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    Clinical Trial Results:
    A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF PF-03049423 IN SUBJECTS WITH ISCHEMIC STROKE

    Summary
    EudraCT number
    2010-021414-32
    Trial protocol
    HU   DE   BG   CZ  
    Global end of trial date
    20 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Feb 2016
    First version publication date
    09 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A9541004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01208233
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc
    Sponsor organisation address
    235 E 42nd Street, New York, NY, United States, 10017
    Public contact
    Clinical Trials.gov Call Centre, Pfizer Inc, 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Clinical Trials.gov Call Centre, Pfizer Inc, 1 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
    27 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary Objective for Part 1: Safety Dose-Ranging Study To evaluate the safety and tolerability of PF-03049423 following multiple dose administration to subjects with ischemic stroke following 14 days of dosing. Primary Objective for Part 2: Proof-of-Concept study To assess the efficacy of PF-03049423, relative to placebo, using the modified Rankin Score (mRS) in subjects with ischemic stroke at Day 90.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2010
    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
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 41
    Worldwide total number of subjects
    178
    EEA total number of subjects
    102
    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)
    81
    From 65 to 84 years
    96
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 181 subjects were assigned to study treatment, 178 of which received study treatment.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: PF-03049423 1 mg
    Arm description
    Subjects received PF-03049423 1 mg once daily for 90 days.
    Arm type
    Experimental

    Investigational medicinal product name
    PF-03049423
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PF-03049423 1 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Arm title
    Cohort 1: Placebo
    Arm description
    Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 1 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Arm title
    Cohort 2: PF-03049423 3 mg
    Arm description
    Subjects received PF-03049423 3 mg once daily for 90 days.
    Arm type
    Experimental

    Investigational medicinal product name
    PF-03049423
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PF-03049423 3 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Arm title
    Cohort 2: Placebo
    Arm description
    Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 3 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Arm title
    Cohort 3: PF-03049423 6 mg
    Arm description
    Subjects received PF-03049423 6 mg once daily for 90 days.
    Arm type
    Experimental

    Investigational medicinal product name
    PF-03049423
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PF-03049423 6 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Arm title
    Cohort 3: Placebo
    Arm description
    Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 6 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

    Number of subjects in period 1
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Started
    11
    9
    11
    10
    70
    67
    Completed
    6
    6
    7
    9
    46
    46
    Not completed
    5
    3
    4
    1
    24
    21
         No longer willing to participate in the trial
    -
    -
    1
    1
    3
    -
         Medication error without adverse event
    -
    -
    -
    -
    -
    1
         Protocol deviation
    -
    -
    -
    -
    3
    -
         Subject withdrawn due to Sponsor request
    1
    1
    -
    -
    -
    -
         Subject took Tamsulosin for urinary disorder
    1
    -
    -
    -
    -
    -
         Adverse event, serious fatal
    -
    -
    -
    -
    3
    5
         Took prohibited concomitant medication: digoxin
    -
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    1
    2
    -
    3
    5
         Study terminated by Sponsor
    -
    -
    -
    -
    10
    7
         Consent withdrawn by subject
    1
    -
    -
    -
    1
    2
         Did not meet entrance criteria
    2
    1
    1
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: PF-03049423 1 mg
    Reporting group description
    Subjects received PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 2: PF-03049423 3 mg
    Reporting group description
    Subjects received PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 3: PF-03049423 6 mg
    Reporting group description
    Subjects received PF-03049423 6 mg once daily for 90 days.

    Reporting group title
    Cohort 3: Placebo
    Reporting group description
    Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

    Reporting group values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo Total
    Number of subjects
    11 9 11 10 70 67 178
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0
        Adults (18-64 years)
    5 4 1 5 33 33 81
        From 65-84 years
    6 5 10 5 36 34 96
        85 years and over
    0 0 0 0 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.3 ± 14.3 64.7 ± 6 69.8 ± 8.3 65.8 ± 13.4 64.2 ± 13.1 65.6 ± 11.3 -
    Gender categorical
    Units: Subjects
        Female
    4 2 7 3 28 26 70
        Male
    7 7 4 7 42 41 108

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: PF-03049423 1 mg
    Reporting group description
    Subjects received PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 2: PF-03049423 3 mg
    Reporting group description
    Subjects received PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 3: PF-03049423 6 mg
    Reporting group description
    Subjects received PF-03049423 6 mg once daily for 90 days.

    Reporting group title
    Cohort 3: Placebo
    Reporting group description
    Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

    Primary: Number of subjects with any abnormal laboratory test results (Part 1* and 2)

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    End point title
    Number of subjects with any abnormal laboratory test results (Part 1* and 2) [1]
    End point description
    The total number of subjects with laboratory test abnormalities (without regard to baseline abnormality) was assessed. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The Full Analysis Set (FAS) consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) up to Day 90
    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: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [2]
    9 [3]
    10 [4]
    10 [5]
    70 [6]
    66 [7]
    Units: subjects
    8
    8
    10
    9
    64
    56
    Notes
    [2] - Subjects analyzed indicated number of subjects evaluated.
    [3] - Subjects analyzed indicated number of subjects evaluated.
    [4] - Subjects analyzed indicated number of subjects evaluated.
    [5] - Subjects analyzed indicated number of subjects evaluated.
    [6] - Subjects analyzed indicated number of subjects evaluated.
    [7] - Subjects analyzed indicated number of subjects evaluated.
    No statistical analyses for this end point

    Primary: Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2)

