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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Masked, Placebo Controlled, Parallel Group, Multi-Center Study to Compare the Efficacy and Safety of a Chemokine CCR2/5 Receptor Antagonist (PF-04634817) With That of Ranibizumab in Adult Subjects With Diabetic Macular Edema

    Summary
    EudraCT number
    		 2013-003147-27
    Trial protocol
    		 HU   DE   CZ   PL  
    Global end of trial date
    11 Aug 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B1261009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate whether the clinical efficacy of PF-04634817 is non-inferior to ranibizumab, as measured by change from baseline in best corrected visual acuity after 12 weeks of treatment in subjects with diabetic macular edema (DME).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Moldova, Republic of: 21
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    198
    EEA total number of subjects
    68
    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)
    121
    From 65 to 84 years
    76
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was planned to enroll approximately 100 subjects per arm and assumed a dropout rate of approximately 10%.

    Pre-assignment
    Screening details
    		 A total of 475 subjects were screened, of which 199 subjects were assigned to study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-04634817 200 mg QD
    Arm description
    		 Participants received 50 mg tablets of PF-04634817 and masked sham therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04634817
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral PF 04634817 200 mg once daily (QD). Each daily dose was comprised of 4 x 50 mg tablets of PF 04634817.

    Arm title
    		 Placebo QD + Ranibizumab 0.3 mg
    Arm description
    		 Participants received Ranibizumab 0.3 mg intravitreal injection and matching placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal administration of ranibizumab 0.3 mg given monthly

    Arm title
    		 Placebo QD + Ranibizumab 0.5 mg
    Arm description
    		 Participants received Ranibizumab 0.5 mg intravitreal injection and matching placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Intravitreal administration of ranibizumab 0.5 mg, given monthly.

    Number of subjects in period 1
    		PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg
    Started
    99
    43
    56
    Received treatment
    99
    43
    56
    Completed
    84
    36
    47
    Not completed
    15
    7
    9
         Consent withdrawn by subject
    6
    3
    5
         Does not meet entrance criteria
    1
    -
    -
         Adverse event, non-fatal
    4
    1
    3
         Unspecified
    1
    2
    -
         Medication error without associated AE
    1
    -
    1
         Lost to follow-up
    1
    1
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-04634817 200 mg QD
    Reporting group description
    		 Participants received 50 mg tablets of PF-04634817 and masked sham therapy.

    Reporting group title
    Placebo QD + Ranibizumab 0.3 mg
    Reporting group description
    		 Participants received Ranibizumab 0.3 mg intravitreal injection and matching placebo.

    Reporting group title
    Placebo QD + Ranibizumab 0.5 mg
    Reporting group description
    		 Participants received Ranibizumab 0.5 mg intravitreal injection and matching placebo.

    Reporting group values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Total
    Number of subjects
    		 99 43 56 198
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 60 33 28 121
        From 65-84 years
    		 39 10 27 76
        85 years and over
    		 0 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ( 8.8 ) 60.4 ( 7.5 ) 63.4 ( 8.4 ) -
    Gender, Male/Female
    Units: Participants
        FEMALE
    		 40 17 18 75
        MALE
    		 59 26 38 123
    Subject analysis sets

    Subject analysis set title
    Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received Ranibizumab 0.3 mg/0.5 mg intravitreal injection and matching placebo.

    Subject analysis sets values
    		 Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects
    99
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    61
        From 65-84 years
    37
        85 years and over
    1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62.1 ( 8.1 )
    Gender, Male/Female
    Units: Participants
        FEMALE
    35
        MALE
    64

    End points

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    End points reporting groups
    Reporting group title
    PF-04634817 200 mg QD
    Reporting group description
    		 Participants received 50 mg tablets of PF-04634817 and masked sham therapy.

    Reporting group title
    Placebo QD + Ranibizumab 0.3 mg
    Reporting group description
    		 Participants received Ranibizumab 0.3 mg intravitreal injection and matching placebo.

    Reporting group title
    Placebo QD + Ranibizumab 0.5 mg
    Reporting group description
    		 Participants received Ranibizumab 0.5 mg intravitreal injection and matching placebo.

