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    Clinical Trial Results:
    An open-label, non-randomized study to evaluate the efficacy and safety of BAY 94-9172 (ZK 6013443) positron emission tomography (PET) imaging for detection/exclusion of cerebral ß-amyloid when compared to postmortem histopathology

    Summary
    EudraCT number
    		 2009-012569-79
    Trial protocol
    		 DE   FR  
    Global end of trial date
    24 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2016
    First version publication date
    16 Jul 2015
    Other versions
    Summary report(s)
    		 Combined File including all EudraCT files and statistics

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY94-9172/14595
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01020838
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Piramal Imaging SA
    Sponsor organisation address
    Route de l'Ecole 13, Matran, Switzerland, 1753
    Public contact
    Jürgen Hirschfeld, PhD, Piramal Imaging GmbH, +49 30461124615, juergen.hirschfeld@piramal.com
    Scientific contact
    Andrew Stephens, MD, PhD, Piramal Imaging GmbH, +49 30461124604, andrew.stephens@piramal.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
    30 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the sensitivity and specificity of the visual assessment of regional tracer uptake in the florbetaben (also referred to as BAY 94-9172) PET images compared to histological verification of the presence or absence of cerebral β-amyloid in the respective postmortem specimens as the standard of truth (SOT). To determine the sensitivity and specificity of the majority read "whole brain" visual assessment in detecting/excluding cerebral neuritic β-amyloid plaques compared with the corresponding histopathological SOT. To determine sensitivity and specificity of the subject level composite SUVR quantification calculated based on pathology results covering all available data. To determine the subject level composite SUVRs by SOT for baseline and available follow-up scans.
    Protection of trial subjects
    The trial was conducted in accordance with GCP Guidelines, the Declaration of Helsinki and according to national law. The trial started only after regulatory and ethical approval. Recruitment only started after the protocol was signed by the investigator. Only patients with informed consent were included in the study. All necessary insurances to guarantee compensation of patients in the case of adverse reactions were in place. In view of the positive safety profile of this investigational drug, including the minimal radiation applied by the tracer administration and transmission scanning, the foreseeable risks to the subjects and negative impact on the subject’s well-being were considered low.
    Background therapy
    		 Prior medication (or medication history) refers to medication taken within 8 weeks (recommended screening period, but up to 12 weeks is acceptable) before injection of the study drug. Concomitant medication refers to medication received by the subject from the point of injection of the study drug. Study participants received prior and concomitant medications during the study. Prior and concomitant medication was frequently used in the study and captured via the CRF. The most frequently documented concomitant medication by MedDRA preferred term included sodium chloride (32.9% of subjects), acetyl salicylic acid (28.2% of subjects), memantine (27.8% of subjects), donepezil (25.0% of subjects), paracetamol (15.7% of subjects), furosemide (13.9% of subjects), rivastigmine (12.0% of subjects), simvastatin (11.6% of subjects), and citalopram (11.1% of subjects).
    Evidence for comparator
    		 There is no comparator group available.
    Actual start date of recruitment
    25 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 70
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Japan: 54
    Country: Number of subjects enrolled
    Australia: 14
    Worldwide total number of subjects
    218
    EEA total number of subjects
    80
    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)
    42
    From 65 to 84 years
    123
    85 years and over
    53

    Subject disposition

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    Recruitment
    Recruitment details
    		 The main study population consisted of male or female subjects of any ethnic group with short life-expectancy (< 3 years). Both, subjects with a low probability of cerebral β-amyloid deposition and those with a high probability of β-amyloid deposition were included. Young cognitively normal HVs served as negative control.

    Pre-assignment
    Screening details
    		 A total of 253 subjects were screened at 15 study centers worldwide. Of the 253 screened subjects, 218 subjects were enrolled and assigned to treatment while 35 subjects were considered screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 253 [1]
    Intermediate milestone: Number of subjects
    Safety Analysis Set: 216
    Number of subjects completed
    		 216

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 35
    Reason: Number of subjects
    		 Never treated: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 35 subjects were screening failures and 2 subjects were never treated.
    Period 1
    Period 1 title
    Safety Analysis Set (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Safety Analysis Set
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Florbetaben
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Study participants were administered florbetaben under the direct supervision of a nuclear physician or designee. Access into a large vein (e.g., antecubital vein) was established using a suitable indwelling catheter (e.g., Venflow). To avoid extravasation of florbetaben, correct localization of the catheter was ensured by a test injection of normal saline prior to the injection of florbetaben.

