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    Clinical Trial Results:
    Open-label, multi-center, two-stage, age stratified, pharmacokinetic, safety, and efficacy study in children 2 months to < 2 years of age undergoing Magnevist Injection enhanced MRI

    Summary
    EudraCT number
    		 2009-013081-17
    Trial protocol
    		 DE  
    Global end of trial date
    09 Sep 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-6661/91784
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00937391
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study number: 312046
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine the optimal efficacious dose [0.05 millimoles per kilogram body weight (mmol/kg BW) or 0.1 mmol/kg BW) of Magnevist injection in Stage 1. 2. To evaluate pharmacokinetics (PK) of Magnevist injection at the optimal efficacious dose from Stage 1 in this population in Stage 2.
    Protection of trial subjects
    To take into account that this clinical trial enrolled children, the following specific ethical considerations and provisions were followed: 1. Minimized as far as feasible the number of pediatric study subjects and examinations to allow for meaningful assessment of PK parameters (the primary objective of this trial) 2. Employed population based PK approach allowing sparse sampling for PK analysis [according to International Conference on Harmonization Efficacy module 11 (ICH E11)] 3. Employed for PK measurements, a sensitive analytical assay requiring only small blood samples and a laboratory experienced with handling small volume samples for safety (in accord with ICH E11) 4. Drew volumes of blood as low as feasible for safety and PK investigations [that is, total sample volumes for safety and PK assessments about 4 to 5 milliliter (mL)] 5. Used indwelling catheters rather than multiple venous punctures whenever feasible and considered topical anesthesia where catheter was placed 6. Minimized, in general, any discomfort, inconvenience, pain, fright, and time of separation from parents or familiar surroundings 7. Provided a child friendly and familiar environment 8. Ensured that only Investigators and staff with pediatric experience participated in this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    54
    EEA total number of subjects
    48
    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)
    54
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The date of the first subject, first visit was 21 January 2010. The date of the last subject, last visit was 09 September 2010. The date of the Blinded Read for Stage 1 was 27 April 2010. The date of the Blinded Read for Stage 2 was 08 September 2010.

    Pre-assignment
    Screening details
    		 A subject was enrolled in either Stage 1 or Stage 2 and not both. Overall for both stages, 61 subjects were screened, 7 were screen failures, and 54 were enrolled and treated of which 53 subjects completed the study (20 unique subjects in Stage 1 and 33 unique subjects in Stage 2).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1
    Arm description
    		 Subjects received an intravenous (IV) injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine. Upon completion of the magnetic resonance (MR) imaging, the subjects received another injection of 0.05 mmol/kg for a total cumulative dose of 0.1 mmol/kg BW (0.2 mL/kg BW).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadopentetate dimeglumine
    Investigational medicinal product code
    BAY86-6661
    Other name
    Magnevist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine. Upon completion of the MR imaging, the subjects received another injection of 0.05 mmol/kg for a total cumulative dose of 0.1 mmol/kg BW (0.2 mL/kg BW).

    Arm title
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Arm description
    		 Subjects received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadopentetate dimeglumine
    Investigational medicinal product code
    BAY86-6661
    Other name
    Magnevist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].

    Number of subjects in period 1
    		Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Started
    20
    34
    Completed
    20
    33
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1
    Reporting group description
    		 Subjects received an intravenous (IV) injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine. Upon completion of the magnetic resonance (MR) imaging, the subjects received another injection of 0.05 mmol/kg for a total cumulative dose of 0.1 mmol/kg BW (0.2 mL/kg BW).

    Reporting group title
    Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Reporting group description
    		 Subjects received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].

    Reporting group values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2 Total
    Number of subjects
    		 20 34 54
    Age categorical
    Units: Subjects
        2 to 6 months
    		 6 11 17
        6 to 12 months
    		 6 11 17
        12 months to 2 years
    		 8 12 20
    Gender categorical
    Units: Subjects
        Female
    		 13 13 26
        Male
    		 7 21 28
    Race, Customized
    Units: Subjects
        White
    		 19 33 52
        Asian
    		 1 0 1
        Multiple
    		 0 1 1
    Body Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 8.4 ( 2.6 ) 8 ( 2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1
    Reporting group description
    		 Subjects received an intravenous (IV) injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine. Upon completion of the magnetic resonance (MR) imaging, the subjects received another injection of 0.05 mmol/kg for a total cumulative dose of 0.1 mmol/kg BW (0.2 mL/kg BW).

