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    Clinical Trial Results:
    Prospective non-randomized (pharmacoepidemiologic) cohort study (open-label, multicenter) to assess the magnitude of potential risk with the administration of Gadovist in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF) based on diagnostically specific clinical and histopathologic information

    Summary
    EudraCT number
    		 2008-004496-22
    Trial protocol
    		 DE   AT   FR  
    Global end of trial date
    27 Jan 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Sep 2016
    First version publication date
    26 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-4875/13273
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00828737
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    27 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the magnitude of potential risk with the administration of Gadovist in subjects with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF), based on diagnostically specific clinical and histopathological information.
    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. 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
    08 Dec 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 170
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 95
    Country: Number of subjects enrolled
    Germany: 277
    Country: Number of subjects enrolled
    Italy: 173
    Country: Number of subjects enrolled
    Korea, Republic of: 95
    Country: Number of subjects enrolled
    Spain: 47
    Country: Number of subjects enrolled
    Switzerland: 40
    Country: Number of subjects enrolled
    Thailand: 12
    Worldwide total number of subjects
    926
    EEA total number of subjects
    667
    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)
    337
    From 65 to 84 years
    552
    85 years and over
    37

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 08 December 2008 (first subject first visit) and 27 January 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Of 926 enrolled subjects, 907 were treated with study drug. The reasons for 19 subjects failure were withdrawal of consent, failed to meet entrance criteria and other reasons.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mild Renal Impairment
    Arm description
    		 Subjects with mild (estimated glomerular filtration rate [eGFR] greater than [>] 65 milliliter [mL]/minute/1.73 square meter [m^2]) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) at a dose range of 0.1 to 0.3 millimole (mmol)/kilogram (kg) body weight (1 mmol/kg=1 mL/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86-4875
    Other name
    Gadovist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with mild (eGFR >65 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) at a dose range of 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Arm title
    		 Extended Moderate Renal Impairment
    Arm description
    		 Subjects with extended moderate (eGFR >59 and less than or equal to (<=) 65 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86-4875
    Other name
    Gadovist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with extended moderate (eGFR >59 and <=65 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Arm title
    		 Moderate Renal Impairment
    Arm description
    		 Subjects with moderate (eGFR greater than or equal to (>=) 30 and <=59 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86- 4875
    Other name
    Gadovist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with moderate (eGFR >=30 and <=59 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Arm title
    		 Severe Renal Impairment
    Arm description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86-4875
    Other name
    Gadovist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Arm title
    		 Severe Renal Impairment Dialysis Dependent
    Arm description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment and dependent on dialysis, received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86-4875
    Other name
    Gadovist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment and dependent on dialysis, received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Number of subjects in period 1 [1]
    		Mild Renal Impairment Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment Severe Renal Impairment Dialysis Dependent
    Started
    38
    46
    539
    202
    82
    Completed
    0
    22
    340
    115
    46
    Not completed
    38
    24
    199
    87
    36
         Consent withdrawn by subject
    -
    3
    24
    10
    6
         Death
    -
    4
    94
    41
    18
         Unspecified
    36
    12
    53
    20
    5
         Lost to follow-up
    -
    2
    27
    16
    7
         Failed to meet entrance criteria
    -
    1
    -
    -
    -
         Protocol deviation
    2
    2
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all enrolled subjects were treated with study drug. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mild Renal Impairment
    Reporting group description
    		 Subjects with mild (estimated glomerular filtration rate [eGFR] greater than [>] 65 milliliter [mL]/minute/1.73 square meter [m^2]) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) at a dose range of 0.1 to 0.3 millimole (mmol)/kilogram (kg) body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Extended Moderate Renal Impairment
    Reporting group description
    		 Subjects with extended moderate (eGFR >59 and less than or equal to (<=) 65 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Moderate Renal Impairment
    Reporting group description
    		 Subjects with moderate (eGFR greater than or equal to (>=) 30 and <=59 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Severe Renal Impairment
    Reporting group description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Severe Renal Impairment Dialysis Dependent
    Reporting group description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment and dependent on dialysis, received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group values
    		 Mild Renal Impairment Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment Severe Renal Impairment Dialysis Dependent Total
    Number of subjects
    		 38 46 539 202 82 907
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ± 13.91 67.2 ± 11.6 68 ± 12.02 66.8 ± 12.18 59.8 ± 13.84 -
    Gender categorical
    Units: Subjects
        Female
    		 14 18 179 75 31 317
        Male
    		 24 28 360 127 51 590