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    End point title
    Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2) [8]
    End point description
    Vital signs included blood pressure (BP; supine, sitting and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic BP (SBP) greater than or equal to (>=) 30 or 50 millimeters of mercury (mm Hg) change from grand baseline in same posture, systolic less than (<) 90 mm Hg; diastolic BP (DBP) >=20 mm Hg change from grand baseline in same posture, diastolic <50 mm Hg; 2), pulse rate (supine, sitting and standing): <40 or greater than (>) 120 beats per minute (bpm); Standing: <40 or >140 bpm. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of evaluable subjects. 99999=No subjects were evaluated.
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) up to follow-up (28 days after Day 90)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [9]
    9 [10]
    11 [11]
    10 [12]
    70 [13]
    67 [14]
    Units: subjects
        Supine SBP <90 mm Hg, n=11,9,11,10,70,67
    0
    1
    1
    0
    3
    0
        Sitting SBP <90 mm Hg, n=10,8,9,5,55,59
    0
    1
    1
    0
    2
    2
        Standing SBP <90 mm Hg, n=7,7,9,8,49,48
    0
    0
    0
    0
    1
    1
        Supine DBP <50 mm Hg, n=11,9,11,10,70,67
    0
    0
    2
    1
    6
    4
        Sitting DBP <50 mm Hg, n=10,8,9,5,55,59
    0
    0
    0
    0
    3
    1
        Standing DBP <50 mm Hg, n=7,7,9,8,49,48
    0
    0
    0
    1
    2
    3
        Supine pulse rate <40 bpm, n=11,9,11,10,70,67
    0
    0
    0
    0
    1
    0
        Supine pulse rate >120 bpm, n=11,9,11,10,70,67
    0
    0
    1
    0
    5
    7
        Increase:supine SBP >=30 mm Hg, n=11,9,11,10,70,67
    2
    3
    5
    3
    13
    17
        Increase: sitting SBP >=30 mm Hg, n=9,6,9,4,48,44
    0
    2
    2
    0
    10
    9
        Increase: standing SBP >=30 mm Hg, n=2,3,3,6,19,22
    0
    0
    0
    2
    2
    1
        Increase:supine DBP >=20 mm Hg, n=11,9,11,10,70,67
    4
    2
    5
    2
    16
    22
        Increase: sitting DBP >=20 mm Hg, n=9,6,9,4,48,44
    3
    1
    2
    2
    9
    12
        Increase: standing DBP >=20 mm Hg, n=2,3,3,6,19,22
    0
    0
    0
    2
    3
    3
        Decrease:supine SBP >=30 mm Hg, n=11,9,11,10,70,67
    7
    6
    5
    4
    37
    37
        Decrease: sitting SBP >=30 mm Hg, n=9,6,9,4,48,44
    3
    4
    6
    2
    26
    18
        Decrease: standing SBP >=30 mm Hg, n=2,3,3,6,19,22
    2
    2
    0
    2
    10
    11
        Decrease:supine DBP >=20 mm Hg, n=11,9,11,10,70,67
    8
    6
    6
    3
    32
    26
        Decrease: sitting DBP >=20 mm Hg, n=9,6,9,4,48,44
    1
    4
    5
    1
    23
    14
        Decrease: standing DBP >=20 mm Hg, n=2,3,3,6,19,22
    2
    2
    1
    2
    6
    11
        Decrease:supine SBP >=50 mm Hg, n=11,9,11,10,70,67
    2
    0
    1
    2
    10
    9
        Decrease: sitting SBP >=50 mm Hg, n=9,6,9,4,48,44
    2
    1
    3
    0
    7
    6
        Decrease: standing SBP >=50 mm Hg, n=2,3,3,6,19,22
    1
    0
    0
    0
    1
    2
        Sitting pulse rate <40 bpm, n=1,0,2,0,3,2
    0
    99999
    0
    99999
    0
    0
        Standing pulse rate <40 bpm, n=0,0,0,2,1,0
    99999
    99999
    99999
    0
    0
    99999
        Sitting pulse rate >120 bpm, n=1,0,2,0,3,2
    0
    99999
    0
    99999
    0
    0
        Standing pulse rate >140 bpm, n=0,0,0,2,1,0
    99999
    99999
    99999
    0
    0
    99999
    Notes
    [9] - All randomized and treated subjects in this group.
    [10] - All randomized and treated subjects in this group.
    [11] - All randomized and treated subjects in this group.
    [12] - All randomized and treated subjects in this group.
    [13] - All randomized and treated subjects in this group.
    [14] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Primary: Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2)

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    End point title
    Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2) [15]
    End point description
    ECG criteria of potential clinical concern were 1), PR interval: >=300 milliseconds (msec); >=25% increase when baseline >200 msec; or increase >=50% when baseline <=200 msec; 2), QRS interval: >=140 msec; >=50% increase from baseline; 3), QT interval: >=500 msec, QTc interval using Fridericia’s formula (QTcF interval): absolute value >=450 - <480 msec, >=480-<500 msec, >=500 msec; absolute change 30 - <60 msec, >=60 msec. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of evaluable subjects.
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) to Day 90
    Notes
    [15] - 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: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [16]
    9 [17]
    11 [18]
    10 [19]
    70 [20]
    67 [21]
    Units: subjects
        PR interval >=300 msec, n=11,9,11,10,70,67
    0
    0
    0
    0
    0
    0
        QRS interval >=140 msec, n=11,9,11,10,70,67
    1
    0
    1
    1
    0
    1
        QT interval >=500 msec, n=11,9,11,10,70,67
    0
    0
    0
    0
    4
    1
        QTcF interval 450-480 msec, n=11,9,11,10,70,67
    2
    3
    4
    2
    14
    14
        QTcF interval 480-500 msec, n=11,9,11,10,70,67
    0
    1
    0
    1
    4
    3
        QTcF interval >=500 msec, n=11,9,11,10,70,67
    0
    0
    1
    0
    0
    1
        PR interval increase >=25%/50%, n=10,7,9,9,52,47
    0
    0
    1
    0
    1
    0
        QRS interval increase >=50%, n=10,9,11,10,69,66
    0
    0
    0
    0
    0
    1
        QTcF increase 30-60 msec, n=10,9,11,10,69,66
    2
    3
    4
    2
    19
    11
        QTcF increase >=60 msec, n=10,9,11,10,69,66
    0
    0
    0
    1
    3
    5
    Notes
    [16] - All randomized and treated subjects in this group.
    [17] - All randomized and treated subjects in this group.
    [18] - All randomized and treated subjects in this group.
    [19] - All randomized and treated subjects in this group.
    [20] - All randomized and treated subjects in this group.
    [21] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Primary: Number of subjects with significant change in physical examination findings (Part 1* and 2)