    Reporting group title
    Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Reporting group description
    		 Subjects received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].

    Subject analysis set title
    Primary Analysis Set (PAS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In order to ensure that there would be 5 valid subjects per age group, more than 5 subjects were enrolled in Stage 1. The determination of the optimal dose was based on 5 valid subjects per age group. Therefore, the PAS (N=15) was defined as an additional analysis set, consisting of the first 5 PPS subjects of each age group (sorted by date of enrollment). The PAS was used for the determination of the optimal efficacious dose in Stage 1 only.

    Subject analysis set title
    Stage 1 (Unenhanced Image)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects (N=20) for whom unenhanced image was taken before administering any injection in Stage 1.

    Subject analysis set title
    Gadopentetate Dimeglumine - Stage 1 and 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Stage 1: All subjects who received the appropriate dose of gadopentetate dimeglumine injection based on kg BW. Stage 2: Subjects who received plus or minus (+/-) 10% of the appropriate dose of gadopentetate dimeglumine injection based on kg BW and had values for both PK samples. Overall, this reporting group consisted of 44 subjects.

    Subject analysis set title
    Full analysis set (FAS) - Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=54) for safety and for efficacy included all subjects who received any amount of the investigational product.

    Subject analysis set title
    Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS defined for Stage 1 as all 18 subjects who received the appropriate dose of gadopentetate dimeglumine Injection based on kg BW and in Stage 2 as 26 subjects who received +/- 10% of the appropriate dose based on kg BW and had values for both PK samples.

    Subject analysis set title
    Stage 2 (Combination Image)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects (N=34) received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].

    Subject analysis set title
    Stage 2 (Unenhanced Image)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects (N=34) for whom unenhanced image was taken before administering any injection in Stage 2.

    Subject analysis set title
    Stage 1 (Combination Image 0.1 mmol/kg)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects (N=20) received an IV injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine.

    Subject analysis set title
    Stage 1 (Combination Image 0.05 mmol/kg)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects (N=20) received an IV injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine.

    Subject analysis set title
    Pharmacokinetic Analysis Set (PKS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PKS (N=44) was based on the PPS defined for Stage 1 as all subjects (N=18) who received the appropriate dose of gadopentetate dimeglumine injection based on kg BW and in Stage 2 as those subjects (N=26) who received +/- 10% of the appropriate dose based on kg BW and had values for both PK samples.

    Primary: Number of Subjects With Diagnostic Adequacy - Open-label Clinical Investigator (CI) (Per Protocol Set)

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    End point title
    		 Number of Subjects With Diagnostic Adequacy - Open-label Clinical Investigator (CI) (Per Protocol Set) [1]
    End point description
    A clinical judgment by the open-label CIs as to whether ("yes") or not ("no") the CI could make a diagnosis from the image.
    End point type
    Primary
    End point timeframe
    Within 5 minutes after 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    3 [2]
    3 [3]
    Units: subjects
        No
    0
    1
        Yes
    3
    2
    Notes
    [2] - Only first 3 subjects of Stage 1 received 2 IV injections of 0.05 mmol/kg BW.
    [3] - Only first 3 subjects of Stage 1 received 2 IV injections of 0.05 mmol/kg BW.
    No statistical analyses for this end point

    Primary: Dose Determined by Blinded Readers (BR) to be Superior for Diagnosis

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    End point title
    		 Dose Determined by Blinded Readers (BR) to be Superior for Diagnosis [4]
    End point description
    Dose superiority was a calculation based upon the BRs' assessment of 4 visualization parameters.
    End point type
    Primary
    End point timeframe
    Within 5 minutes after 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Primary Analysis Set (PAS)
    Number of subjects analysed
    15
    Units: subjects
        BR 1, 0.05 mmol/kg
    0
        BR 2, 0.05 mmol/kg
    1
        BR 3, 0.05 mmol/kg
    6
        BR 1, 0.1 mmol/kg
    15
        BR 2, 0.1 mmol/kg
    14
        BR 3, 0.1 mmol/kg
    9
    No statistical analyses for this end point