    Number of subjects in period 1 [2]
    		Safety Analysis Set
    Started
    216
    Completed
    216
    Notes
    [2] - 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: Two patients were excluded from this population because injection of florbetaben was not done.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 -

    Reporting group values
    		 Safety Analysis Set Total
    Number of subjects
    		 216 216
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 42 42
        From 65-84 years
    		 121 121
        85 years and over
    		 53 53
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.39 ± 15.44 -
    Gender categorical
    Units: Subjects
        Female
    		 104 104
        Male
    		 112 112
    Subject analysis sets

    Subject analysis set title
    Primary Efficacy Analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To determine the sensitivity and specificity of the visual assessment of regional tracer uptake in the florbetaben (also referred to as BAY 94-9172) PET images compared to histological verification of the presence or absence of cerebral-amyloid in the respective postmortem specimens as the standard of truth (SoT).

    Subject analysis set title
    Final Analysis-Whole Brain
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To determine the sensitivity and specificity of the composite “whole brain” (per subject) regional visual assessment collapsed from the regional PET visual assessment results in detecting/excluding cerebral β-amyloid plaques based on the "whole brain" histopathological verification of the presence/absence of β-amyloid deposition based on the corresponding histopathological standard of truth.

    Subject analysis set title
    First Annual Repeat Injection
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients returning for first follow-up administration and PET scan.

    Subject analysis set title
    Second Annual Repeat Injection
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients returning for second follow-up Administration and PET scan.

    Subject analysis sets values
    		 Primary Efficacy Analysis Final Analysis-Whole Brain First Annual Repeat Injection Second Annual Repeat Injection
    Number of subjects
    41
    97
    91
    34
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    11
    18
    19
    8
        From 65-84 years
    18
    49
    51
    19
        85 years and over
    12
    30
    21
    7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.51 ± 24.96
    74.65 ± 18.94
    75 ± 11.33
    74.35 ± 11.67
    Gender categorical
    Units: Subjects
        Female
    15
    40
    48
    18
        Male
    26
    57
    43
    16

    End points

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    End points reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    		 -

    Subject analysis set title
    Primary Efficacy Analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To determine the sensitivity and specificity of the visual assessment of regional tracer uptake in the florbetaben (also referred to as BAY 94-9172) PET images compared to histological verification of the presence or absence of cerebral-amyloid in the respective postmortem specimens as the standard of truth (SoT).

    Subject analysis set title
    Final Analysis-Whole Brain
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To determine the sensitivity and specificity of the composite “whole brain” (per subject) regional visual assessment collapsed from the regional PET visual assessment results in detecting/excluding cerebral β-amyloid plaques based on the "whole brain" histopathological verification of the presence/absence of β-amyloid deposition based on the corresponding histopathological standard of truth.

    Subject analysis set title
    First Annual Repeat Injection
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients returning for first follow-up administration and PET scan.

    Subject analysis set title
    Second Annual Repeat Injection
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients returning for second follow-up Administration and PET scan.

    Primary: Sensitivity (Primary Efficacy Analysis)

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    End point title
    		 Sensitivity (Primary Efficacy Analysis) [1]
    End point description
    The sensitivity/specificity of the visual assessment were calculated based on the majority read assessment of regional tracer uptake. This result was derived from assessments by 3 independent readers for brain regions of a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was a centralized histopathological determination of β-amyloid presence/absence based on both Bielschowsky silver and immunohistochemical staining. Based on the PET images, a brain region was classified as “normal” or “abnormal” depending on the presence or absence of regional tracer uptake in the respective region. “Normal” therefore meant absence of β-amyloid and “abnormal” presence of β-amyloid. Sensitivity was defined as the percentage of abnormal brain regions from all regions where an SOT was available and the SOT was "β-amyloid present". Specificity was defined as the percentage of normal brain regions from all regions where an SOT was available and was "β-amyloid not present".
    End point type
    Primary
    End point timeframe
    90-110 minutes post injection (PET image acquisition)
    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: The statistical analysis is provided as separate attachment.
    End point values
    		 Primary Efficacy Analysis
    Number of subjects analysed
    41
    Units: Sensitivity [%]
    number (not applicable)
        Total
    77.36
        Frontal Cortex
    85.71
        Occipital Cortex
    88.89
        Hippocampus
    57.14
        Anterior Cingulate Cortex
    90
        Posterior Cingulate Cortex
    81.82
        Cerebellar Cortex
    0
    Attachments
    		 Sensitivity Statistical Analysis Primary Outcome
    No statistical analyses for this end point

