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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind Placebo Controlled Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of PF-04360365 (Ponezumab) in Adult Subjects With Probable Cerebral Amyloid Angiopathy

    Summary
    EudraCT number
    2013-001557-27
    Trial protocol
    GB   NL  
    Global end of trial date
    23 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Sep 2016
    First version publication date
    30 Sep 2016
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    A9951024
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01821118
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    23 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To evaluate the efficacy of PF-04360365 (ponezumab) in subjects with probable cerebral amyloid angiopathy (CAA) as compared to placebo on a blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) measure of cerebrovascular reactivity. Secondary Objectives: To evaluate the efficacy of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on additional BOLD fMRI measures of cerebrovascular reactivity and to evaluate the effect of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on changes in the concentration of total plasma amyloid beta (AB). Safety Objective: To evaluate the safety, tolerability and pharmacokinetics (PK) of PF-04360365 (ponezumab) in subjects with probable CAA.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study subjects.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Netherlands: 2
    Worldwide total number of subjects
    36
    EEA total number of subjects
    11
    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)
    12
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted in 5 countries (Canada, France, Netherlands, United Kingdom, and United States). Male or female subjects of non childbearing potential between the ages of 55 and 80 years old were enrolled. Subjects must have had the diagnosis of probable CAA using the Modified Boston criteria.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Double-blind (subject and investigator blinded)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PF-04360365
    Arm description
    Subjects received a loading dose of PF-04360365 10 milligrams (mg)/kilograms (kg) on Day 1, followed by PF-04360365 7.5 mg/kg on Days 30 and 60. PF-04360365 was administered via intravenous (IV) infusion over a period of 10-15 minutes (min) and dosing was based on subject weight.
    Arm type
    Experimental

    Investigational medicinal product name
    PF-04360365
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 milligrams/kilograms (mg/kg) at Day 1, followed by 7.5 mg/kg at Days 30 and 60. Administered via intravenous (IV) infusion over a period of 10-15 minutes (mins).

    Arm title
    Placebo
    Arm description
    Subjects received a loading dose of placebo matching PF-04360365 10 mg/kg on Day 1, followed by placebo matching PF-04360365 7.5 mg/kg on Days 30 and 60. Placebo was also administered via IV infusion over a period of 10-15 min.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg at Day 1, followed by 7.5 mg/kg at Days 30 and 60 administered via IV infusion over a period of 10-15 mins.

    Number of subjects in period 1
    PF-04360365 Placebo
    Started
    24
    12
    Completed
    24
    11
    Not completed
    0
    1
         Adverse event, serious fatal
    -
    1

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    PF-04360365
    Reporting group description
    Subjects received a loading dose of PF-04360365 10 milligrams (mg)/kilograms (kg) on Day 1, followed by PF-04360365 7.5 mg/kg on Days 30 and 60. PF-04360365 was administered via intravenous (IV) infusion over a period of 10-15 minutes (min) and dosing was based on subject weight.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a loading dose of placebo matching PF-04360365 10 mg/kg on Day 1, followed by placebo matching PF-04360365 7.5 mg/kg on Days 30 and 60. Placebo was also administered via IV infusion over a period of 10-15 min.

    Reporting group values
    PF-04360365 Placebo Total
    Number of subjects
    24 12 36
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    6 6 12
        From 65-84 years
    18 6 24
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    68.8 ± 6.8 65 ± 5.7 -
    Gender, Male/Female
    Units: participants
        Female
    8 5 13
        Male
    16 7 23

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    PF-04360365
    Reporting group description
    Subjects received a loading dose of PF-04360365 10 milligrams (mg)/kilograms (kg) on Day 1, followed by PF-04360365 7.5 mg/kg on Days 30 and 60. PF-04360365 was administered via intravenous (IV) infusion over a period of 10-15 minutes (min) and dosing was based on subject weight.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a loading dose of placebo matching PF-04360365 10 mg/kg on Day 1, followed by placebo matching PF-04360365 7.5 mg/kg on Days 30 and 60. Placebo was also administered via IV infusion over a period of 10-15 min.