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    End point title
    Number of subjects with significant change in physical examination findings (Part 1* and 2) [22]
    End point description
    The complete physical examination included examination of the skin, eyes, ears, throat, neck, cardiac, respiratory, gastrointestinal, and musculoskeletal systems. The limited physical examination included examination of the cardiac, respiratory, gastrointestinal, and musculoskeletal systems. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) up to Day 90
    Notes
    [22] - 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: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [23]
    9 [24]
    11 [25]
    10 [26]
    70 [27]
    66 [28]
    Units: subjects
    1
    1
    0
    0
    2
    0
    Notes
    [23] - Subjects who had physical examinations done at both baseline and last visit in this group.
    [24] - Subjects who had physical examinations done at both baseline and last visit in this group.
    [25] - Subjects who had physical examinations done at both baseline and last visit in this group.
    [26] - Subjects who had physical examinations done at both baseline and last visit in this group.
    [27] - Subjects who had physical examinations done at both baseline and last visit in this group.
    [28] - Subjects who had physical examinations done at both baseline and last visit in this group.
    No statistical analyses for this end point

    Primary: Number of subjects with significant change in neurological examination findings (Part 1* and 2)

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    End point title
    Number of subjects with significant change in neurological examination findings (Part 1* and 2) [29]
    End point description
    The complete neurological examination included an assessment of the motor, sensory, cranial nerves, reflexes, mental status and associated motor functions. The limited neurological exam could examine the same categories of neurologic assessments as the full examination, but would differ by the depth in the examination. The examination was required to be done to the extent needed to assess the subject for any potential changes in neurological status, as determined by the Investigator, but had to always include an assessment of motor, vision and hearing. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) up to Day 90
    Notes
    [29] - 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: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [30]
    9 [31]
    11 [32]
    10 [33]
    70 [34]
    66 [35]
    Units: subjects
    1
    1
    0
    0
    4
    0
    Notes
    [30] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    [31] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    [32] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    [33] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    [34] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    [35] - Subjects who had neurological examinations done at both baseline and last visit in this group.
    No statistical analyses for this end point

    Primary: Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2)

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    End point title
    Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2) [36]
    End point description
    Data were mapped to Columbia-Classification Algorithm of Suicide Assessment (C-CASA) event codes. C-SSRS assessed if subject experienced: completed suicide (Code 1), suicide attempt (Code 2), preparatory acts toward imminent suicidal behavior (Code 3), suicidal ideation (Code 4), self-injurious behavior, no suicidal intent (Code 7). Number of subjects with "Yes" response was assessed. *This was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for it were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of subjects who had C-SSRS assessed at that visit. 99999=No subjects had C-SSRS assessed.
    End point type
    Primary
    End point timeframe
    Day 7 (Baseline) up to follow up (28 days after Day 90)
    Notes
    [36] - 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: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [37]
    9 [38]
    11 [39]
    10 [40]
    70 [41]
    67 [42]
    Units: subjects
        Day 7, n=0, 0, 1, 1, 64, 57
    99999
    99999
    0
    0
    1
    2
        Day 14, n=0, 0, 1, 1, 59, 53
    99999
    99999
    0
    0
    1
    0
        Day 30, n=0, 0, 1, 1, 60, 47
    99999
    99999
    0
    0
    2
    0
        Day 60, n=0, 0, 1, 1, 55, 44
    99999
    99999
    0
    0
    2
    0
        Day 90, n=0, 0, 1, 1, 61, 53
    99999
    99999
    0
    0
    1
    1
        Follow-up, n=0, 0, 1, 1, 59, 51
    99999
    99999
    0
    0
    0
    0
    Notes
    [37] - All randomized and treated subjects in this group.
    [38] - All randomized and treated subjects in this group.
    [39] - All randomized and treated subjects in this group.
    [40] - All randomized and treated subjects in this group.
    [41] - All randomized and treated subjects in this group.
    [42] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Primary: Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2)

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    End point title
    Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2) [43]
    End point description
    The mRS is a 6-point scale of functional recovery. The scale grades subjects as having no symptoms (0), minor symptoms (1), minor handicap (2), moderate handicap (3), moderately severe handicap (4), severe handicap (5), or death (6). n=number of subjects included for comparison between active drug and placebo. The Inferential-Full Analysis Set (I-FAS) consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Primary
    End point timeframe
    Day 90
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a primary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [44]
    65 [45]
    Units: subjects
        Last Observation Carried Forward (LOCF), n=68, 65
    29
    30
        Observed Cases (OC), n=51, 52
    24
    26
    Notes
    [44] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [45] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo (LOCF)
    Statistical analysis description
    LOCF was used to impute missing data.
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4962
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.735
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.31
    Statistical analysis title
    PF-03049423 6 mg versus Placebo (OC)
    Statistical analysis description
    The analysis was based on OC.
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    = 0.2517
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.561
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    1.07
    Notes
    [46] - The analysis was based on OC.