    Primary: Paired-dose Comparison of Number of Subjects With Dose Superiority Determined for 4 Lesion Visualization Variables - Blinded Readers (BRs)

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    End point title
    		 Paired-dose Comparison of Number of Subjects With Dose Superiority Determined for 4 Lesion Visualization Variables - Blinded Readers (BRs) [5]
    End point description
    For each subject, the BR indicated which dose had better contrast enhancement, better border delineation, clearer internal morphology, and provided more diagnostic information. The dose chosen for 3 or 4 of these variables was the selected dose for that BR and subject. If each dose was superior on 2 variables, the dose which provided more diagnostic information was selected for that subject. The dose selected for the majority of subjects was the dose selected by that BR; if chosen by 2 or 3 BRs, it was the selected dose.
    End point type
    Primary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [5] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    15 [6]
    15 [7]
    Units: subjects
        BR 1 - Diagnostic information
    15
    0
        BR 2 - Diagnostic information
    14
    1
        BR 3 - Diagnostic information
    9
    6
        BR 1 - Contrast enhancement
    15
    0
        BR 2 - Contrast enhancement
    14
    1
        BR 3 - Contrast enhancement
    8
    7
        BR 1 - Border delineation
    15
    0
        BR 2 - Border delineation
    14
    1
        BR 3 - Border delineation
    9
    6
        BR 1 - Internal morphology
    15
    0
        BR 2 - Internal morphology
    14
    1
        BR 3 - Internal morphology
    9
    6
    Notes
    [6] - PAS.
    [7] - PAS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Total Clearance (CL)

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    End point title
    		 Pharmacokinetic Analysis - Total Clearance (CL) [8]
    End point description
    Total clearance is the fraction of the volume of distribution (Vd) which is completely purified per unit of time and depends also on the plasma half-life of the drug.
    End point type
    Primary
    End point timeframe
    20 to 45 min and 4 to 8 hours post injection
    Notes
    [8] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [9]
    Units: liters/hour
        median (full range (min-max))
    1.012 (0.272 to 1.588)
    Notes
    [9] - PKS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Total Clearance (CL)/Body Weight (BW)

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    End point title
    		 Pharmacokinetic Analysis - Total Clearance (CL)/Body Weight (BW) [10]
    End point description
    CL/BW = total clearance normalized by BW.
    End point type
    Primary
    End point timeframe
    20 to 45 min and 4 to 8 hours 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [11]
    Units: liters/hour/kg
        median (full range (min-max))
    0.129 (0.059 to 0.166)
    Notes
    [11] - PKS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Volume of Distribution at Steady State (Vss)

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    End point title
    		 Pharmacokinetic Analysis - Volume of Distribution at Steady State (Vss) [12]
    End point description
    Vss is an estimate of drug distribution independent of the elimination process and is proportional to the amount of drug in the body versus the drug plasma concentration at steady-state.
    End point type
    Primary
    End point timeframe
    20 to 45 min and 4 to 8 hours 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [13]
    Units: liters
        median (full range (min-max))
    1.784 (0.68 to 3.11)
    Notes
    [13] - PKS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Volume of Distribution at Steady State (Vss) /Body Weight (BW)

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    End point title
    		 Pharmacokinetic Analysis - Volume of Distribution at Steady State (Vss) /Body Weight (BW) [14]
    End point description
    PK Analysis - Volume of Distribution at Steady State (Vss) /Body Weight (BW).
    End point type
    Primary
    End point timeframe
    20 to 45 min and 4 to 8 hours post injection
    Notes
    [14] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [15]
    Units: liters/kg
        median (full range (min-max))
    0.232 (0.192 to 0.27)
    Notes
    [15] - PKS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Area Under the Drug Concentration-time Curve (AUC)

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    End point title
    		 Pharmacokinetic Analysis - Area Under the Drug Concentration-time Curve (AUC) [16]
    End point description
    AUC = Area under the drug concentration-time curve from administration to infinity.
    End point type
    Primary
    End point timeframe
    Samples taken 20 to 45 min and 4 to 8 hours post injection. AUC calculated from time of injection to infinity.
    Notes
    [16] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [17]
    Units: micromoles*hour/liter
        median (full range (min-max))
    777.5 (600.8 to 1686.3)
    Notes
    [17] - PKS.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Analysis - Terminal Elimination Half life (t1/2)