    Primary: Specificity (Primary Efficacy Analysis)

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    End point title
    		 Specificity (Primary Efficacy Analysis) [2]
    End point description
    The sensitivity/specificity of the visual assessment were calculated based on the majority read assessment of regional tracer uptake. This result was derived from assessments by 3 independent readers for brain regions of a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was a centralized histopathological determination of β-amyloid presence/absence based on both Bielschowsky silver and immunohistochemical staining. Based on the PET images, a brain region was classified as “normal” or “abnormal” depending on the presence or absence of regional tracer uptake in the respective region. “Normal” therefore meant absence of β-amyloid and “abnormal” presence of β-amyloid. Sensitivity was defined as the percentage of abnormal brain regions from all regions where an SOT was available and the SOT was "β-amyloid present". Specificity was defined as the percentage of normal brain regions from all regions where an SOT was available and was "β-amyloid not present".
    End point type
    Primary
    End point timeframe
    90-110 minutes post injection (PET image acquisition)
    Notes
    [2] - 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: The statistical analysis is provided as separate attachment.
    End point values
    		 Primary Efficacy Analysis
    Number of subjects analysed
    41
    Units: Specificity [%]
    number (not applicable)
        Total
    94.2
        Frontal Cortex
    95
        Occipital Cortex
    86.36
        Hippocampus
    100
        Anterior Cingulate Cortex
    85.71
        Posterior Cingulate Cortex
    94.44
        Cerebellar Cortex
    100
    Attachments
    		 Specificity Statistical Analysis Primary Outcome
    No statistical analyses for this end point

    Secondary: Sensitivity and Specificity (Whole brain, BSS)

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    End point title
    		 Sensitivity and Specificity (Whole brain, BSS)
    End point description
    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a centralized histopathological assessment of the presence/absence of β-amyloid based on Bielschowsky silver staining (SOT 1). The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".
    End point type
    Secondary
    End point timeframe
    90-110 minutes post injection (PET image acquisition)
    End point values
    		 Final Analysis-Whole Brain
    Number of subjects analysed
    97
    Units: [%]
    number (confidence interval 95%)
        Sensitivity
    96.49 (91.71 to 100)
        Specificity
    85 (73.93 to 96.07)
    No statistical analyses for this end point

    Secondary: Sensitivity and Specificity (Whole brain, BSS+IHC)

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    End point title
    		 Sensitivity and Specificity (Whole brain, BSS+IHC)
    End point description
    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a centralized histopathological assessment of the presence/absence of β-amyloid based on Bielschowsky silver staining and immunohistochemistry (SOT 2). The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".
    End point type
    Secondary
    End point timeframe
    90-110 minutes post injection (PET image acquisition)
    End point values
    		 Final Analysis-Whole Brain
    Number of subjects analysed
    97
    Units: [%]
    number (confidence interval 95%)
        Sensitivity
    96.72 (92.25 to 100)
        Specificity
    94.44 (86.96 to 100)
    No statistical analyses for this end point

    Secondary: Sensitivity and Specificity (Whole brain, CERAD)

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    End point title
    		 Sensitivity and Specificity (Whole brain, CERAD)
    End point description
    Sensitivity and specificity of the whole brain visual assessment were calculated. Any brain with a region classified as abnormal from PET imaging was to be classified as abnormal for the "whole brain" assessment. This result was derived from assessments by 3 independent readers for a subject where a Standard of Truth (SOT) was available. The SOT for this analysis was based on a histopathological assessment of the presence/absence of β-amyloid according to CERAD Criteria (SOT 3). The sensitivity was defined as the proportion of brains classified as abnormal from all brains where this SOT was available and was "β-amyloid present". The specificity was defined as the proportion of brains classified as normal from all brains where this SOT was available and was "β-amyloid not present".
    End point type
    Secondary
    End point timeframe
    90-110 minutes post injection (PET image acquisition)
    End point values
    		 Final Analysis-Whole Brain
    Number of subjects analysed
    97
    Units: [%]
    number (confidence interval 95%)
        Sensitivity
    96.49 (91.71 to 100)
        Specificity
    85 (73.93 to 96.07)
    No statistical analyses for this end point