    Subject analysis set title
    Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received Ranibizumab 0.3 mg/0.5 mg intravitreal injection and matching placebo.

    Primary: Mean Letter Change from Baseline at Week 12 in Best Corrected Visual Acuity (BCVA) Compared to Ranibizumab

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    End point title
    		 Mean Letter Change from Baseline at Week 12 in Best Corrected Visual Acuity (BCVA) Compared to Ranibizumab
    End point description
    Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated early treatment diabetic retinopathy study (ETDRS) charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Week 12
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    87
    38
    53
    91
    Units: Letters
        least squares mean (confidence interval 80%)
    1.55 (-2.21 to 5.3)
    3.87 (0.09 to 7.65)
    4.03 (0.17 to 7.9)
    3.96 (0.28 to 7.64)
    Statistical analysis title
    		 Change From Baseline in BCVA Score
    Statistical analysis description
    The null hypothesis was that the difference, in the mean change from baseline in BCVA in the PF-04634817 group,and the control group is less than or equal to -3 letters.
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.1271
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.32
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.27
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.52
    Notes
    [1] - Non inferiority was to be declared if the lower limit of the confidence interval for the mean difference at Week 12 is greater than -3.0 letters.
    Statistical analysis title
    		 Change From Baseline in BCVA Score
    Statistical analysis description
    The null hypothesis was that the difference, in the mean change from baseline in BCVA in the PF-04634817 group,and the control group is less than or equal to -3 letters.
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0699
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.48
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.24
         upper limit
    		 -0.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.36
    Notes
    [2] - Non inferiority was to be declared if the lower limit of the confidence interval for the mean difference at Week 12 is greater than -3.0 letters.
    Statistical analysis title
    		 Change From Baseline in BCVA Score
    Statistical analysis description
    The null hypothesis was that the difference, in the mean change from baseline in BCVA in the PF-04634817 group,and the control group is less than or equal to -3 letters.
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0399
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    -2.41
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.91
         upper limit
    		 -0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.17
    Notes
    [3] - Non inferiority was to be declared if the lower limit of the confidence interval for the mean difference at Week 12 is greater than -3.0 letters.

    Secondary: Proportion of Subjects Gaining 15 ETDRS Letters in BCVA from Baseline at Week 12

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    End point title
    		 Proportion of Subjects Gaining 15 ETDRS Letters in BCVA from Baseline at Week 12
    End point description
    Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated ETDRS charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 12
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    87
    38
    53
    91
    Units: percentage of participants
        number (not applicable)
    0.069
    0.2105
    0.1132
    0.1538
    Statistical analysis title
    		 Proportion of Subjects Gaining 15 ETDRS Letters
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0218
    Method
    		 Barnard test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.1416
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.2483
         upper limit
    		 -0.0467
    Statistical analysis title
    		 Proportion of Subjects Gaining 15 ETDRS Letters
    Statistical analysis description
    Baseline in BCVA in the PF-04634817 group,and the control group is less than or equal to -3 letters.
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4209
    Method
    		 Barnard test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.0442
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.1217
         upper limit
    		 0.0261
    Statistical analysis title
    		 Proportion of Subjects Gaining 15 ETDRS Letters
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0778
    Method
    		 Barnard test.
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.0849
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.1516
         upper limit
    		 -0.0168

    Secondary: Mean Change From Baseline in Central Subfield Retinal Thickness in the Study Eye at Week 12

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    End point title
    		 Mean Change From Baseline in Central Subfield Retinal Thickness in the Study Eye at Week 12
    End point description
    A central reading center was used for the evaluation. A photographer or technician pre certified (“study certified”) by the Central Reading Center ought to perform all optical coherence tomography (OCT) imaging. Use of a Spectralis or Cirrus OCT was acceptable.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 12
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    83
    36
    43
    79
    Units: Letters
        least squares mean (confidence interval 80%)
    1.73 (-50.41 to 53.87)
    -112.35 (-164.5 to -60.23)
    -64.09 (-118 to -10.17)
    -85.59 (-136.8 to -34.43)
    Statistical analysis title
    		 Changes in Central Subfield Retinal Thickness
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    114.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 88.56
         upper limit
    		 139.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.84
    Statistical analysis title
    		 Changes in Central Subfield Retinal Thickness
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0004
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    65.81
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 42.2
         upper limit
    		 89.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.36
    Statistical analysis title
    		 Changes in Central Subfield Retinal Thickness
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Point estimate
    87.32
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 67.45
         upper limit
    		 107.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.44