    Primary: Change from baseline to Day 2 in cerebrovascular reactivity as measured by the slope (amplitude over time to peak) from visual task-evoked functional magnetic resonance imaging (fMRI)

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    End point title
    Change from baseline to Day 2 in cerebrovascular reactivity as measured by the slope (amplitude over time to peak) from visual task-evoked functional magnetic resonance imaging (fMRI)
    End point description
    Blood Oxygen Level Dependant (BOLD) fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using Arterial Spin Labeled (ASL) scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. "n" signifies number of evaluable subjects for the specified region of interest (ROI) at Day 2. Geometric means are presented in original scale and standard errors (SE) are presented in natural logarithmic (log e) scale.
    End point type
    Primary
    End point timeframe
    Baseline, Day 2
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: percent/second
    geometric mean (standard error)
        Region of interest (ROI) 1 (n=20, 11)
    0.954 ± 0.085
    0.969 ± 0.073
        ROI2 (n=23, 11)
    0.933 ± 0.05
    0.999 ± 0.055
    Statistical analysis title
    ROI1 Day 2 geometric mean ratio
    Statistical analysis description
    Bayesian analysis of covariance (ANCOVA) model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-04360365/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.984
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.184
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.112
    Notes
    [1] - SE of mean presented in log e scale.
    Statistical analysis title
    ROI2 Day 2 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-04360365/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.934
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.825
         upper limit
    1.056
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.075
    Notes
    [2] - SE of mean presented on log e scale.

    Primary: Change from baseline to Day 90 in cerebrovascular reactivity as measured by the slope (amplitude over time to peak) from visual task-evoked fMRI

    Close Top of page
    End point title
    Change from baseline to Day 90 in cerebrovascular reactivity as measured by the slope (amplitude over time to peak) from visual task-evoked fMRI
    End point description
    BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. "n" signifies number of evaluable subjects for the specified region of interest (ROI) at Day 90. Geometric means are presented in original scale and SEs are presented in log e scale.
    End point type
    Primary
    End point timeframe
    Baseline, Day 90
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: percent/second
    geometric mean (standard error)
        ROI1 (n=20, 10)
    0.817 ± 0.064
    0.958 ± 0.063
        ROI2 (n=23, 10)
    0.857 ± 0.055
    0.95 ± 0.06
    Statistical analysis title
    ROI1 Day 90 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.852
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.735
         upper limit
    0.989
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.091
    Notes
    [3] - SE of mean presented on log e scale.
    Statistical analysis title
    ROI2 Day 90 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.902
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.788
         upper limit
    1.031
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.082
    Notes
    [4] - SE of mean presented on log e scale.

    Secondary: Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the time to peak from visual task-evoked fMRI

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    End point title
    Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the time to peak from visual task-evoked fMRI
    End point description
    BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. "n" signifies number of evaluable subjects for the specified ROI at the specified days. Geometric means are presented in original scale and SEs are presented in log e scale.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 90
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: seconds
    geometric mean (standard error)
        ROI1, Day 2 (n=20, 11)
    1.012 ± 0.028
    1.007 ± 0.037
        ROI1, Day 90 (n=20, 10)
    1.065 ± 0.02
    1.015 ± 0.03
        ROI2, Day 2 (n=23, 11)
    1.008 ± 0.018
    1.01 ± 0.026
        ROI2, Day 90 (n=23, 10)
    1.039 ± 0.018
    1.028 ± 0.026
    Statistical analysis title
    ROI1 Day 2 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    1.005
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.933
         upper limit
    1.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046
    Notes
    [5] - SE of mean presented on log e scale.
    Statistical analysis title
    ROI1 Day 90 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    1.049
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.114
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Notes
    [6] - SE of mean presented on log e scale.
    Statistical analysis title
    ROI2 Day 2 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.998
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.947
         upper limit
    1.052
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.032
    Notes
    [7] - SE of mean presented on log e scale.
    Statistical analysis title
    ROI2 Day 90 geometric mean ratio
    Statistical analysis description
    Bayesian ANCOVA model with treatment fitted as a fixed effect and baseline as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    Method
    Bayesian ANCOVA
    Parameter type
    Geometric Mean Ratio
    Point estimate
    1.01
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.063
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.031
    Notes
    [8] - SE of mean presented on log e scale.

    Secondary: Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the amplitude from visual task-evoked fMRI