    Secondary: Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2)

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    End point title
    Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2) [47]
    End point description
    The B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the subject. The subject was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The subject was then required to do the test with his/her paretic hand. If more than 1 block was picked up at a time it was counted as 1 block. The subject's fingertips needed to cross the partition for the block to be counted. The performance measure for this task was number of blocks moved within 1 minute. I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [47] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [48]
    65 [49]
    Units: blocks moved per minute
    least squares mean (standard error)
        Paretic Hand, n=21, 24
    26.881 ± 3.8667
    26.741 ± 3.5627
        Non-Paretic Hand, n=45, 41
    17.797 ± 2.1676
    18.313 ± 2.2407
    Notes
    [48] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [49] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - Paretic Hand
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9716
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.141
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.972
         upper limit
    5.254
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.942
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - Non-Paretic Hand
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8501
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.516
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.026
         upper limit
    2.995
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7201

    Secondary: Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

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    End point title
    Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2) [50]
    End point description
    he B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the subject. The subject was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The subject was then required to do the test with his/her paretic hand. The subject was told that if more than 1 block was picked up at a time it was to only count as 1 block. The subject was also told that their fingertips needed to cross the partition for the block to be counted. The performance measure for this task was the number of blocks moved within 1 minute. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    21 [51]
    24 [52]
    Units: percentage change
        least squares mean (standard error)
    41.83 ± 7.781
    31.041 ± 7.1284
    Notes
    [51] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [52] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Statistical analysis description
    This comparison is for paretic to non-paretic hand ratio.
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1417
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    10.789
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    1.401
         upper limit
    20.177
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.2392

    Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2)

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    End point title
    Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2) [53]
    End point description
    The Hand Grip Strength Test measures the maximum isometric strength of the hand and forearm muscles. The subject was required to squeeze the dynamometer with maximum isometric effort while sitting with shoulder adducted and neutrally roated, elbow flexed at 90 degrees and the forearm in neutral position and wrist between 0 to 30 degrees dorsiflexion and a 0 to 15 degrees ulnar deviation. The subject performed this task 3 times with each hand, starting with the non-paretic hand. The performance measure for this task was the average score measured in pounds of pressure exerted. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [53] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [54]
    65 [55]
    Units: pounds
    least squares mean (standard error)
        Paretic Hand, n=26, 26
    20.556 ± 4.1829
    30.886 ± 3.9964
        Non-Paretic Hand, n=46, 41
    12.546 ± 2.3612
    12.312 ± 2.5029
    Notes
    [54] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [55] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - Paretic Hand
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0611
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    -10.33
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -17.351
         upper limit
    -3.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.4241
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - Non-Paretic Hand
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9433
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.235
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.011
         upper limit
    4.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.2899

    Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

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    End point title
    Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2) [56]
    End point description
    The Hand Grip Strength Test measures the maximum isometric strength of the hand and forearm muscles. The subject was required to squeeze the dynamometer with maximum isometric effort while sitting with shoulder adducted and neutrally roated, elbow flexed at 90 degrees and the forearm in neutral position and wrist between 0 to 30 degrees dorsiflexion and a 0 to 15 degrees ulnar deviation. The subject performed this task 3 times with each hand, starting with the non-paretic hand. The performance measure for this task was the average score measured in pounds of pressure exerted. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    26 [57]
    26 [58]
    Units: percentage change
        least squares mean (standard error)
    23.949 ± 5.4499
    36.761 ± 5.1182
    Notes
    [57] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [58] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Statistical analysis description
    This analysis was for paretic to non-paretic hand ratio.
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0654
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -12.812
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -21.668
         upper limit
    -3.957
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.8448

    Secondary: Number of subjects with mRS (0-1) at Day 90 (Part 2)

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    End point title
    Number of subjects with mRS (0-1) at Day 90 (Part 2) [59]
    End point description
    The mRS is a 6-point scale of functional recovery. The scale grades subjects as having no symptoms (0), minor symptoms (1), minor handicap (2), moderate handicap (3), moderately severe handicap (4), severe handicap (5), or death (6). The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 90
    Notes
    [59] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [60]
    65 [61]
    Units: subjects
    17
    16
    Notes
    [60] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [61] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.951
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.972
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.76

    Secondary: Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2)

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    End point title
    Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2) [62]
    End point description
    The NIHSS is a graded 11-item neurological examination rating speech and language, cognition, visual field deficits, motor and sensory impairments and ataxia used for the clinical assessment of acute stroke therapy. The maximum total score is 42 in a subject with a severe neurological deficit; the minimum score is 0 in a subject without gross neurological deficits. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 90
    Notes
    [62] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [63]
    65 [64]
    Units: subjects
    17
    17
    Notes
    [63] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [64] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7234
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.854
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.51

    Secondary: Change from baseline in NIHSS at Day 90 (Part 2)

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    End point title
    Change from baseline in NIHSS at Day 90 (Part 2) [65]
    End point description
    The NIHSS is a graded 11-item neurological examination rating speech and language, cognition, visual field deficits, motor and sensory impairments and ataxia used for the clinical assessment of acute stroke therapy. The maximum total score is 42 in a subject with a severe neurological deficit; the minimum score is 0 in a subject without gross neurological deficits. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [65] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    49 [66]
    47 [67]
    Units: unit on a scale
        least squares mean (standard error)
    -6.511 ± 0.5384
    -6.228 ± 0.5655
    Notes
    [66] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [67] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6759
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.283
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.156
         upper limit
    0.589
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6755