    Secondary: Mean Change From Baseline in the Area of Fluorescein Leakage in the Study Eye at Week 12

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    End point title
    		 Mean Change From Baseline in the Area of Fluorescein Leakage in the Study Eye at Week 12
    End point description
    Fluorescein Angiography (FA) using certified digital systems was taken by a photographer who had been pre-certified (“study-certified”) by the Central Reading Center. They were evaluated by the Central Reading Center.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 12
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    86
    36
    50
    86
    Units: Letters
        least squares mean (confidence interval 80%)
    1.02 (-3.8 to 5.85)
    -6.96 (-11.66 to -2.26)
    -5.32 (-10.23 to -0.41)
    -6.05 (-10.76 to -1.34)
    Statistical analysis title
    		 Changes in the Area of Fluorescein Leakage
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    7.98
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 6.13
         upper limit
    		 9.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.44
    Statistical analysis title
    		 Changes in the Area of Fluorescein Leakage
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    6.34
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 4.7
         upper limit
    		 7.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.28
    Statistical analysis title
    		 Changes in the Area of Fluorescein Leakage
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    7.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 5.66
         upper limit
    		 8.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09

    Secondary: Mean Change From Baseline in Steps of Diabetic Retinopathy Step (ETDRS Severity Scale) in the Study Eye at Week 12

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    End point title
    		 Mean Change From Baseline in Steps of Diabetic Retinopathy Step (ETDRS Severity Scale) in the Study Eye at Week 12
    End point description
    Stereo color fundus photographs using certified digital systems were taken by a photographer who had been pre-certified (“study certified”) by the Central Reading Center. They were evaluated by the Central Reading Center.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 12
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    82
    36
    44
    80
    Units: Letters
        least squares mean (confidence interval 80%)
    0.11 (-0.44 to 0.66)
    -0.23 (-0.76 to 0.31)
    -0.44 (-1 to 0.12)
    -0.35 (-0.89 to 0.19)
    Statistical analysis title
    		 Change in Steps of Diabetic Retinopathy
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0423
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    0.34
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Change in Steps of Diabetic Retinopathy
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    0.55
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Statistical analysis title
    		 Change in Steps of Diabetic Retinopathy
    Comparison groups
    PF-04634817 200 mg QD v Placebo QD + Ranibizumab 0.3 mg v Placebo QD + Ranibizumab 0.5 mg
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    0.46
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Plasma concentration of PF-04634817 up to Week 12

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    End point title
    		 Plasma concentration of PF-04634817 up to Week 12 [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0, Week 4, Week 8, and Week 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per statistical analysis plan, placebo samples were not analyzed for PF 04634817 exposure. Only the plasma exposure of PF 04634817 was evaluated at the prespecified timepoints
    End point values
    		 PF-04634817 200 mg QD
    Number of subjects analysed
    96
    Units: nanogram (ng)/milliliter (mL)
    geometric mean (geometric coefficient of variation)
        Week 0, Hour 2 (N = 91)
    612.5 ( 61 )
        Week 4, Hour 0 (N = 88)
    180 ( 81 )
        Week 4, Hour 2 (N = 87)
    682 ( 61 )
        Week 8, Hour 0 (N = 90)
    159.9 ( 68 )
        Week 8, Hour 2 (N = 89)
    752 ( 57 )
        Week 12 (N = 86)
    285.2 ( 105 )
    No statistical analyses for this end point

    Other pre-specified: Number of Participants with Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
    End point type
    Other pre-specified
    End point timeframe
    Week 0 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    43
    56
    99
    Units: participants
        Number of Participants with AEs
    53
    32
    27
    59
        Number of Participants with SAEs
    7
    2
    3
    5
    No statistical analyses for this end point