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    End point title
    		 Pharmacokinetic Analysis - Terminal Elimination Half life (t1/2) [18]
    End point description
    t1/2 = termination elimination half-life calculated from the area under the drug concentration-time curve from administration to infinity.
    End point type
    Primary
    End point timeframe
    Samples taken at 20 to 45 min and at 4 to 8 hours post injection; t1/2 calculated from area under the drug concentration-time curve from administration to infinity
    Notes
    [18] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Gadopentetate Dimeglumine - Stage 1 and 2
    Number of subjects analysed
    44 [19]
    Units: hour
        median (full range (min-max))
    1.483 (1.142 to 8.427)
    Notes
    [19] - PKS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Number of Lesions Detected - Stage 1

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    End point title
    		 Number of Subjects With Number of Lesions Detected - Stage 1
    End point description
    The BRs and the open-label Clinical Investigators determined the number of subjects with 0, 1, 2, and 3 or more lesions.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Unenhanced Image) Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [20]
    20 [21]
    20 [22]
    Units: subjects
        BR 1 - 0 lesions
    5
    5
    5
        BR 2 - 0 lesions
    7
    7
    6
        BR 3 - 0 lesions
    8
    6
    5
        CI - 0 lesions
    11
    11
    11
        BR 1 - 1 lesion
    7
    7
    7
        BR 2 - 1 lesion
    8
    7
    8
        BR 3 - 1 lesion
    8
    9
    10
        CI - 1 lesion
    6
    6
    6
        BR 1 - 2 lesions
    5
    5
    5
        BR 2 - 2 lesions
    1
    2
    2
        BR 3 - 2 lesions
    0
    1
    1
        CI - 2 lesions
    1
    1
    1
        BR 1 - 3 or more lesions
    3
    3
    3
        BR 2 - 3 or more lesions
    4
    4
    4
        BR 3 - 3 or more lesions
    4
    4
    4
        CI - 3 or more lesions
    2
    2
    2
    Notes
    [20] - FAS.
    [21] - FAS.
    [22] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Number of Lesions Detected - Stage 2

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    End point title
    		 Number of Subjects With Number of Lesions Detected - Stage 2
    End point description
    The BRs and the open-label CIs determined the number of subjects with 0, 1, 2, and 3 or more lesions.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 2 (Unenhanced Image) Stage 2 (Combination Image)
    Number of subjects analysed
    34 [23]
    34 [24]
    Units: subjects
        BR 1 - 0 lesions
    13
    13
        BR 2 - 0 lesions
    12
    11
        BR 3 - 0 lesions
    14
    10
        CI - 0 lesions
    17
    15
        BR 1 - 1 lesions
    18
    17
        BR 2 - 1 lesions
    15
    16
        BR 3 - 1 lesions
    11
    13
        CI - 1 lesions
    15
    15
        BR 1 - 2 lesions
    1
    2
        BR 2 - 2 lesions
    5
    4
        BR 3 - 2 lesions
    3
    4
        CI - 2 lesions
    0
    1
        BR 1 - 3 or more lesions
    2
    2
        BR 2 - 3 or more lesions
    2
    3
        BR 3 - 3 or more lesions
    6
    7
        CI - 3 or more lesions
    2
    3
    Notes
    [23] - FAS.
    [24] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Quality of Lesion Visualization - Stage 1

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    End point title
    		 Number of Subjects With Quality of Lesion Visualization - Stage 1
    End point description
    The BRs and the open-label CIs determined the quality of lesion visualization with the unenhanced and the combined image sets based on a 3-point scale (1=excellent - lesion clearly seen and diagnosis possible; 2=fair but adequate - most of lesion seen and diagnosis possible; and 3=poor - lesion barely seen and diagnosis not possible).
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Unenhanced Image) Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [25]
    20 [26]
    20 [27]
    Units: subjects
        BR 1 - Excellent (1)
    4
    9
    7
        BR 2 - Excellent (1)
    3
    8
    6
        BR 3 - Excellent (1)
    2
    3
    3
        CI - Excellent (1)
    12
    20
    16
        BR 1 - Fair but adequate (2)
    16
    10
    12
        BR 2 - Fair but adequate (2)
    17
    12
    14
        BR 3 - Fair but adequate (2)
    16
    15
    15
        CI - Fair but adequate (2)
    4
    0
    4
        BR 1 - Poor (3)
    0
    1
    1
        BR 2 - Poor (3)
    0
    0
    0
        BR 3 - Poor (3)
    2
    2
    2
        CI - Poor (3)
    4
    0
    0
    Notes
    [25] - FAS.
    [26] - FAS.
    [27] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Quality of Lesion Visualization - Stage 2