    Secondary: Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2)

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    End point title
    Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2) [68]
    End point description
    The BI is an index of independence to score the ability of a subject with a neuromuscular or musculoskeletal disorder to care for him or herself. The index rates a subject’s ability on the following 10 activities: feeding, moving from wheelchair to bed, personal toilet, getting on and off toilet, bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. The maximum total score is 100 in a subject without functional impairment; the minimum score is 0 in a subject with major functional impairment. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 90
    Notes
    [68] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [69]
    65 [70]
    Units: subjects
        BI >=95
    32
    26
        BI=100
    29
    23
    Notes
    [69] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [70] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo (BI >=95)
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4213
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.433
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    2.54
    Statistical analysis title
    PF-03049423 6 mg versus Placebo (BI=100)
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.276
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.651
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    2.98

    Secondary: BI at Day 90 (Part 2)

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    End point title
    BI at Day 90 (Part 2) [71]
    End point description
    The BI is an index of independence to score the ability of a subject with a neuromuscular or musculoskeletal disorder to care for him or herself. The index rates a subject’s ability on the following 10 activities: feeding, moving from wheelchair to bed, personal toilet, getting on and off toilet, bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. The maximum total score is 100 in a subject without functional impairment; the minimum score is 0 in a subject with major functional impairment. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 90
    Notes
    [71] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    49 [72]
    47 [73]
    Units: unit on a scale
        least squares mean (standard error)
    79.151 ± 3.6248
    73.552 ± 3.8471
    Notes
    [72] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [73] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2118
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    5.599
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    11.348
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.4547

    Secondary: Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2)

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    End point title
    Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2) [74]
    End point description
    The test uses a reference key, the subject had 90 seconds to pair specific numbers with given geometric figures. Responses could be written or oral. The performance measure for this task was the total number of correct responses. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [74] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    33 [75]
    28 [76]
    Units: number of correct responses
        least squares mean (standard error)
    13.748 ± 1.5321
    12.686 ± 1.6282
    Notes
    [75] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [76] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5541
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.062
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.252
         upper limit
    3.375
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7844

    Secondary: Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2)

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    End point title
    Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2) [77]
    End point description
    This test requires the subject to name 10 objects drawn in ink. The tester asked the subject to identify the picture. The subject had 20 seconds to respond to each picture presented. The performance measure was the number of objects named correctly. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [77] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    41 [78]
    37 [79]
    Units: number of objects named correctly
        least squares mean (standard error)
    0.989 ± 0.3676
    1.324 ± 0.3666
    Notes
    [78] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [79] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.426
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    -0.334
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.874
         upper limit
    0.205
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4178

    Secondary: Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2)

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    End point title
    Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2) [80]
    End point description
    The subject was presented with a page that had lines placed across the page. The subject was required to cross out all the lines on the page using their non-paretic hand after the tester had demonstrated what was required by crossing out the center line. The performance measure for this task was the total number of omissions made expressed as a percentage of the total number of items in the test. The test contains 4 variables: (L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%, and (L-R)/(L+R), where L = number of lines crossed on the left side of the paper; R = number of lines crossed on the right side of the paper. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [80] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    68 [81]
    65 [82]
    Units: change in percentage of lines crossed
    least squares mean (standard error)
        (L+R)/28 × 100%, n=39, 35
    19.459 ± 4.4433
    16.983 ± 4.4551
        (L/14) × 100%, n=39, 35
    22.824 ± 5.6691
    18.95 ± 5.6639
        (R/14) × 100%, n=39, 35
    16.481 ± 4.3564
    15.431 ± 4.3647
    Notes
    [81] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
    [82] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - (L+R)/28 × 100%
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.65
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.477
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.547
         upper limit
    9.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.4394
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - (L/14) × 100%
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5671
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.874
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.834
         upper limit
    12.583
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.7431
    Statistical analysis title
    PF-03049423 6 mg versus Placebo - (R/14) × 100%
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.843
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.049
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -5.771
         upper limit
    7.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.2816

    Secondary: Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2)

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    End point title
    Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2) [83]
    End point description
    This test assesses the ability to recognize pictures of objects. The subject was presented a series of pictures, a subset of which were the objects presented in the RBANS Naming Sub Test. After each picture was presented, the subject indicated either manually (ie, affirmative head nod) or verbally whether the picture was seen previously. The subject was given 5 seconds per picture to respond. The performance measure for this task was the total number of pictures correctly identified. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [83] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    44 [84]
    37 [85]
    Units: pictures correctly identified
        least squares mean (standard error)
    -1.135 ± 0.4743
    0.144 ± 0.4797
    Notes
    [84] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [85] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0128
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.279
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.929
         upper limit
    -0.629
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5041

    Secondary: Gait Velocity Test at Day 90 (Part 2)

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    End point title
    Gait Velocity Test at Day 90 (Part 2) [86]
    End point description
    The 10-meter walk test requires a 20 meter straight path, with 5 meters for acceleration, 10 meters for steady state walking, and 5 meters for deceleration. Markers were placed at the 5 and 15 meter positions along the path. The subject began to walk “at a comfortable pace” at 1 end of the path, and continued walking until he/she reached the other end. The rater used a stopwatch to determine how much time it took for the subject to traverse the 10 meter center of the path, starting the stopwatch as soon as the subject’s limb crossed the first marker and stopping the stopwatch as soon as the subject’s limb crossed the second marker. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 90
    Notes
    [86] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    41 [87]
    36 [88]
    Units: meters/second (m/s)
        least squares mean (standard error)
    1.064 ± 0.104
    0.975 ± 0.1128
    Notes
    [87] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [88] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4713
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.089
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.248
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1226

