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    Clinical Trial Results:
    A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ONCE-DAILY ADMINISTRATION OF A PHOSPHODIESTERASE 5 INHIBITOR (PF-00489791) IN ADULTS WITH TYPE 2 DIABETES AND OVERT NEPHROPATHY

    Summary
    EudraCT number
    		 2010-021358-20
    Trial protocol
    		 GB   PL   SK   SE   DK  
    Global end of trial date
    12 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A7331011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01200394
    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
    Clinical Trials.gov Call Center, Pfizer Inc., 1-800- 718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Clinical Trials.gov Call Center, Pfizer Inc., 1-800- 718-1021, 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
    24 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of PF-00489791 in the reduction of albuminuria in subjects with type 2 diabetes and overt nephropathy.
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Hong Kong: 19
    Country: Number of subjects enrolled
    India: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Malaysia: 29
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Serbia: 31
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    256
    EEA total number of subjects
    15
    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)
    155
    From 65 to 84 years
    101
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study was started on 17 December 2010 and ended on 12 August 2013. Overall, 256 subjects were enrolled into the study across 14 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to PF-00489791 tablet once daily for 12 weeks.
    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
    Subjects received Placebo matched to PF-00489791 tablet once daily for 12 weeks. Each daily dose comprised of two 10 milligram (mg) tablets of placebo.

    Arm title
    		 PF-00489791 20 mg
    Arm description
    		 PF-00489791 tablet once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-00489791
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-00489791 20 mg tablet once daily for 12 weeks. Each daily dose comprised of two 10 mg tablets of PF-00489791.

    Number of subjects in period 1
    		Placebo PF-00489791 20 mg
    Started
    64
    192
    Completed
    62
    164
    Not completed
    2
    28
         'Protocol Violation '
    -
    3
         Consent withdrawn by subject
    -
    5
         Did not meet entrance criteria
    1
    4
         Adverse Event
    -
    14
         'Death '
    1
    -
         'Unspecified '
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to PF-00489791 tablet once daily for 12 weeks.

    Reporting group title
    PF-00489791 20 mg
    Reporting group description
    		 PF-00489791 tablet once daily for 12 weeks.

    Reporting group values
    		 Placebo PF-00489791 20 mg Total
    Number of subjects
    		 64 192 256
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.8 ± 11 62 ± 8.8 -
    Gender categorical
    Units: Subjects
        Female
    		 13 48 61
        Male
    		 51 144 195

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to PF-00489791 tablet once daily for 12 weeks.

    Reporting group title
    PF-00489791 20 mg
    Reporting group description
    		 PF-00489791 tablet once daily for 12 weeks.

    Primary: Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12

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    End point title
    		 Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12
    End point description
    UACR is a ratio between 2 measured substances in urine: milligram of albumin per millimole (mmol) of creatinine. A decrease in UACR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to, and with last sample collected on the morning of scheduled clinic visit) were used to determine UACR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UACR. Full analysis set (FAS) was performed for this endpoint. Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: milligram per millimole (mg/mmol)
    arithmetic mean (standard deviation)
        Baseline (n = 63, 191)
    195.13 ± 171.8116
    182.378 ± 156.5097
        Change at Week 12 (n = 60, 164)
    9.072 ± 176.436
    -6.539 ± 128.4866
    Statistical analysis title
    		 Week 12: 0 percent (%) reduction in UACR
    Statistical analysis description
    Analysis of covariance (ANCOVA) model within an outlier robust Bayesian framework on normal logarithmic scale with treatment as fixed effect, baseline UACR and baseline supine systolic blood pressure (BP) as covariate. Values were back transformed from log scale. Model used informative prior distribution for placebo.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.9889 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.843
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.728
         upper limit
    		 0.975
    Notes
    [1] - Bayesian Design was used in the study.
    [2] - Posterior distribution was used to calculate a posterior probability (presented as p-value) that PF­00489791 has a greater than 0 percent (%) reduction in UACR compared to placebo.
    Statistical analysis title
    		 Week 12: 20% reduction in UACR
    Statistical analysis description
    ANCOVA model within an outlier robust Bayesian framework on normal logarithmic scale with treatment as fixed effect, baseline UACR and baseline supine systolic BP as covariate. Values were back transformed from log scale. Model used informative prior distribution for placebo.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.2402 [4]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - Bayesian Design was used in the study.
    [4] - Posterior distribution was used to calculate a posterior probability (presented as p-value) that PF­00489791 has a greater than 0 percent (%) reduction in UACR compared to placebo.