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    End point title
    		 Number of Subjects With Quality of Lesion Visualization - Stage 2
    End point description
    The BRs and the open-label CIs determined the quality of lesion visualization with the unenhanced and the combined image sets based on a 3-point scale (1=excellent - lesion clearly seen and diagnosis possible; 2=fair but adequate - most of lesion seen and diagnosis possible; and 3=poor - lesion barely seen and diagnosis not possible).
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 2 (Unenhanced Image) Stage 2 (Combination Image)
    Number of subjects analysed
    34 [28]
    34 [29]
    Units: subjects
        BR 1 - Excellent (1)
    3
    25
        BR 2 - Excellent (1)
    7
    25
        BR 3 - Excellent (1)
    5
    18
        CI - Excellent (1)
    12
    32
        BR 1 - Fair but adequate (2)
    25
    8
        BR 2 - Fair but adequate (2)
    27
    9
        BR 3 - Fair but adequate (2)
    28
    16
        CI - Fair but adequate (2)
    14
    2
        BR 1 - Poor (3)
    6
    1
        BR 2 - Poor (3)
    0
    0
        BR 3 - Poor (3)
    1
    0
        CI - Poor (3)
    8
    0
    Notes
    [28] - FAS.
    [29] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Quality of Border Delineation - Stage 1

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    End point title
    		 Number of Subjects With Quality of Border Delineation - Stage 1
    End point description
    The BRs and the open-label CIs determined the quality of border delineation based on a 3-point scale (1=excellent - border completely delineated; 2=fair but adequate - some of the border is delineated; and 3=poor - entire or almost the entire border is not delineated) by image set.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Unenhanced Image) Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [30]
    20 [31]
    20 [32]
    Units: subjects
        BR 1 - Excellent (1)
    4
    10
    6
        BR 2 - Excellent (1)
    3
    8
    6
        BR 3 - Excellent (1)
    3
    4
    3
        CI - Excellent (1)
    12
    19
    16
        BR 1 - Fair but adequate (2)
    15
    9
    13
        BR 2 - Fair but adequate (2)
    16
    12
    14
        BR 3 - Fair but adequate (2)
    13
    15
    14
        CI - Fair but adequate (2)
    5
    1
    4
        BR 1 - Poor (3)
    1
    1
    1
        BR 2 - Poor (3)
    1
    0
    0
        BR 3 - Poor (3)
    4
    3
    3
        CI - Poor (3)
    3
    0
    0
    Notes
    [30] - FAS.
    [31] - FAS.
    [32] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Quality of Border Delineation - Stage 2

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    End point title
    		 Number of Subjects With Quality of Border Delineation - Stage 2
    End point description
    The BRs and the open-label CIs determined the quality of border delineation based on a 3-point scale (1=excellent - border completely delineated; 2=fair but adequate - some of the border is delineated; and 3=poor - entire or almost the entire border is not delineated) by image set.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 2 (Unenhanced Image) Stage 2 (Combination Image)
    Number of subjects analysed
    34 [33]
    34 [34]
    Units: subjects
        BR 1 - Excellent (1)
    4
    21
        BR 2 - Excellent (1)
    6
    17
        BR 3 - Excellent (1)
    8
    24
        CI - Excellent (1)
    12
    32
        BR 1 - Fair but adequate (2)
    24
    12
        BR 2 - Fair but adequate (2)
    28
    17
        BR 3 - Fair but adequate (2)
    25
    10
        CI - Fair but adequate (2)
    14
    2
        BR 1 - Poor (3)
    6
    1
        BR 2 - Poor (3)
    0
    0
        BR 3 - Poor (3)
    1
    0
        CI - Poor (3)
    8
    0
    Notes
    [33] - FAS.
    [34] - FAS.
    No statistical analyses for this end point