    Secondary: Plasma concentrations of PF-03049423 (Part 1 and 2)

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    End point title
    Plasma concentrations of PF-03049423 (Part 1 and 2) [89]
    End point description
    Pharmacokinetic (PK) concentration population included all subjects who were treated with PF-03049423 who had at least 1 measurable concentration. n=subjects with concentration above lower limit of quantification at the corresponding sampling time. 99999=No sample was collected. 99990=1 subject had concentration above lower limit of quantification, standard deviation cannot be calculated.
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 7, 14, 30, 60 and 90
    Notes
    [89] - 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: The plasma concentration of PF-03049423 can only be reported in those subjects who received active treamtment but not placebo.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 2: PF-03049423 3 mg Cohort 3: PF-03049423 6 mg
    Number of subjects analysed
    11 [90]
    11 [91]
    70 [92]
    Units: nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1 (0 hour predose), n=0, 1, 3
    99999 ± 99999
    0.05245 ± 0.17397
    1.42 ± 11.591
        Day 1 (1 hour post dose), n=11, 10, 63
    5.825 ± 4.3514
    17.5 ± 12.814
    46.76 ± 36.153
        Day 1 (2 hours post dose), n=11, 11, 61
    7.063 ± 3.2729
    30.18 ± 11.313
    58.19 ± 32.837
        Day 1 (8 hours post dose), n=11, 11, 68
    7.361 ± 2.4032
    25.39 ± 8.6644
    52.47 ± 23.25
        Day 2 (0 hour, predose), n=11, 11, 67
    4.521 ± 1.5265
    18.05 ± 4.7834
    32.07 ± 13.776
        Day 7 (0 hour, post dose), n=9, 7, 64
    8.601 ± 2.9609
    27.79 ± 7.6945
    53.08 ± 30.237
        Day 7 (1 hour post dose), n=0, 1, 59
    99999 ± 99999
    51.8 ± 99990
    115.9 ± 65.329
        Day 7 (2 hours post dose), n=0, 1, 59
    99999 ± 99999
    58.1 ± 99990
    126.3 ± 57.759
        Day 7 (6 hours post dose), n=0, 1, 61
    99999 ± 99999
    51.1 ± 99990
    103.8 ± 41.09
        Day 14 (0 hour predose), n=10, 8, 59
    7.805 ± 2.9278
    31.13 ± 9.8243
    53.1 ± 28.085
        Day 14 (1 hour post dose), n=9, 7, 0
    16.47 ± 7.1782
    76.71 ± 32.657
    99999 ± 99999
        Day 14 (2 hours post dose), n=9, 6, 0
    17.06 ± 7.3799
    70.37 ± 14.795
    99999 ± 99999
        Day 14 (6 [cohort 3:4] hours post dose), n=9,7,31
    17.57 ± 4.1614
    58.36 ± 11.72
    118.2 ± 41.967
        Day 30 (0 hour predose), n=6, 6, 58
    5.339 ± 3.5712
    29.68 ± 11.015
    50.77 ± 31.473
        Day 30 (4 hours post dose), n=2, 5, 25
    11.55 ± 2.6234
    57.08 ± 13.99
    96.27 ± 49.929
        Day 60 (0 hour predose), n=6, 6, 53
    6.36 ± 3.1028
    24.55 ± 5.8206
    49.37 ± 33.747
        Day 60 (4 hours post dose), n=2, 5, 27
    13.25 ± 0.7778
    47.86 ± 7.3296
    112.1 ± 58.56
        Day 90 (0 hour predose), n=5, 6, 45
    5.252 ± 1.5161
    29.18 ± 15.909
    47.02 ± 24.065
        Day 90 (4 hours post dose), n=2, 5, 20
    12.8 ± 0
    49.4 ± 13.962
    82.69 ± 29.005
    Notes
    [90] - All randomized and treated subjects in this group.
    [91] - All randomized and treated subjects in this group.
    [92] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Secondary: Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2)

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    End point title
    Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2) [93]
    End point description
    The subject was presented with a page that had lines placed across the page. The subject was required to cross out all the lines on the page using their non-paretic hand after the tester had demonstrated what was required by crossing out the center line. The performance measure for this task was the total number of omissions made expressed as a percentage of the total number of items in the test. The test contains 4 variables: (L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%, and (L-R)/(L+R), where L = number of lines crossed on the left side of the paper; R = number of lines crossed on the right side of the paper. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 90
    Notes
    [93] - 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: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.
    End point values
    Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    39 [94]
    34 [95]
    Units: change in ratio
    least squares mean (standard error)
        (L-R)/(L+R)
    0.083 ± 0.062
    -0.023 ± 0.0625
    Notes
    [94] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
    [95] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.
    Statistical analysis title
    PF-03049423 6 mg versus Placebo
    Comparison groups
    Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1512
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.106
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.201
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0733

    Other pre-specified: All-cause mortality (Part 2)

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    End point title
    All-cause mortality (Part 2)
    End point description
    Deaths regardless causality were reported. The FAS consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Other pre-specified
    End point timeframe
    The time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [96]
    9 [97]
    11 [98]
    10 [99]
    70 [100]
    67 [101]
    Units: subjects
    0
    0
    0
    0
    6
    7
    Notes
    [96] - All randomized and treated subjects in this group.
    [97] - All randomized and treated subjects in this group.
    [98] - All randomized and treated subjects in this group.
    [99] - All randomized and treated subjects in this group.
    [100] - All randomized and treated subjects in this group.
    [101] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Other pre-specified: Mortality directly related to stroke (Part 2)