    Secondary: Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16

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    End point title
    		 Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16
    End point description
    UACR is a ratio between 2 measured substances in urine: milligram of albumin per mmol of creatinine. A decrease in UACR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to, and with last sample collected on the morning of scheduled clinic visit) were used to determine UACR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UACR. Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3, 6, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: mg/mmol
    arithmetic mean (standard deviation)
        Change at Week 3 (n = 60, 171)
    -11.805 ± 161.7282
    -14.268 ± 94.8469
        Change at Week 6 (n = 62, 171)
    -7.772 ± 162.0838
    -2.546 ± 179.5896
        Change at Week 16 (n = 60, 162)
    16.5 ± 202.76
    2.802 ± 107.9582
    Statistical analysis title
    		 Week 3
    Statistical analysis description
    Mixed model repeated measures (MMRM) on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0382
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8759
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7727
         upper limit
    		 0.9927
    Notes
    [5] - Sensitivity analysis was used for this endpoint.
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.0112
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8311
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7208
         upper limit
    		 0.9584
    Notes
    [6] - Sensitivity analysis was used for this endpoint.
    Statistical analysis title
    		 Week 16
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.149
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8816
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7427
         upper limit
    		 1.0465
    Notes
    [7] - Sensitivity analysis was used for this endpoint.

    Secondary: Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16

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    End point title
    		 Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16
    End point description
    UPCR is a ratio between two measured substances in urine: milligram of protein per millimole (mmol) of creatinine. A decrease in UPCR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to, and with last sample collected on the morning of scheduled clinic visit) were used to determine UPCR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UPCR. Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: mg/mmol
    arithmetic mean (standard deviation)
        Baseline (n = 63, 191)
    282.208 ± 259.8496
    261.015 ± 220.526
        Change at Week 3 (n = 60, 170)
    -20.302 ± 247.449
    -26.883 ± 161.0038
        Change at Week 6 (n = 62, 170)
    -10.278 ± 256.7216
    10.699 ± 290.5749
        Change at Week 12 (n = 59, 164)
    14.632 ± 283.9874
    -5.371 ± 207.3333
        Change at Week 16 (n = 60, 162)
    30.88 ± 332.0766
    20.299 ± 190.3546
    Statistical analysis title
    		 Week 3
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0297
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8565
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.745
         upper limit
    		 0.9847
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0305
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8524
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7376
         upper limit
    		 0.985
    Statistical analysis title
    		 Week 12
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0068
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.7937
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6717
         upper limit
    		 0.9378
    Statistical analysis title
    		 Week 16
    Statistical analysis description
    MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1151
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.8634
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.719
         upper limit
    		 1.0368

    Secondary: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16

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    End point title
    		 Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16
    End point description
    The eGFR was calculated using 4 variable formula developed by the modification of diet in renal disease (MDRD) study group. The 4 variables needed to estimate glomerular filtration rate (GFR) using this formula were serum creatinine concentration (sCr), age, sex (for females, eGFR was multiplied by 0.742) and ethnic origin (for African-Caribbean people only, eGFR was multiplied by 1.212). Thus eGFR in milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) = 175*(sCr/88.4)^-1.154*(Age) ^-0.203*(0.742 if female)*(1.212 if African-Caribbean). Baseline eGFR was determined predose at Week 0 (Day 1). Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline (n = 61, 188)
    38.575 ± 11.9122
    37.74 ± 9.8834
        Change at Week 3 (n = 59, 172)
    0.069 ± 6.2868
    -0.156 ± 4.6044
        Change at Week 6 (n = 59, 166)
    -0.93 ± 5.3513
    -0.755 ± 5.2701
        Change at Week 12 (n = 58, 161)
    -1.435 ± 5.3757
    -1.463 ± 5.1074
        Change at Week 16 (n = 59, 163)
    -1.915 ± 5.9005
    -1.659 ± 6.0659
    Statistical analysis title
    		 Week 3
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3585
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.9816
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9434
         upper limit
    		 1.0214
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7475
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.9939
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9577
         upper limit
    		 1.0315
    Statistical analysis title
    		 Week 12
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4972
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.9866
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9488
         upper limit
    		 1.0259
    Statistical analysis title
    		 Week 16
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9146
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.0024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9588
         upper limit
    		 1.0481