    Secondary: Most Frequent Diagnostic Findings With Unenhanced Images - Stage 1

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    End point title
    		 Most Frequent Diagnostic Findings With Unenhanced Images - Stage 1 [35]
    End point description
    The BRs and the open-label CIs determined the most frequent diagnostic findings with the unenhanced images.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1
    Number of subjects analysed
    20 [36]
    Units: subjects
        BR 1 - No lesion
    4
        BR 2 - No lesion
    7
        BR 3 - No lesion
    8
        CI - No lesion
    6
        BR 1 - Brain lesion
    8
        BR 2 - Brain lesion
    6
        BR 3 - Brain lesion
    4
        CI - Brain lesion
    7
    Notes
    [36] - FAS.
    No statistical analyses for this end point

    Secondary: Most Frequent Diagnostic Findings With Unenhanced Images - Stage 2

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    End point title
    		 Most Frequent Diagnostic Findings With Unenhanced Images - Stage 2
    End point description
    The BRs and the open-label CIs determined the most frequent diagnostic findings with the unenhanced images.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 2 (Combination Image)
    Number of subjects analysed
    34
    Units: subjects
        BR 1 - No lesion
    13
        BR 2 - No lesion
    12
        BR 3 - No lesion
    14
        CI - No lesion
    11
        BR 1 - Brain lesion
    9
        BR 2 - Brain lesion
    10
        BR 3 - Brain lesion
    10
        CI - Brain lesion
    10
    No statistical analyses for this end point

    Secondary: Overall Number of Subjects With Change in Diagnosis From Unenhanced to Combined Images - Stage 1

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    End point title
    		 Overall Number of Subjects With Change in Diagnosis From Unenhanced to Combined Images - Stage 1
    End point description
    The BRs and the open-label CIs determined the number of subjects with a change in diagnosis from unenhanced to combined images.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [37]
    20 [38]
    Units: subjects
        BR 1
    6
    6
        BR 2
    0
    1
        BR 3
    6
    6
        CI
    4
    4
    Notes
    [37] - FAS.
    [38] - FAS.
    No statistical analyses for this end point

    Secondary: Overall Number of Subjects With Change in Diagnosis From Unenhanced to Combined Images - Stage 2

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    End point title
    		 Overall Number of Subjects With Change in Diagnosis From Unenhanced to Combined Images - Stage 2 [39]
    End point description
    The BRs and the open-label CIs determined the number of subjects with a change in diagnosis from unenhanced to combined images.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Number of subjects analysed
    34 [40]
    Units: subjects
        BR 1
    10
        BR 2
    6
        BR 3
    10
        CI
    8
    Notes
    [40] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Specific Change in the Diagnosis From Unenhanced to Combined Images - Stage 1

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    End point title
    		 Number of Subjects With Specific Change in the Diagnosis From Unenhanced to Combined Images - Stage 1
    End point description
    Those subjects for whom the diagnosis changed for at least 1 BR from unenhanced to combined images are presented for Stage 1. For completeness, the corresponding data for these subjects are presented for the open-label CIs.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [41]
    20 [42]
    Units: subjects
        BR 1 - from "metastasis" to "liver lesion"
    0
    1
        BR 2 - from "no lesion" to "vascular malformation"
    0
    1
        BR 3 - from "no lesion" to "vascular malformation"
    0
    2
        BR 3 - from "no lesion" to "brain lesion"
    2
    1
        BR 1 - from "vasc. malform." to "vasc. malfrom."
    2
    2
        BR 1 - from "brain lesion" to "brain lesion"
    2
    2
        BR 3 - from "brain lesion" to "brain lesion"
    2
    2
        BR 1 - from "other" to "other"
    1
    1
        BR 3 - from "other" to "vascular malformation"
    1
    1
        BR 1 - from "metastasis" to "metastasis"
    1
    0
        BR 3 - from "liver lesion" to "metastasis"
    1
    0
    Notes
    [41] - FAS.
    [42] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Specific Change in the Diagnosis From Unenhanced to Combined Images - Stage 2