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    End point title
    Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the amplitude from visual task-evoked fMRI
    End point description
    BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. "n" signifies number of evaluable subjects for the specified ROI at the specified days. All values presented are on log e scale.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 90
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: percent
    least squares mean (confidence interval 90%)
        ROI1, Day 2 (n=20, 11)
    -0.0381 (-0.1655 to 0.0894)
    -0.0983 (-0.2715 to 0.075)
        ROI1, Day 90 (n=20, 10)
    -0.1389 (-0.2513 to -0.0264)
    -0.053 (-0.2135 to 0.1075)
        ROI2, Day 2 (n=23, 11)
    -0.0714 (-0.1584 to 0.0156)
    -0.0226 (-0.1484 to 0.1033)
        ROI2, Day 90 (n=23, 10)
    -0.1245 (-0.2236 to -0.0254)
    -0.0357 (-0.1861 to 0.1146)
    Statistical analysis title
    ROI1 Day 2 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    0.0602
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.1576
         upper limit
    0.2781
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1281
    Statistical analysis title
    ROI1 Day 90 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    -0.0859
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.2843
         upper limit
    0.1124
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1165
    Statistical analysis title
    ROI2 Day 2 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    -0.0488
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.2018
         upper limit
    0.1042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0902
    Statistical analysis title
    ROI2 Day 90 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    -0.0888
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.2689
         upper limit
    0.0914
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1061

    Secondary: Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the time to return to baseline from visual task-evoked fMRI

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    End point title
    Change from baseline to Day 2 and Day 90 in cerebrovascular reactivity as measured by the time to return to baseline from visual task-evoked fMRI
    End point description
    BOLD fMRI was performed at Screening (Baseline) and on Days 2 and 90. During each of these sessions, BOLD fMRI images were acquired in rapid succession as a flashing radial black and white checkerboard was presented alternately with a gray screen. This well established visual stimulus is known to produce a reliable increase in BOLD fMRI signal within the visual cortex region of the occipital lobe. The time course of the BOLD fMRI signal was used to assess the vascular reactivity. Imaging sites also acquired cerebral blood flow data using ASL scans at Screening and on Days 2 and 90. A standard T1-weighted image was also acquired to aid image analysis. All efficacy scans were analyzed centrally. "n" signifies number of evaluable subjects for the specified ROI at the specified days. All values presented are on log e scale.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2, Day 90
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: seconds
    least squares mean (confidence interval 90%)
        ROI1, Day 2 (n=20, 11)
    0.0245 (-0.0155 to 0.0644)
    -0.022 (-0.0759 to 0.0319)
        ROI1, Day 90 (n=20, 10)
    0.0558 (0.0182 to 0.0934)
    -0.0179 (-0.0711 to 0.0354)
        ROI2, Day 2 (n=23, 11)
    0.0045 (-0.028 to 0.0369)
    -0.0174 (-0.0643 to 0.0295)
        ROI2, Day 90 (n=23, 10)
    0.0275 (-0.004 to 0.0589)
    0.0158 (-0.0322 to 0.0637)
    Statistical analysis title
    ROI1 Day 2 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    0.0464
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.0207
         upper limit
    0.1136
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0395
    Statistical analysis title
    ROI2 Day 2 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    0.0219
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.0352
         upper limit
    0.079
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0337
    Statistical analysis title
    ROI1 Day 90 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    0.0737
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.0084
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0383
    Statistical analysis title
    ROI2 Day 90 geometric mean ratio
    Statistical analysis description
    ANCOVA model with log e (baseline value) as a covariate, analyzed on a log e scale. Geometric mean ratio: PF-03084014/placebo.
    Comparison groups
    PF-04360365 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Estimated Treatment Difference (log e)
    Point estimate
    0.0117
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.046
         upper limit
    0.0694
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034

    Secondary: Change from baseline in concentration of total plasma amyloid beta (AB)

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    End point title
    Change from baseline in concentration of total plasma amyloid beta (AB)
    End point description
    Cerebral amyloid angiopathy (CAA) is caused by the progressive deposition of amyloid, predominantly AB40, within the walls of cerebral blood vessels with a predisposition for the vessels of the occipital lobe. As such, it is of interest to investigate the effect of PF-04360365 on AB concentrations. AB1-x and AB1-40 were investigated. "n" signifies number of subjects with measurable AB at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre dose and 8 hours post dose), Day 2, Day 30, Day 90, Day 240 (or at Early Termination)
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: picograms (pg)/milliliter (mL)
    arithmetic mean (standard deviation)
        AB1-x, Day 1 (n=4, 3)
    4374 ± 420.62
    5.3 ± 26.01
        AB1-x, Day 2 (n=4, 3)
    13911.8 ± 3292.88
    -37.7 ± 29.02
        AB1-x, Day 30 (n=4, 3)
    94468.5 ± 11946.21
    -48.3 ± 103.32
        AB1-x, Day 90 (n=4, 2)
    111312.8 ± 24677.74
    -62 ± 141.42
        AB1-x, Day 240 (n=4, 3)
    30495.8 ± 10931.16
    13 ± 116.76
        AB1-40, Day 1 (n=23, 11)
    4747.6 ± 1039.96
    -8.4 ± 30.08
        AB1-40, Day 2 (n=23, 11)
    12845.2 ± 2887.91
    0.5 ± 30.9
        AB1-40, Day 30 (n=23, 10)
    68010.1 ± 17396.04
    -5 ± 46.81
        AB1-40, Day 90 (n=23, 10)
    87710.8 ± 18699.28
    0.7 ± 44.02
        AB1-40, Day 240 (n=23, 9)
    20665.6 ± 7132.91
    -6.2 ± 35.63
    No statistical analyses for this end point