    Other pre-specified: Number of Participants with Potentially Clinically Important Post-Baseline Vital Signs

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    End point title
    		 Number of Participants with Potentially Clinically Important Post-Baseline Vital Signs
    End point description
    Number of participants who met the categorical summary of post-baseline criteria at any time point, defined as: supine pulse rate <40 beats per minute (bpm) or >120 bpm; supine systolic blood pressure (SBP) ≥30 millimeters of mercury (mmHg) change from baseline in same posture; supine diastolic BP (DBP) ≥20 mmHg change from baseline in same posture; supine SBP <90 mmHg; supine DBP <50 mmHg.
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    42
    55
    97
    Units: participants
        Absolute Supine SBP <90 mm Hg
    1
    0
    0
    0
        Increase from Baseline in Supine SBP >=30 mm Hg
    3
    4
    3
    7
        Increase from Baseline in Supine DBP >=20 mm Hg
    2
    2
    2
    4
        Decrease from Baseline in Supine SBP >=30 mm Hg
    3
    0
    2
    2
        Decrease from Baseline in Supine DBP >=20 mm Hg
    2
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Laboratory Abnormalities

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    End point title
    		 Number of Participants With Laboratory Abnormalities
    End point description
    The following laboratory parameters were analyzed for abnormalities at any time point: hematology (hemoglobin, hematocrit, red blood cell count (RBC), white blood cell count (WBC) with differential, and platelet count); blood chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, albumin, calcium, total, direct and indirect bilirubin, gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), alkaline phosphatase, creatine phosphokinase (CPK), uric acid, amylase and lipase); follicle-stimulating hormone (FSH) (Weeks -5 to 0 only, for postmenopausal women who have been amenorrheic for at least 12 consecutive months prior to screening visit).
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    42
    55
    97
    Units: participants
    45
    19
    21
    40
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
    End point description
    ECG parameters included PR interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (>=)300 milliseconds (msec) or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QRS interval >=200 msec or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QT interval >=500 msec; and QTcF >=450 msec or >=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    43
    56
    99
    Units: participants
        QTcF Interval 450-<480 msec
    13
    2
    4
    6
        QTcF Interval 480-<500 msec
    1
    0
    0
    0
        QRS Interval >=50% increase from baseline
    0
    1
    0
    1
        QTcF Interval 30-<60 msec increase from baseline
    6
    2
    1
    3
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Changes in the Anterior Segment of the Study Eye at Week 12

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    End point title
    		 Number of Participants With Changes in the Anterior Segment of the Study Eye at Week 12
    End point description
    The anterior biomicroscopy exam was done undilated in order to assess whether there was any anterior segment inflammation caused either by ranibizumab or PF-04634817.
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    43
    56
    99
    Units: participants
        Improvement of findings in Lids
    1
    0
    0
    0
        New finding (NF)/worsening of findings in Lids
    1
    0
    0
    0
        Improvement of findings in conjunctiva palpebrae
    0
    0
    0
    1
        NF/worsening of findings in conjunctiva palpebrae
    0
    1
    0
    0
        Improvement of findings in conjunctiva bulbi
    2
    0
    0
    0
        NF/worsening of findings in conjunctiva bulbi
    0
    0
    0
    0
        Improvement of findings in sclera
    0
    0
    0
    0
        NF/worsening of findings in sclera
    0
    0
    0
    0
        Improvement of findings in cornea
    1
    0
    0
    0
        NF/worsening of findings in cornea
    0
    0
    0
    0
        Improvement of findings in anterior chamber
    0
    0
    0
    0
        NF/worsening of findings in anterior chamber
    0
    0
    0
    0
        Improvement of findings in iris
    0
    0
    0
    0
        NF/worsening of findings in iris
    0
    0
    0
    0
        Improvement of findings in lens
    0
    0
    0
    0
        NF/worsening of findings in lens
    0
    0
    1
    1
    No statistical analyses for this end point

    Other pre-specified: Maximum increase of intraocular pressure (IOP) from Baseline in Study Eye