    Secondary: Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16

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    End point title
    		 Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16
    End point description
    Systolic Blood Pressure (SBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is contracting; it is the maximum arterial pressure during contraction of left ventricle of heart. Diastolic Blood Pressure (DBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is relaxing; it is the minimum arterial pressure during relaxation and dilation of ventricles of heart. Mean blood pressure (MBP) = diastolic blood pressure + ([systolic blood pressure - diastolic blood pressure]/3). After a minimum of 5 minutes of rest, supine BP was measured with the subject's arm supported at the level of the heart. Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement.
    End point type
    Secondary
    End point timeframe
    Week 0, 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: millimeter of mercury (mmHg)
    least squares mean (confidence interval 95%)
        Supine Systolic BP, Week 0
    137.2 (135.01 to 139.4)
    131.81 (130.53 to 133.1)
        Supine Diastolic BP, Week 0
    76.98 (75.53 to 78.42)
    73.27 (72.43 to 74.11)
        Supine Mean BP, Week 0
    107.27 (105.66 to 108.88)
    102.68 (101.74 to 103.62)
        Supine Systolic BP, Week 3
    136.68 (134.3 to 139.05)
    136.15 (134.74 to 137.56)
        Supine Diastolic BP, Week 3
    76.78 (75.25 to 78.31)
    77.18 (76.27 to 78.1)
        Supine Mean BP, Week 3
    107.06 (105.32 to 108.8)
    106.9 (105.86 to 107.94)
        Supine Systolic BP, Week 6
    137.41 (134.9 to 139.93)
    136.94 (135.42 to 138.45)
        Supine Diastolic BP, Week 6
    76.88 (75.32 to 78.43)
    76.41 (75.48 to 77.35)
        Supine Mean BP, Week 6
    107.37 (105.58 to 109.15)
    106.7 (105.62 to 107.77)
        Supine Systolic BP, Week 12
    136.89 (133.73 to 140.06)
    137.7 (135.79 to 139.6)
        Supine Diastolic BP, Week 12
    77.32 (75.51 to 79.13)
    76.69 (75.61 to 77.78)
        Supine Mean BP, Week 12
    107.41 (105.27 to 109.55)
    107.14 (105.85 to 108.42)
        Supine Systolic BP, Week 16
    138.38 (135.51 to 141.25)
    138.89 (137.15 to 140.63)
        Supine Diastolic BP, Week 16
    77.25 (75.59 to 78.92)
    77.9 (76.9 to 78.91)
        Supine Mean BP, Week 16
    108 (106.1 to 109.91)
    108.47 (107.31 to 109.62)
    Statistical analysis title
    		 Supine Systolic BP, Week 0
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -5.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.94
         upper limit
    		 -2.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2942
    Statistical analysis title
    		 Supine Diastolic BP, Week 0
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.38
         upper limit
    		 -2.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.849
    Statistical analysis title
    		 Supine Mean BP, Week 0
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.46
         upper limit
    		 -2.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9489
    Statistical analysis title
    		 Supine Systolic BP, Week 3
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7093
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.29
         upper limit
    		 2.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4056
    Statistical analysis title
    		 Supine Diastolic BP, Week 3
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6564
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9089
    Statistical analysis title
    		 Supine Mean BP, Week 3
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8763
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 1.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0334
    Statistical analysis title
    		 Supine Systolic BP, Week 6
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7491
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.42
         upper limit
    		 2.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4926
    Statistical analysis title
    		 Supine Diastolic BP, Week 6
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6141
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.29
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9235
    Statistical analysis title
    		 Supine Mean BP, Week 6
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5281
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.75
         upper limit
    		 1.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0582
    Statistical analysis title
    		 Supine Systolic BP, Week 12
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6695
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 4.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8764
    Statistical analysis title
    		 Supine Diastolic BP, Week 12
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5607
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 1.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.073
    Statistical analysis title
    		 Supine Mean BP, Week 12
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8297
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 2.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2722
    Statistical analysis title
    		 Supine Systolic BP, Week 16
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7644
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.85
         upper limit
    		 3.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7065
    Statistical analysis title
    		 Supine Diastolic BP, Week 16
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5123
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 2.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9917
    Statistical analysis title
    		 Supine Mean BP, Week 16
    Statistical analysis description
    MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within subject across time points.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6838
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1355

    Secondary: Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16

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    End point title
    		 Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16
    End point description
    Serum creatinine concentration was used as a marker of renal function. Baseline serum creatinine concentration was determined predose at Week 0 (Day 1). Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: micromole per liter (mcmol/L)
    arithmetic mean (standard deviation)
        Baseline (n = 61, 188)
    164.929 ± 42.0837
    163.637 ± 42.9529
        Change at Week 3 (n = 59, 172)
    1.232 ± 23.9961
    2.691 ± 20.6884
        Change at Week 6 (n = 59, 166)
    3.158 ± 18.0835
    4.974 ± 21.7977
        Change at Week 12 (n = 58, 161)
    6.139 ± 20.7198
    8.11 ± 22.3709
        Change at Week 16 (n = 59, 163)
    11.527 ± 28.5175
    9.269 ± 26.647
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16