    Post-hoc: Sensitivity of Subject Level Composite SUVR by SOT

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    End point title
    		 Sensitivity of Subject Level Composite SUVR by SOT
    End point description
    Sensitivity and Specificity of subject level composite Standard Uptake Value Ratios (SUVR) by SOT for subjects with available brain tissue and 10 healthy volunteers. The SUVR were determined as a quantitative measure of tracer uptake. The SUV is defined as the ratio of the tissue radioactivity concentration c (in MBq/kg) at time point t, and the injected activity (in MBq), extrapolated to the same time (t) divided by the body weight (in kg). SUV numbers were then used to derive SUV ratios (SUVR) using the SUV from the cerebellar cortex as reference. SOTs comprised Bielschowsky silver staining (SOT 1), Bielschowsky silver staining with immunohistochemistry (SOT 2) and neuropathology assessment according to CERAD (SOT 3). SUVR analysis was performed for baseline and available follow-up scans. The optimal threshold for the distinction between β-amyloid present yes/no according to the respective SOT was derived based on ROC curve analyses and used to calculate Sensitivity and Specificity.
    End point type
    Post-hoc
    End point timeframe
    90-110 minutes post injection (PET image acquisition).
    End point values
    		 Final Analysis-Whole Brain
    Number of subjects analysed
    96 [3]
    Units: Sensitivity [%]
    number (not applicable)
        SOT 1 (initial period)
    89
        SOT 2 (initial period)
    90
        SOT 3 (initial period)
    89
        SOT 1 (last available scan)
    88
        SOT 2 (last available scan)
    89
        SOT 3 (last available scan)
    95
    Notes
    [3] - One subject not evaluable.
    No statistical analyses for this end point

    Post-hoc: Specificity of Subject Level Composite SUVR by SOT

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    End point title
    		 Specificity of Subject Level Composite SUVR by SOT
    End point description
    Sensitivity and Specificity of subject level composite Standard Uptake Value Ratios (SUVR) by SOT for subjects with available brain tissue and 10 healthy volunteers. The SUVR were determined as a quantitative measure of tracer uptake. The SUV is defined as the ratio of the tissue radioactivity concentration c (in MBq/kg) at time point t, and the injected activity (in MBq), extrapolated to the same time (t) divided by the body weight (in kg). SUV numbers were then used to derive SUV ratios (SUVR) using the SUV from the cerebellar cortex as reference. SOTs comprised Bielschowsky silver staining (SOT 1), Bielschowsky silver staining with immunohistochemistry (SOT 2) and neuropathology assessment according to CERAD (SOT 3). SUVR analysis was performed for baseline and available follow-up scans. The optimal threshold for the distinction between β-amyloid present yes/no according to the respective SOT was derived based on ROC curve analyses and used to calculate Sensitivity and Specificity
    End point type
    Post-hoc
    End point timeframe
    90-110 minutes post injection (PET image acquisition).
    End point values
    		 Final Analysis-Whole Brain
    Number of subjects analysed
    96 [4]
    Units: Specificty [%]
    number (not applicable)
        SOT 1 (initial period)
    82
        SOT 2 (initial period)
    91
        SOT 3 (initial period)
    90
        SOT 1 (last available scan)
    85
        SOT 2 (last available scan)
    94
        SOT 3 (last available scan)
    87
    Notes
    [4] - One subject was not evaluable.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All treatment emergent adverse events were recorded within 7 days of the application or follow-up application of study drug.
    Adverse event reporting additional description
    As this study was conducted in an end-of-life population, death occurring outside 7 day follow-up period after administration of the drug, was not collected as part of the study SAE data unless investigator considered the event to be related to drug administration or study procedure. None of the SAEs reported was causally related to the treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Initial Drug administration
    Reporting group description
    		 Subjects with TEAEs within 7 days of the initial administration of florbetaben.

    Reporting group title
    1st Repeat Drug Administration
    Reporting group description
    		 Subjects with TEAEs within 7 days of the 1st repeat drug administration.

    Reporting group title
    2nd Repeat Drug Administration
    Reporting group description
    		 Subjects with TEAEs within 7 days of the 2nd repeat drug administration.