    End points

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    End points reporting groups
    Reporting group title
    Mild Renal Impairment
    Reporting group description
    		 Subjects with mild (estimated glomerular filtration rate [eGFR] greater than [>] 65 milliliter [mL]/minute/1.73 square meter [m^2]) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) at a dose range of 0.1 to 0.3 millimole (mmol)/kilogram (kg) body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Extended Moderate Renal Impairment
    Reporting group description
    		 Subjects with extended moderate (eGFR >59 and less than or equal to (<=) 65 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Moderate Renal Impairment
    Reporting group description
    		 Subjects with moderate (eGFR greater than or equal to (>=) 30 and <=59 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Severe Renal Impairment
    Reporting group description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Severe Renal Impairment Dialysis Dependent
    Reporting group description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment and dependent on dialysis, received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Subject analysis set title
    Severe Renal Impairment-Combined
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Severe renal impairment-combined (N= 284) was classified or splitted into two groups one was severe renal imapairment (N= 202) and the other was severe renal impairment dialysis dependent (N= 82).

    Subject analysis set title
    Full Analysis Set (FAS) Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were enrolled into the study and received Gadovist were included in the FAS.

    Subject analysis set title
    Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS included all subjects except the subjects with an eGFR greater than (>) 59 to less than or equal to (=<) 65 mL/min/1.73 m^2 as determined by the central laboratory, who were received a Gadolinium based contrast agent (GBCA) other than study drug in the 12 months prior to the magnetic resonance imaging (MRI) examination were not included.

    Primary: Number of Subjects With Moderate to Severe Renal Impairment, who Develop Nephrogenic Systemic Fibrosis (NSF), Based on Diagnostically Specific Clinical and Histopathological Information

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    End point title
    		 Number of Subjects With Moderate to Severe Renal Impairment, who Develop Nephrogenic Systemic Fibrosis (NSF), Based on Diagnostically Specific Clinical and Histopathological Information [1] [2]
    End point description
    Clinicopathological definition of NSF requires both clinical symptoms and histopathological findings to make a confident diagnosis. Scores range of clinicopathological were 0 to 4, where 0= another diagnosis can be made, 1= inconsistent, 2= suggestive, 3= consistent, 4= highly consistent. A diagnosis of NSF was made to subjects in whom the clinicopathological score was at least consistent. Either the clinical score or the histopathology score had to be at least 2, and the other at least 3.
    End point type
    Primary
    End point timeframe
    From the time of MRI until the end of follow-up period (24 months)
    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.
    [2] - 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: As the endpoint states "Subjects with Moderate and Severe Renal Impairment", subjects with mild renal impairment were not included. "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment-Combined
    Number of subjects analysed
    39 [3]
    516 [4]
    275 [5]
    Units: Subjects
    0
    0
    0
    Notes
    [3] - PPS
    [4] - PPS
    [5] - PPS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Moderate to Severe Renal Impairment in Whom no Biopsy was Obtained who Develop Nephrogenic Systemic Fibrosis (NSF) Based on Diagnostically Specific Clinical Information

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    End point title
    		 Number of Subjects With Moderate to Severe Renal Impairment in Whom no Biopsy was Obtained who Develop Nephrogenic Systemic Fibrosis (NSF) Based on Diagnostically Specific Clinical Information [6]
    End point description
    Subjects in whom no biopsy was obtained with a clinical score of 4 on a scale comprising 0-other diagnosis, 1-inconsistent, 2-suggestive, 3-consistent, 4-highly consistent.
    End point type
    Secondary
    End point timeframe
    From the time of MRI until the end of follow-up period (24 months)
    Notes
    [6] - 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: As the endpoint states "Subjects with Moderate and Severe Renal Impairment", subjects with mild renal impairment were not included. "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment-Combined
    Number of subjects analysed
    39 [7]
    516 [8]
    275 [9]
    Units: Subjects
    0
    0
    0
    Notes
    [7] - PPS
    [8] - PPS
    [9] - PPS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Different Criteria of Diagnostic Confidence of the Investigator Based on the Gadovist-enhanced Magnetic Resonance Imaging (MRI)

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    End point title
    		 Number of Subjects With Different Criteria of Diagnostic Confidence of the Investigator Based on the Gadovist-enhanced Magnetic Resonance Imaging (MRI) [10]
    End point description
    The investigator was to record subjects confidence in making a diagnosis using a 4-point scale (Very high confidence, High confidence, Moderate, Low confidence). The number of subjects who reported different criteria of diagnostic confidence of the investigator based on the gadovist-enhanced MRI, were presented below.
    End point type
    Secondary
    End point timeframe
    Immediately after Gadovist-enhanced MRI
    Notes
    [10] - 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: "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Mild Renal Impairment Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment-Combined
    Number of subjects analysed
    38 [11]
    46 [12]
    539 [13]
    284 [14]
    Units: Subjects
        Very High
    23
    31
    251
    150
        High
    14
    11
    250
    110
        Moderate
    1
    3
    33
    21
        Low
    0
    0
    5
    3
        Missing
    0
    1
    0
    0
    Notes
    [11] - FAS population
    [12] - FAS population
    [13] - FAS population
    [14] - FAS population
    No statistical analyses for this end point