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    End point title
    		 Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16
    End point description
    TGF Beta-1 is a major fibrogenic growth factor implicated in the pathogenesis of renal scarring. It is overexpressed in the diabetic kidney where it may promote matrix accumulation. Baseline TGF Beta-1 concentration was determined predose at Week 0 (Day 1). Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: picogram per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Baseline (n = 55, 159)
    177.88 ± 231.154
    213.37 ± 274.409
        Change at Week 3 (n = 52, 145)
    -22.81 ± 260.14
    -54.06 ± 349.817
        Change at Week 6 (n = 53, 141)
    23.33 ± 345.304
    -68.59 ± 333.378
        Change at Week 12 (n = 49, 136)
    -36.2 ± 281.523
    -11.87 ± 328.482
        Change at Week 16 (n = 49, 125)
    -23.54 ± 134.752
    -31.32 ± 299.546
    Statistical analysis title
    		 Week 3
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5422
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.9282
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7297
         upper limit
    		 1.1807
    Statistical analysis title
    		 Week 6
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    0.7998
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6402
         upper limit
    		 0.999
    Statistical analysis title
    		 Week 12
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7264
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.0435
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8211
         upper limit
    		 1.3262
    Statistical analysis title
    		 Week 16
    Statistical analysis description
    MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within subject across time points. Values were back-transformed from log scale.
    Comparison groups
    Placebo v PF-00489791 20 mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3733
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.1154
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8761
         upper limit
    		 1.4201

    Secondary: Change From Baseline in Serum High Sensitivity C-Reactive Protein (hs-CRP) Concentration at Week 12 and 16

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    End point title
    		 Change From Baseline in Serum High Sensitivity C-Reactive Protein (hs-CRP) Concentration at Week 12 and 16
    End point description
    The CRP is an acute phase reactant which is virtually absent from the blood serum of healthy persons but rapidly appears in blood and body fluids in response to injurious stimuli. Baseline hs-CRP was determined predose at Week 0 (Day 1). Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: milligram per liter (mg/L)
    arithmetic mean (standard deviation)
        Baseline (n = 60, 187)
    3.019 ± 3.4924
    4.33 ± 8.6809
        Change at Week 12 (n = 56, 160)
    1.183 ± 3.46
    0.106 ± 7.4909
        Change at Week 16 (n = 57, 161)
    0.317 ± 2.9508
    -0.102 ± 6.3317
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16

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    End point title
    		 Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16
    End point description
    Cystatin C is produced by all nucleated cells at a constant rate and is freely filtered at the glomerulus. The blood concentration of cystatin C depends almost entirely on the GFR and is not substantially affected by diet, nutritional status or inflammatory disease. Serum cystatin C had been proposed as an endogenous marker of GFR in subject with chronic kidney disease (CKD) than sCr. Baseline serum cystatin C was determined predose at Week 0 (Day 1). Full analysis set included all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: mg/L
    arithmetic mean (standard deviation)
        Baseline (n = 60, 188)
    1.659 ± 0.4122
    1.695 ± 0.4497
        Change at Week 12 (n = 56, 161)
    0.096 ± 0.1844
    0.07 ± 0.289
        Change at Week 16 (n = 57, 162)
    0.104 ± 0.3234
    0.075 ± 0.3176
    No statistical analyses for this end point

    Secondary: Population Pharmacokinetics (PK)

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    End point title
    		 Population Pharmacokinetics (PK)
    End point description
    Data for this Outcome Measure are not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: mg\mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [8] - Data was not reported here as the analysis population includes subjects not enrolled in study.
    [9] - Data was not reported here as the analysis population includes subjects not enrolled in study.
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16

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    End point title
    		 Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16
    End point description
    Level of HbA1c is an indicator for the average level of blood glucose over the previous 3 months. Baseline HbA1c level was determined predose at Week 0 (Day 1). Safety analysis set (SAS) was performed for this endpoint. Safety analysis set consists of all subjects who received at least 1 dose of study medication. Here ‘n’ signifies subjects evaluable at specified time point for each arm, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: percentage of hemoglobin
    arithmetic mean (standard deviation)
        Baseline (n = 61, 187)
    7.13 ± 1.023
    7.39 ± 1.135
        Change at Week 12 (n = 56, 157)
    0.12 ± 0.856
    -0.28 ± 0.975
        Change at Week 16 (n = 58, 161)
    0.14 ± 1.009
    -0.09 ± 0.986
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Vital Signs Abnormalities