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    End point title
    		 Maximum increase of intraocular pressure (IOP) from Baseline in Study Eye
    End point description
    IOP was measured using Goldmann applanation tonometry. To maintain consistency, it was recommended that the same examiner ought to measure IOP with the same tonometer at each visit for a given subject. Intraocular pressure ought to be measured in the study eye approximately 30 minutes after intravitreal injection or masked sham therapy (performed by unmasked study team member).
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    43
    56
    99
    Units: mmHg
        arithmetic mean (standard deviation)
    2.5 ( 2.58 )
    6 ( 4.74 )
    3 ( 3.32 )
    4.3 ( 4.24 )
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Change in Ophthalmoscopy Examination Results in Study Eye after Administration of Ranibizumab or Masked Sham Therapy at Week 8

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    End point title
    		 Number of Participants With Change in Ophthalmoscopy Examination Results in Study Eye after Administration of Ranibizumab or Masked Sham Therapy at Week 8
    End point description
    Ophthalmoscopy ought to be performed after pupillary dilation to examine the vitreous body, optic nerve head, macular and peripheral retina. All findings, including the presence or absence of vitreous inflammation, ought to be documented. All post-dose ophthalmoscopy assessments ought to be made immediately following the administration of ranibizumab or masked sham therapy.
    End point type
    Other pre-specified
    End point timeframe
    Week -5 to Week 16
    End point values
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.3 mg Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg/0.5 mg
    Number of subjects analysed
    99
    43
    56
    99
    Units: participants
        Improvement of findings in vitreous body
    0
    0
    0
    0
        NF/worsening of findings in vitreous body
    0
    0
    0
    0
        Improvement of findings in optic nerve head
    0
    0
    0
    0
        NF/worsening of findings in optic nerve head
    0
    0
    0
    0
        Improvement of findings in retina macula
    0
    0
    0
    0
        NF/worsening of findings in retina macula
    0
    0
    0
    0
        Improvement of findings in retina non-macula
    0
    0
    0
    0
        NF/worsening of findings in retina non-macula
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 12
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    PF-04634817 200 mg QD
    Reporting group description
    		 Participants received 50 mg tablets of PF 04634817 and masked sham therapy.

    Reporting group title
    Placebo QD + Ranibizumab 0.5 mg
    Reporting group description
    		 Participants received Ranibizumab 0.5 mg intravitreal injection and matching placebo.

    Reporting group title
    Placebo QD + Ranibizumab 0.3 mg
    Reporting group description
    		 Participants received Ranibizumab 0.3 mg intravitreal injection and matching placebo.

    Serious adverse events
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 99 (7.07%)
    3 / 56 (5.36%)
    2 / 43 (4.65%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis chronic
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Personality disorder
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 56 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Paronychia
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 56 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 56 (1.79%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PF-04634817 200 mg QD Placebo QD + Ranibizumab 0.5 mg Placebo QD + Ranibizumab 0.3 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 99 (17.17%)
    7 / 56 (12.50%)
    15 / 43 (34.88%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 99 (0.00%)
    3 / 56 (5.36%)
    1 / 43 (2.33%)
         occurrences all number
    0
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 99 (3.03%)
    0 / 56 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    3
    0
    4
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 56 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    1
    0
    3
    Conjunctival haemorrhage
         subjects affected / exposed
    5 / 99 (5.05%)
    0 / 56 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    8
    0
    1
    Diabetic retinal oedema
         subjects affected / exposed
    4 / 99 (4.04%)
    3 / 56 (5.36%)
    7 / 43 (16.28%)
         occurrences all number
    5
    3
    9
    Eye irritation
         subjects affected / exposed
    6 / 99 (6.06%)
    0 / 56 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    6
    0
    0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 56 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    0
    4
    Vitreous haemorrhage
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 56 (1.79%)
    3 / 43 (6.98%)
         occurrences all number
    2
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2015
    Futility analysis was updated to occur after 50% of planned subjects were available and use conditional power for the futility assessment. Update to interim analysis parameters were made to provide a more robust futility analysis.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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