    Secondary: Number of Subjects With Image Quality Sufficient for Diagnosis

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    End point title
    		 Number of Subjects With Image Quality Sufficient for Diagnosis [15]
    End point description
    The investigator was to record image quality of the Gadovist enhanced magnetic resonance (MR) image on qualitative assessment basis. The recordings were reported as 'yes', 'no' and 'missing'.
    End point type
    Secondary
    End point timeframe
    Immediately after Gadovist-enhanced MRI
    Notes
    [15] - 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: "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Mild Renal Impairment Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment-Combined
    Number of subjects analysed
    38 [16]
    46 [17]
    539 [18]
    284 [19]
    Units: Subjects
        No
    0
    0
    4
    3
        Yes
    38
    45
    535
    281
        Missing
    0
    1
    0
    0
    Notes
    [16] - FAS population
    [17] - FAS population
    [18] - FAS population
    [19] - FAS population
    No statistical analyses for this end point

    Secondary: Evaluation of C-reactive Protein (CRP) in Subjects With Moderate and Severe Renal Impairment

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    End point title
    		 Evaluation of C-reactive Protein (CRP) in Subjects With Moderate and Severe Renal Impairment [20]
    End point description
    Specific cytokine CRP was evaluated and reported to characterize any potentially existing differences in subjects with moderate and severe renal impairment.
    End point type
    Secondary
    End point timeframe
    Within 48 hours prior to the Gadovist administration
    Notes
    [20] - 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: As the endpoint states "Subjects with Moderate and Severe Renal Impairment", subjects with mild renal impairment were not included. "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment Severe Renal Impairment Dialysis Dependent
    Number of subjects analysed
    18 [21]
    283 [22]
    133 [23]
    53 [24]
    Units: miligram per liter
        arithmetic mean (standard deviation)
    32.42 ± 45.563
    31.31 ± 41.364
    41.84 ± 70.345
    34.95 ± 46.465
    Notes
    [21] - FAS population with subjects evaluable for this outcome.
    [22] - FAS population with subjects evaluable for this outcome.
    [23] - FAS population with subjects evaluable for this outcome.
    [24] - FAS population with subjects evaluable for this outcome.
    No statistical analyses for this end point

    Secondary: Evaluation of Macrophage Inflammatory Proteins (MIP) and Monocyte Chemotactic Proteins (MCP) in Subjects With Moderate and Severe Renal Impairment

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    End point title
    		 Evaluation of Macrophage Inflammatory Proteins (MIP) and Monocyte Chemotactic Proteins (MCP) in Subjects With Moderate and Severe Renal Impairment [25]
    End point description
    MIPs (MIP-1 beta, MIP-2) and MCPs (MCP-1, MCP-3) were evaluated and reported to characterize any potentially existing differences in subjects with moderate and severe renal impairment. In the categories listed below, "N" signifies the number of subjects evaluable for the respective category.
    End point type
    Secondary
    End point timeframe
    Within 48 hours prior to the Gadovist administration
    Notes
    [25] - 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: As the endpoint states "Subjects with Moderate and Severe Renal Impairment", subjects with mild renal impairment were not included. "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment Severe Renal Impairment Dialysis Dependent
    Number of subjects analysed
    46 [26]
    539 [27]
    202 [28]
    82 [29]
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        MIP-1 beta (N= 44, 526, 198, 79)
    311.89 ± 188.875
    363.28 ± 532.692
    396.79 ± 648.74
    791.21 ± 3814.956
        MIP-2 (N= 42, 525, 198, 79)
    786.37 ± 776.666
    619.54 ± 588.275
    670.63 ± 598.305
    456.67 ± 330.863
        MCP-1 (N= 42, 526, 195, 78)
    125.96 ± 61.889
    130.76 ± 189.794
    139.2 ± 142.496
    144.54 ± 83.585
        MCP-3 (N=25, 214, 95, 32)
    31.47 ± 37.966
    33.84 ± 30.506
    46.83 ± 66.211
    36.02 ± 29.092
    Notes
    [26] - FAS population
    [27] - FAS population
    [28] - FAS population
    [29] - FAS population
    No statistical analyses for this end point

    Secondary: Evaluation of Osteopontin and Tissue Inhibitor of Metallo Proteinase 1 (TIMP1) in Subjects With Moderate and Severe Renal Impairment