    Secondary: Number of subjects with brain structural magnetic resonance imaging (sMRI) abnormalities

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    End point title
    Number of subjects with brain structural magnetic resonance imaging (sMRI) abnormalities
    End point description
    Brain sMRI abnormalities included cerebral edema and total infarcts (including cortical infarcts, white matter infarcts, and subcortical gray matter infarcts). "Total infarcts" is the total number of subjects with at least 1 type of infarct.
    End point type
    Secondary
    End point timeframe
    Baseline/Screening, Day 15, Day 45, Day 90.
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
        Cerebral edema, Screening
    0
    1
        Cerebral edema, Day 15
    0
    1
        Cerebral edema, Day 45
    0
    1
        Cerebral edema, Day 90
    1
    1
        Total infarcts, Screening
    5
    3
        Total infarcts, Day 15
    5
    3
        Total infarcts, Day 45
    5
    3
        Total infarcts, Day 90
    5
    3
        Cortical infarcts, Screening
    0
    0
        Cortical infarcts, Day 15
    0
    0
        Cortical infarcts, Day 45
    0
    0
        Cortical infarcts, Day 90
    0
    0
        White matter infarcts, Screening
    3
    2
        White matter infarcts, Day 15
    3
    2
        White matter infarcts, Day 45
    3
    2
        White matter infarcts, Day 90
    3
    2
        Subcortical gray matter infarcts, Screening
    3
    1
        Subcortical gray matter infarcts, Day 15
    3
    1
        Subcortical gray matter infarcts, Day 45
    3
    1
        Subcortical gray matter infarcts, Day 90
    3
    1
    No statistical analyses for this end point

    Secondary: Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time

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    End point title
    Mean Montreal Cognitive Assessment (MoCA) Total Score Over Time
    End point description
    The Montreal Cognitive Assessment (MoCA) was used as a safety outcome measure to assess any changes in cognition. The MoCA is a 1-page 30-point test administered in approximately 10 minutes. The MoCA assessed short term memory, visuospatial abilities, multiple aspects of executive functions, attention, concentration, working memory, and language, as well as orientation to time and place. A score of more than or equal to (>=) 26 to 30 (maximum possible point) is considered as normal. An average of 22 points is considered as mild cognitive impairment. Lower scores indicate decreasing cognitive function. On Day 240, the number of evaluable participants in the placebo group was 11 instead of 12.
    End point type
    Secondary
    End point timeframe
    Screening; Days 0, 1, 30, 60, 90, and 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Screening
    25.4 ± 4.24
    25.9 ± 1.73
        Day 0
    25.5 ± 3.41
    25.9 ± 3.34
        Day 1
    25.1 ± 3.1
    25.8 ± 2.73
        Day 30
    27 ± 2.46
    26.8 ± 2.53
        Day 60
    26.6 ± 3.12
    26.8 ± 3.33
        Day 90
    26 ± 3.46
    26.7 ± 3.14
        Day 240
    26.1 ± 3.43
    26.5 ± 2.73
    No statistical analyses for this end point

    Secondary: Number of subjects with all causality and treatment-related treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events (AEs)

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    End point title
    Number of subjects with all causality and treatment-related treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events (AEs)
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. AEs comprised both SAEs and non-SAEs. An 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. Treatment-emergent adverse events (TEAEs) were defined as newly occurring AEs or those worsening after first dose.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
        All causality TEAEs
    16
    8
        Treatment-related TEAEs
    2
    2
        All causality SAEs
    2
    2
        Treatment-related SAEs
    0
    1
        All causality severe TEAEs
    2
    2
        Treatment-related severe TEAEs
    0
    1
        Discontinued due to all causality TEAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with laboratory abnormalities

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    End point title
    Number of subjects with laboratory abnormalities
    End point description
    Number of subjects with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, liver function (including Hy's Law Criteria), renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy).
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
    14
    10
    No statistical analyses for this end point

    Secondary: Number of subjects with vital signs values meeting categorical summarization criteria