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    End point title
    Mortality directly related to stroke (Part 2)
    End point description
    Deaths caused by stroke were reported. The FAS consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Other pre-specified
    End point timeframe
    The time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [102]
    9 [103]
    11 [104]
    10 [105]
    70 [106]
    67 [107]
    Units: subjects
    0
    0
    0
    0
    3
    0
    Notes
    [102] - All randomized and treated subjects in this group.
    [103] - All randomized and treated subjects in this group.
    [104] - All randomized and treated subjects in this group.
    [105] - All randomized and treated subjects in this group.
    [106] - All randomized and treated subjects in this group.
    [107] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Other pre-specified: Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)

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    End point title
    Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. The FAS consisted of all randomized subjects who took any study medication (active or placebo).
    End point type
    Other pre-specified
    End point timeframe
    Day 1 (Baseline) up to follow-up (28 days after Day 90)
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [108]
    9 [109]
    11 [110]
    10 [111]
    70 [112]
    67 [113]
    Units: subjects
    0
    1
    2
    0
    3
    5
    Notes
    [108] - All randomized and treated subjects in this group.
    [109] - All randomized and treated subjects in this group.
    [110] - All randomized and treated subjects in this group.
    [111] - All randomized and treated subjects in this group.
    [112] - All randomized and treated subjects in this group.
    [113] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with neuro-worsening (Part 2)

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    End point title
    Number of subjects with neuro-worsening (Part 2)
    End point description
    NIHSS change of 4 points or greater. The FAS consisted of all randomized subjects who took any study medication (active or placebo). 99999=No data were reported separately for this outcome measure, which was instead included in routine clinical review of NIHSS data.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 (Baseline) up to Day 90
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [114]
    9 [115]
    11 [116]
    10 [117]
    70 [118]
    67 [119]
    Units: subjects
    99999
    99999
    99999
    99999
    99999
    99999
    Notes
    [114] - All randomized and treated subjects in this group.
    [115] - All randomized and treated subjects in this group.
    [116] - All randomized and treated subjects in this group.
    [117] - All randomized and treated subjects in this group.
    [118] - All randomized and treated subjects in this group.
    [119] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)

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    End point title
    Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)
    End point description
    The FAS consisted of all randomized subjects who took any study medication (active or placebo). 99999=No data were reported separately for this outcome measure, which was instead included in routine clinical review of BP data.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 (Baseline) up to Day 14
    End point values
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Number of subjects analysed
    11 [120]
    9 [121]
    11 [122]
    10 [123]
    70 [124]
    67 [125]
    Units: subjects
    99999
    99999
    99999
    99999
    99999
    99999
    Notes
    [120] - All randomized and treated subjects in this group.
    [121] - All randomized and treated subjects in this group.
    [122] - All randomized and treated subjects in this group.
    [123] - All randomized and treated subjects in this group.
    [124] - All randomized and treated subjects in this group.
    [125] - All randomized and treated subjects in this group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the subject had taken at least 1 dose of study treatment through last subject visit. For SAEs, the time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.
    Adverse event reporting additional description
    The same event may appear as both an AE and a 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 nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cohort 1: PF-03049423 1 mg
    Reporting group description
    Subjects received PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

    Reporting group title
    Cohort 2: PF-03049423 3 mg
    Reporting group description
    Subjects received PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

    Reporting group title
    Cohort 3: PF-03049423 6 mg
    Reporting group description
    Subjects received PF-03049423 6 mg once daily for 90 days.

    Reporting group title
    Cohort 3: Placebo
    Reporting group description
    Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

