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The pre-specified frequency threshold for non-serious adverse events was set at >=1%. There were quite a few non-serious adverse events but none reached above the pre-specified threshold.
    Serious adverse events
    		 Gadobutrol (Gadavist, BAY 86-4875)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 479 (0.21%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Nervous system disorders
    Cerebrovascular accident
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 479 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Gadobutrol (Gadavist, BAY 86-4875)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 479 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2013
    The blinded readers interpreted the initial batches of CTA images for the SoR and found the rate of disease prevalence (even with the restriction of 70% or greater stenosis) to be lower than that seen at the sites, and most importantly, the site-reads were used to predict the blinded reader disease prevalence. Therefore the targeted prevalence of disease for the sitereads had to be increased proportionately in order for the blinded reader disease prevalence to approach 40%, as planned. This was accomplished by further restricting the enrollment to only those subjects with a clinically significant stenosis, 70 to 99%, in order to drive the site disease prevalence for the study closer to 60%. (Note: Site disease prevalence for the study could only be increased to 60% in order to maintain consistency between the individual blinded read batch’s disease prevalence, as required by the FDA).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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