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    End point title
    		 Number of Subjects With Specific Change in the Diagnosis From Unenhanced to Combined Images - Stage 2 [43]
    End point description
    Those subjects for whom the diagnosis changed for at least 1 BR from unenhanced to combined images are presented for Stage 2. For completeness, the corresponding data for these subjects are presented for the open-label CIs.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Number of subjects analysed
    34 [44]
    Units: subjects
        BR 1 - from "no lesion" to "brain lesion"
    1
        BR 2 - from "no lesion" to "other"
    1
        BR 3 - from "no lesion" to "other"
    2
        BR 3 - from "no lesion" to "infectious disorder"
    2
        BR 1 - from "vasc. malform." to "vasc. malform."
    1
        BR 1 - from "inf. disorder" to "inf. disorder"
    1
        BR 1 - from "brain lesion" to "no lesion"
    1
        BR 1 - from "brain lesion" to "inf. disorder"
    1
        BR 1 - from "brain lesion" to "brain lesion"
    4
        BR 2 - from "brain lesion" to "brain lesion"
    1
        BR 3 - from "brain lesion" to "brain lesion"
    2
        BR 2 - from "renal lesion" to "renal lesion"
    1
        BR 3 - from "renal lesion" to "renal lesion"
    1
        BR 3 - from "not assessable" to "other"
    1
        BR 1 - from "other" to "vascular malformation"
    1
        BR 2 - from "other" to "vascular malformation"
    2
        BR 2 - from "other" to "other"
    1
        BR 3 - from "other" to "other"
    2
    Notes
    [44] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Diagnostic Confidence - Stage 1

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    End point title
    		 Number of Subjects With Diagnostic Confidence - Stage 1
    End point description
    The overall diagnostic confidence of the BRs and the open-label CIs was indicated on a 3-point scale: 1=not confident; 2=confident; and 3=very confident.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Unenhanced Image) Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [45]
    20 [46]
    20 [47]
    Units: subjects
        BR 1 - not confident
    1
    0
    0
        BR 2 - not confident
    3
    0
    0
        BR 3 - not confident
    2
    1
    0
        CI - not confident
    8
    0
    1
        BR 1 - confident
    17
    17
    17
        BR 2 - confident
    14
    6
    7
        BR 3 - confident
    13
    10
    13
        CI - confident
    3
    1
    5
        BR 1 - very confident
    2
    3
    3
        BR 2 - very confident
    3
    14
    13
        BR 3 - very confident
    5
    9
    7
        CI - very confident
    9
    19
    14
    Notes
    [45] - FAS.
    [46] - FAS.
    [47] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Diagnostic Confidence - Stage 2

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    End point title
    		 Number of Subjects With Diagnostic Confidence - Stage 2
    End point description
    The overall diagnostic confidence of the BRs and the open-label CIs was indicated on a 3-point scale: 1=not confident; 2=confident; and 3=very confident.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 2 (Unenhanced Image) Stage 2 (Combination Image)
    Number of subjects analysed
    34 [48]
    34 [49]
    Units: subjects
        BR 1 - not confident
    3
    0
        BR 2 - not confident
    3
    1
        BR 3 - not confident
    1
    0
        CI - not confident
    10
    0
        BR 1 - confident
    28
    18
        BR 2 - confident
    23
    4
        BR 3 - confident
    27
    8
        CI - confident
    18
    4
        BR 1 - very confident
    3
    16
        BR 2 - very confident
    8
    29
        BR 3 - very confident
    6
    26
        CI - very confident
    6
    30
    Notes
    [48] - FAS.
    [49] - FAS.
    No statistical analyses for this end point

    Secondary: Management Based on Unenhanced Images - Stage 1

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    End point title
    		 Management Based on Unenhanced Images - Stage 1 [50]
    End point description
    For Stage 1 based on unenhanced images, the recommended management is presented as determined by the open-label CIs.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes before injection
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 1, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 2".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1
    Number of subjects analysed
    18 [51]
    Units: subjects
        biopsy
    1
        surgery
    2
        follow-up
    3
        medical treatment
    2
        imaging
    10
    Notes
    [51] - FAS with only subjects for whom information on management was given.
    No statistical analyses for this end point

    Secondary: Management Based on Unenhanced Images - Stage 2

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    End point title
    		 Management Based on Unenhanced Images - Stage 2 [52]
    End point description
    For Stage 2 based on unenhanced images, the recommended management is presented as determined by the open-label CIs.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes before injection
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Number of subjects analysed
    32 [53]
    Units: subjects
        follow-up
    2
        imaging
    30
    Notes
    [53] - FAS with only subjects for whom information on management was given.
    No statistical analyses for this end point