    Serious adverse events
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 9 (11.11%)
    3 / 11 (27.27%)
    1 / 10 (10.00%)
    15 / 70 (21.43%)
    18 / 67 (26.87%)
         number of deaths (all causes)
    0
    0
    0
    0
    6
    7
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram ST-T change
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1: PF-03049423 1 mg Cohort 1: Placebo Cohort 2: PF-03049423 3 mg Cohort 2: Placebo Cohort 3: PF-03049423 6 mg Cohort 3: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 11 (90.91%)
    7 / 9 (77.78%)
    7 / 11 (63.64%)
    9 / 10 (90.00%)
    50 / 70 (71.43%)
    47 / 67 (70.15%)
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 9 (44.44%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    2 / 67 (2.99%)
         occurrences all number
    1
    5
    0
    1
    3
    2
    Hypotension
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    4 / 70 (5.71%)
    7 / 67 (10.45%)
         occurrences all number
    1
    1
    0
    3
    8
    12
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    2
    0
    4
    3
    Pyrexia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    7 / 70 (10.00%)
    6 / 67 (8.96%)
         occurrences all number
    1
    0
    3
    0
    9
    6
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    3 / 67 (4.48%)
         occurrences all number
    0
    1
    0
    0
    5
    3
    Depression
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    0
    4
    4
    Insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    7 / 70 (10.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    0
    0
    8
    2
    Sleep disorder
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    1 / 67 (1.49%)
         occurrences all number
    5
    0
    0
    0
    5
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    Excoriation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    3
    0
    2
    4
    Joint dislocation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lip injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Radius fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    1
    0
    0
    4
    Blood bilirubin abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    1
    1
    4
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Red blood cells urine positive
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    Bradycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Coronary artery occlusion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    0
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Bronchiectasis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    4 / 70 (5.71%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    3 / 67 (4.48%)
         occurrences all number
    1
    0
    0
    0
    1
    3
    Pleural effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    4 / 70 (5.71%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    0
    2
    4
    3
    Leukocytosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neutrophilia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Nervous system disorders
    Dementia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 9 (11.11%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    2
    3
    1
    0
    0
    3
    Haemorrhagic transformation stroke
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    4 / 11 (36.36%)
    3 / 9 (33.33%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    7 / 67 (10.45%)
         occurrences all number
    4
    6
    1
    0
    5
    7
    Somnolence
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    2 / 67 (2.99%)
         occurrences all number
    1
    0
    0
    0
    3
    2
    Syncope
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    2
    0
    1
    0
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Eye disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    2 / 70 (2.86%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    0
    1
    4
    1
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    14 / 67 (20.90%)
         occurrences all number
    0
    1
    1
    1
    10
    16
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    9 / 70 (12.86%)
    10 / 67 (14.93%)
         occurrences all number
    0
    0
    0
    1
    10
    11
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    3 / 67 (4.48%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    Gastritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 9 (22.22%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    2 / 70 (2.86%)
    4 / 67 (5.97%)
         occurrences all number
    1
    3
    2
    0
    2
    4
    Vomiting
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    4
    0
    1
    7
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    4 / 67 (5.97%)
         occurrences all number
    1
    0
    0
    0
    5
    4
    Haematuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    7 / 70 (10.00%)
    2 / 67 (2.99%)
         occurrences all number
    1
    0
    0
    0
    9
    2
    Renal cyst
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal failure acute
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 70 (1.43%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Urethral haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 67 (1.49%)
         occurrences all number
    1
    0
    0
    0
    3
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    5 / 70 (7.14%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    3 / 70 (4.29%)
    3 / 67 (4.48%)
         occurrences all number
    0
    0
    0
    2
    4
    4
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    1 / 67 (1.49%)
         occurrences all number
    1
    0
    4
    0
    1
    2
    Gouty arthritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    4
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    2
    0
    5
    1
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    9 / 70 (12.86%)
    4 / 67 (5.97%)
         occurrences all number
    0
    1
    1
    0
    13
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fluid imbalance
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    7 / 70 (10.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    1
    1
    4
    11
    3
    Infections and infestations
    Genitourinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 70 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 70 (1.43%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 70 (4.29%)
    2 / 67 (2.99%)
         occurrences all number
    1
    1
    0
    0
    3
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    8 / 70 (11.43%)
    8 / 67 (11.94%)
         occurrences all number
    1
    0
    1
    1
    8
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2010
    Addition of a safety Follow-Up visit 14 days after Day 90.
    12 Nov 2010
    To integrate recording of the time of last meal on PK days to follow an Food and Drug Administration (FDA) recommendation and to add measurement of direct and indirect bilirubin to comply with the corporate recommendations as to detect potential Hy’s law cases.
    01 Aug 2011
    To reduce the number of procedures: particularly blood pressure measurements to eliminate the visits from Day 8 to Day 13. This change – supported by extrapolation of available data – was subject to review of Cohort 1 patients data and approval by the Data and Safety Monitoring Board (DSMB). Allowed patients with total paresis of the upper extremity to enter the study. Clarified the eligibility criteria on the type of stroke. Updated the suicidality assessments: addition of the Columbia Suicide Severity Rating Scale (C-SSRS). Removed "Criteria for ECG Parameters and Vital Signs of Potential Clinical Concern for Pediatric Subjects".
    26 Mar 2012
    Addition of digoxin and digitoxin to prohibited concomitant medications list. Study Procedures: Clarification of drug dispensing at day 7 and day 14. The caregiver could not give drug if the subject had an nasogastric tube and further clarification regarding the use of an nasogastric tube. FOR FRANCE ONLY according to local clinical guidelines approved November 2011: 1. Removed option for manual BP measurements, 2. Removed option for BP assessments in standing position, 3. Increased frequency of BP assessments in Part 2 of the study, 4. Required use of an electronic blood pressure measuring device.
    24 Aug 2012
    Change to inclusion criteria to allow computed tomography (CT) or magnetic resonance imaging (MRI) scan at screening and Day 90 for all subjects (ie, CT was not just for subjects contraindicated for MRI). Change to inclusion criteria to advise that an additional 6 hours (ie, up to a total of 78 hours) could be allowable from stroke onset to initial dose of study drug in exceptional circumstances, such as an unexpected delay in receiving the data to allow randomisation, after consultation with the sponsor. Change to inclusion criteria to expectation that subjects had to remain as in patients for the first 3 days. Subjects could remain as in-patients for the first seven days of dosing if that complies with regional standard of care. Change to the inclusion criterion regarding ECG measurements. If a subject was ineligible on ECG and if it considered likely that there was a temporary perturbation of the subject’s cardiac function related to the stroke, at the discretion of the investigator this ECG analysis could be repeated on one occasion within the 72 hour screening window. If the subject met the ECG eligibility criteria at the second timepoint, this would take precedence over the first analysis. Change to inclusion criteria to note that participation in non-interventional studies (eg, solely involving blood draws for genetic analysis) could be allowable after consultation with the sponsor. Update to the wording on definition of women of child bearing potential to bring into line with revised Pfizer policy. Added wording to advise that the study is now in Part 2 at a 6 mg dose, and to update some procedures to bring them in line with the amended selection criteria.

    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.
    The study was terminated prematurely due to demonstrated futility at interim analysis. The final results are consistent with interim results.
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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