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    End point title
    Number of subjects with vital signs values meeting categorical summarization criteria
    End point description
    Categorical summarization criteria in vital signs included: supine systolic blood pressure (SBP) of less than (<)90 millimeters of mercury (mm Hg) or more than (>) 160 mm Hg; supine diastolic blood pressure (DBP) <50 mm Hg or >100 mm Hg; supine pulse rate of <60 beats per minute (bpm) or >100 bpm; maximum changes (increase or decrease) from baseline in supine SBP of >=20 mm Hg; maximum increase from baseline in supine DBP of >=20 mm Hg; and maximum decrease from baseline in supine DBP of >=10 mm Hg.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
        Supine SBP <90 mm Hg
    1
    0
        Supine SBP >160 mm Hg
    2
    2
        Supine DBP <50 mm Hg
    1
    0
        Supine DBP >100 mm Hg
    0
    1
        Supine pulse rate <60 bpm
    16
    7
        Supine pulse rate >100 bpm
    0
    1
        Increase from baseline in supine SBP >=20 mm Hg
    6
    4
        Increase from baseline in supine DBP >=20 mm Hg
    1
    1
        Decrease from baseline in supine SBP >=20 mm Hg
    9
    6
        Decrease from baseline in supine DBP >=10 mm Hg
    13
    5
    No statistical analyses for this end point

    Secondary: Overall number of subjects with positive responses to questions on the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    Overall number of subjects with positive responses to questions on the Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS assessed whether subject responded "yes" to the following: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, self-injurious behavior with no suicidal intent.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
        Completed suicide
    0
    0
        Suicide attempt
    0
    0
        Preparatory acts to imminent suicidal behaviour
    0
    0
        Self-injurious behaviour, no suicidal intent
    1
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with significant changes from baseline in physical examination at final visit

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    End point title
    Number of subjects with significant changes from baseline in physical examination at final visit
    End point description
    A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.
    End point type
    Secondary
    End point timeframe
    Baseline up to Final Visit (Day 240)
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with significant changes in neurological examination results

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    End point title
    Number of subjects with significant changes in neurological examination results
    End point description
    A complete/full neurological examination included assessment of the cranial nerves; muscle strength, tone, cortical drift, abnormal movements; deep tendon reflexes; sensory exam, coordination, gait and station.
    End point type
    Secondary
    End point timeframe
    Baseline up till Day 240
    End point values
    PF-04360365 Placebo
    Number of subjects analysed
    24
    12
    Units: subjects
    2
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PF-04360365 antibodies

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    End point title
    Number of subjects with anti-PF-04360365 antibodies [9]
    End point description
    Blood samples were collected from subjects who received active treatment to assess for presence/absence of anti-PF-04360365 antibodies.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 240
    Notes
    [9] - 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: Statistical Analysis was not performed for this endpoint
    End point values
    PF-04360365
    Number of subjects analysed
    24
    Units: subjects
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and serious AEs (SAEs) monitoring started from screening through and including 28 calendar days after the last administration of the investigational product.
    Adverse event reporting additional description
    All treated subjects were analyzed for AEs. The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and a nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received a loading dose of placebo matching PF-04360365 10 mg/kg at Day 1, followed by placebo matching PF-04360365 7.5 mg/kg at Days 30 and 60. Placebo was also administered via IV infusion over a period of 10-15 min.

    Reporting group title
    PF-04360365
    Reporting group description
    Subjects received a loading dose of PF-04360365 10 milligrams (mg)/kilograms (kg) at Day 1, followed by PF-04360365 7.5 mg/kg at Days 30 and 60. PF-04360365 was administered via intravenous (IV) infusion over a period of 10-15 minutes (min) and dosing was based on subject weight.

    Serious adverse events
    Placebo PF-04360365
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 24 (8.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo PF-04360365
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
    16 / 24 (66.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Emotional disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Testicular cyst
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Jaw fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Balance disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Cerebellar syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Coordination abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Epilepsy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Hypoaesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Migraine
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Partial seizures
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Superficial siderosis of central nervous system
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Vitreous floaters
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Neck pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Infections and infestations
    Fungal skin infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2012
    Inclusion/exclusion criteria updated and other minor updates/clarifications
    23 Jul 2013
    Minor wording updates/changes
    09 Apr 2014
    Acknowledge safety and tolerability profile in the protocol is in line with past Alzheimer's Disease studies; updated exclusion criteria related to seizure history, body weight, and use of anti-epileptic drugs; Other clarifications and updates to reflect the updated protocol template.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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