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    End point title
    		 Evaluation of Osteopontin and Tissue Inhibitor of Metallo Proteinase 1 (TIMP1) in Subjects With Moderate and Severe Renal Impairment [30]
    End point description
    Osteopontin and TIMP1 were evaluated and reported to characterize any potentially existing differences in subjects with moderate and severe renal impairment. In the categories listed below, "N" signifies the number of subjects evaluable for the respective category.
    End point type
    Secondary
    End point timeframe
    Within 48 hours prior to the Gadovist administration
    Notes
    [30] - 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: As the endpoint states "Subjects with Moderate and Severe Renal Impairment", subjects with mild renal impairment were not included. "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment Severe Renal Impairment Dialysis Dependent
    Number of subjects analysed
    44 [31]
    525 [32]
    198 [33]
    79 [34]
    Units: nanogram per milliliter
    arithmetic mean (standard deviation)
        Osteopontin
    27.23 ± 15.899
    41.44 ± 61.48
    87.66 ± 112.252
    101.2 ± 76.857
        TIMP1
    158.85 ± 59.179
    187.6 ± 99.455
    253.72 ± 237.127
    268.27 ± 99.728
    Notes
    [31] - FAS population with subjects evaluable for this outcome.
    [32] - FAS population with subjects evaluable for this outcome.
    [33] - FAS population with subjects evaluable for this outcome.
    [34] - FAS population with subjects evaluable for this outcome.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAE), Drug-related Treatmentemergent Adverse Events (TEAEs) and Drug-related Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Event (TESAE), Drug-related Treatmentemergent Adverse Events (TEAEs) and Drug-related Treatment-emergent Serious Adverse Events (TESAEs) [35]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A TEAE was defined as any AE arising or worsening after the start of study drug administration.
    End point type
    Secondary
    End point timeframe
    From the time of MRI until the end of follow-up period (24 months)
    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: "Severe renal impairment" and "severe renal impairment dialysis dependent" reporting groups in the baseline period were combined in the subject analysis set "Severe Renal ImpairmentCombined" which was created to report the data for this endpoint. Hence, the end point is not reporting statistics for all the arms in the baseline period.
    End point values
    		 Mild Renal Impairment Extended Moderate Renal Impairment Moderate Renal Impairment Severe Renal Impairment-Combined
    Number of subjects analysed
    38 [36]
    46 [37]
    539 [38]
    284 [39]
    Units: Subjects
        At Least One TEAE
    0
    0
    2
    3
        At Least One Serious TEAE
    0
    0
    0
    0
        At Least One TEAE related to BAY86-4875
    0
    0
    1
    2
        At Least One TEAE related to study conduct
    0
    0
    1
    0
        At Least One Serious TEAE related to BAY86-4875
    0
    0
    0
    0
    Notes
    [36] - FAS population
    [37] - FAS population
    [38] - FAS population
    [39] - FAS population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of study drug treatment until the end of follow-up period (24 months)
    Adverse event reporting additional description
    A treatment-emergent adverse event was defined as any adverse event arising or worsening after the start of study drug administration.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Mild Renal Impairment
    Reporting group description
    		 Subjects with mild (eGFR >65 mL/minute/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) at a dose range of 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Severe Renal Impairment-Combined
    Reporting group description
    		 Subjects with severe (eGFR <30 mL/minute/1.73 m^2) renal impairment whether dialysis dependent or not, received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg). This reporting group is a combined group of both ‘severe renal impairment’ and ‘severe renal impairment dialysis dependent’ reporting groups.

    Reporting group title
    Moderate Renal Impairment
    Reporting group description
    		 Subjects with moderate (eGFR >=30 and <=59 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Reporting group title
    Extended Moderate Renal Impairment
    Reporting group description
    		 Subjects with extended moderate (eGFR >59 and <=65 mL/min/1.73 m^2) renal impairment received single intravenous injection of Gadobutrol (Gadovist, BAY86-4875) 0.1 to 0.3 mmol/kg body weight (1 mmol/kg=1 mL/kg).

    Serious adverse events
    		 Mild Renal Impairment Severe Renal Impairment-Combined Moderate Renal Impairment Extended Moderate Renal Impairment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 284 (0.00%)
    0 / 539 (0.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Mild Renal Impairment Severe Renal Impairment-Combined Moderate Renal Impairment Extended Moderate Renal Impairment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 284 (1.06%)
    2 / 539 (0.37%)
    0 / 46 (0.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 284 (0.00%)
    1 / 539 (0.19%)
    0 / 46 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Retching
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 284 (0.35%)
    0 / 539 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 284 (0.35%)
    0 / 539 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 284 (0.00%)
    1 / 539 (0.19%)
    0 / 46 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Groin infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 284 (0.35%)
    0 / 539 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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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.
    Since the final datasets are not yet available, the current results have been prepared using draft datasets. Therefore, data should be interpreted with caution. Decimal places were automatically truncated if last decimal equals zero.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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