    Serious adverse events
    		 Initial Drug administration 1st Repeat Drug Administration 2nd Repeat Drug Administration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 216 (5.56%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         number of deaths (all causes)
    88
    20
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Pubis fracture
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Frontotemporal dementia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Heat stroke
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cancer metastatic
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Initial Drug administration 1st Repeat Drug Administration 2nd Repeat Drug Administration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 216 (22.22%)
    22 / 91 (24.18%)
    14 / 34 (41.18%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 216 (1.39%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    Injury, poisoning and procedural complications
    Procedural hypertension
         subjects affected / exposed
    0 / 216 (0.00%)
    0 / 91 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 216 (0.46%)
    5 / 91 (5.49%)
    6 / 34 (17.65%)
         occurrences all number
    1
    5
    6
    Hypertension
         subjects affected / exposed
    5 / 216 (2.31%)
    1 / 91 (1.10%)
    1 / 34 (2.94%)
         occurrences all number
    5
    1
    1
    Hypotension
         subjects affected / exposed
    3 / 216 (1.39%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 216 (1.39%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    5 / 216 (2.31%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    5
    0
    0
    Injection site erythema
         subjects affected / exposed
    4 / 216 (1.85%)
    0 / 91 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    4
    0
    1
    Injection site haematoma
         subjects affected / exposed
    10 / 216 (4.63%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    10
    1
    0
    Injection site haemorrhage
         subjects affected / exposed
    1 / 216 (0.46%)
    4 / 91 (4.40%)
    2 / 34 (5.88%)
         occurrences all number
    1
    4
    2
    Injection site pain
         subjects affected / exposed
    4 / 216 (1.85%)
    0 / 91 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    0
    Puncture site reaction
         subjects affected / exposed
    7 / 216 (3.24%)
    4 / 91 (4.40%)
    0 / 34 (0.00%)
         occurrences all number
    7
    4
    0
    Pyrexia
         subjects affected / exposed
    7 / 216 (3.24%)
    2 / 91 (2.20%)
    0 / 34 (0.00%)
         occurrences all number
    8
    2
    0
    Vessel puncture site swelling
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 91 (1.10%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    Gastrointestinal disorders
    Frequent bowel movements
         subjects affected / exposed
    1 / 216 (0.46%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 216 (0.00%)
    0 / 91 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Emphysema
         subjects affected / exposed
    0 / 216 (0.00%)
    0 / 91 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 216 (0.46%)
    4 / 91 (4.40%)
    3 / 34 (8.82%)
         occurrences all number
    1
    5
    3
    Haemorrhage subcutaneous
         subjects affected / exposed
    1 / 216 (0.46%)
    3 / 91 (3.30%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    1
    Papule
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    2 / 216 (0.93%)
    1 / 91 (1.10%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 216 (0.00%)
    0 / 91 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2009
    Local amendment for Japan only. • FDG PET imaging supplementary efficacy variables • Changes to meet Japanese specific GCP requirements
    03 Jun 2010
    • Duration of screening period • Description of subject recruitment sources • Exclusion criterion 6 – Radiation exposure • Exclusion criterion 6 – More rapid enrollment • Use of a MRI performed outside the study • Biomarkers • injection procedure • Autopsy and histopathology evaluation of brains • Use of the Boston Naming Test • Description of drug product characteristics and formulation
    28 Sep 2010
    • Title Page - Change in the name of the Study Medical Expert and one of the Authors • Synopsis - Study Design - Change in the wording • Section 4.1.1.1 Inclusion criteria for the additional 10 negative controls only – Change in criteria 10 • Change in Exclusion Criteria #1 and #7 • Yearly follow-up visits (amended) • Editorial change in Table 4
    08 Dec 2010
    • A new inclusion criterion (no. 8) was added. • Statistical evaluation has been revised according to the recommendation made by FDA during the Type C meeting relating to the study-specific SAP. • In addition minor changes to the protocol were made: Correction of some mistakes eg, forgotten to adopt the corrections made in Amendment 3 and to correct the description of the non-demented volunteers, which are not healthy subjects .
    17 Oct 2011
    • Secondary objectives • Administration of the commercial formulation • Related to the audit function • PET scan visual assessment algorithm • Clarification that the 3-year follow-up was not mandatory • Several other (additional) minor editorial changes
    06 Dec 2012
    • Change of sponsor • Change of sponsor’s medical expert • Change of study administrative structur • Change of subsection “Actions and reporting obligations in case of serious adverse events” within section Serious adverse events • Change of section Monitoring

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25741488
    http://www.ncbi.nlm.nih.gov/pubmed/25824567
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