    Secondary: Overall Number of Subjects With Change in Management From Unenhanced to Combined Images - Stage 1

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    End point title
    		 Overall Number of Subjects With Change in Management From Unenhanced to Combined Images - Stage 1
    End point description
    For Stage 1, the number of subjects for whom the recommended management of the open-label CIs changed from unenhanced to combined images is presented for both doses.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [54]
    20 [55]
    Units: subjects
    12
    5
    Notes
    [54] - FAS.
    [55] - FAS.
    No statistical analyses for this end point

    Secondary: Overall Number of Subjects With Change in Management From Unenhanced to Combined Images - Stage 2

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    End point title
    		 Overall Number of Subjects With Change in Management From Unenhanced to Combined Images - Stage 2 [56]
    End point description
    For Stage 2, the number of subjects for whom the recommended management of the open-label CIs changed from unenhanced to combined images is presented for the optimal efficacious dose determined in Stage 1.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Number of subjects analysed
    34 [57]
    Units: subjects
    30
    Notes
    [57] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Specific Change in Management From Unenhanced to Combined Images - Stage 1

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    End point title
    		 Number of Subjects With Specific Change in Management From Unenhanced to Combined Images - Stage 1
    End point description
    The actual change in management from unenhanced to combined images recommended by the open-label CIs is presented for both doses in Stage 1.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    End point values
    		 Stage 1 (Combination Image 0.1 mmol/kg) Stage 1 (Combination Image 0.05 mmol/kg)
    Number of subjects analysed
    20 [58]
    20 [59]
    Units: subjects
        from "follow-up" to "surgery"
    1
    1
        from "imaging" to "surgery"
    3
    2
        from "imaging" to "follow-up"
    1
    0
        from "imaging" to "imaging"
    0
    1
        from "imaging" to "other"
    6
    0
        from "other" to "follow-up"
    1
    1
    Notes
    [58] - FAS.
    [59] - FAS.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Specific Change in Management From Unenhanced to Combined Images - Stage 2

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    End point title
    		 Number of Subjects With Specific Change in Management From Unenhanced to Combined Images - Stage 2 [60]
    End point description
    The actual change in management from unenhanced to combined images recommended by the open-label CIs is presented in Stage 2 for the optimal efficacious dose determined in Stage 1.
    End point type
    Secondary
    End point timeframe
    Within 5 minutes after injection
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Since this endpoint was analysed only in Stage 2, statistics were not reported for other arm in the baseline period, that is, "Gadopentetate dimeglumine (Magnevist, BAY86-6661) - Stage 1".
    End point values
    		 Gadopentetate dimeglumine (Magnevist, BAY86-6661) – Stage 2
    Number of subjects analysed
    34 [61]
    Units: subjects
        from "imaging" to "surgery"
    3
        from "imaging" to "follow-up"
    16
        from "imaging" to "medical treatment"
    3
        from "imaging" to "imaging"
    3
        from "imaging" to "other"
    7
    Notes
    [61] - FAS.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment up to 30 days after last dose (follow-up)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Gadopentetate Dimeglumine - Stage 2
    Reporting group description
    		 Subjects received the optimal efficacious dose established in Stage 1 as a single IV injection of gadopentetate dimeglumine [0.1 mmol/kg BW (0.2 mL/kg BW)].

    Reporting group title
    Gadopentetate Dimeglumine - Stage 1
    Reporting group description
    		 Subjects received an IV injection of 0.05 mmol/kg BW (0.1 mL/kg BW) gadopentetate dimeglumine. Upon completion of the MR imaging, the subjects received another injection of 0.05 mmol/kg for a total cumulative dose of 0.1 mmol/kg BW (0.2 mL/kg BW).

    Serious adverse events
    		 Gadopentetate Dimeglumine - Stage 2 Gadopentetate Dimeglumine - Stage 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 34 (23.53%)
    4 / 20 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Krabbe's disease
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alagille syndrome
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital aortic anomaly
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Adenoidectomy
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor developmental delay
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal cyst
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Laryngeal stenosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Neurogenic bladder
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Gadopentetate Dimeglumine - Stage 2 Gadopentetate Dimeglumine - Stage 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 34 (5.88%)
    6 / 20 (30.00%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Decimal places were automatically truncated if last decimal equals zero.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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