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    End point title
    		 Number of Subjects With Vital Signs Abnormalities
    End point description
    Criteria for determining vital signs abnormalities: supine or standing systolic BP (SBP) (less than [<] 90 mmHg and increase or decrease of greater than or equal to [>=] 30 mmHg compared to baseline value), supine or standing diastolic BP (DBP) (<50 mmHg and increase or decrease of >=20 mmHg compared to baseline value), supine pulse rate (>120 beats per minute [bpm] or <40 bpm), standing pulse rate (>140 bpm or <40 bpm). For supine, baseline was the average of the triplicate predose readings at Week 0 (Day 1). For standing, baseline is the predose reading at Week 0 (Day 1). Only subjects who met the specified criteria are reported. Safety analysis set consists of all subjects who received at least 1 dose of study medication. Here ‘n’ signifies subjects evaluable for specified category for each arm, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: subjects
        Supine SBP <90 mmHg (n = 64, 192)
    0
    1
        Standing SBP <90 mmHg (n = 64, 189)
    0
    2
        Supine DBP <50 mmHg (n = 64, 192)
    0
    3
        Standing DBP <50 mmHg (n = 64, 189)
    0
    3
        Supine Pulse Rate <40 bpm (n = 64, 192)
    0
    1
        Increase in Supine SBP >=30 mmHg (n = 64, 192)
    0
    14
        Increase in Standing SBP >=30 mmHg (n = 64, 189)
    1
    1
        Increase in Supine DBP >=20 mmHg (n = 64, 192)
    0
    7
        Increase in Standing DBP >=20 mmHg (n = 64, 189)
    1
    0
        Decrease in Supine SBP >=30 mmHg (n = 64, 192)
    0
    9
        Decrease in Standing SBP >=30 mmHg (n = 64, 189)
    2
    11
        Decrease in Supine DBP >=20 mmHg (n = 64, 192)
    0
    5
        Decrease in Standing DBP >=20 mmHg (n = 64, 189)
    1
    11
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Edema and Fluid Overload

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    End point title
    		 Number of Subjects With Edema and Fluid Overload
    End point description
    Subjects were assessed for signs of edema and fluid overload. Safety analysis set consists of all subjects who received at least 1 dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Week 0, 3, 6, 12, 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: subjects
        Week 0
    0
    4
        Week 3
    1
    8
        Week 6
    1
    11
        Week 12
    4
    9
        Week 16
    5
    6
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Increased Use of Diuretics

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    End point title
    		 Number of Subjects With Increased Use of Diuretics
    End point description
    The number of subjects, who had dose of diuretics increased during the study were reported. Safety analysis set consists of all subjects who received at least 1 dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: subjects
    3
    10
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Test Abnormalities

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    End point title
    		 Number of Subjects With Laboratory Test Abnormalities
    End point description
    Criteria for laboratory test abnormalities: Hematology (hemoglobin [<0.8*lower limit of normal{LLN}], hematocrit [<0.8*LLN], red blood cells [<0.8*LLN], platelet [<0.5*LLN/>1.75*upper limit of normal {ULN}], white blood cells [<0.6*LLN/>1.5*ULN], lymphocytes [<0.8*LLN/>1.2*ULN], neutrophils [<0.8*LLN/>1.2*ULN], basophils [>1.2*ULN], eosinophils [>1.2*ULN], monocytes [>1.2*ULN]); Liver Function (total/direct/indirect bilirubin [>1.5*ULN], aspartate aminotransferase/ alanine aminotransferase/ gamma glutamyl transpeptidase/ lactate dehydrogenase/ alkaline phosphatase [>3.0*ULN]); Renal Function (blood urea nitrogen/ creatinine [>1.3*ULN], uric acid [>1.2*ULN]); Electrolytes (sodium [<0.95*LLN/>1.05*ULN], potassium, chloride, calcium, bicarbonate [<0.9*LLN/>1.1*ULN]); Clinical Chemistry (glucose [<0.6*LLN/>1.5*ULN], glycosylated hemoglobin [>1.3*ULN], Creatine Kinase [>2.0*ULN], Amylase, Lipase[>1.5*ULN]). Safety analysis set.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    63 [10]
    190 [11]
    Units: subjects
    62
    190
    Notes
    [10] - Here 'N' (number of subjects analyzed) signifies subjects evaluable for this measure.
    [11] - Here 'N' (number of subjects analyzed) signifies subjects evaluable for this measure.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study medication without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study medication and up to Week 16 (follow-up) that were absent before treatment or that worsened relative to pre-treatment state. Safety analysis set consists of all subjects who received at least 1 dose of study medication.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16 (follow-up)
    End point values
    		 Placebo PF-00489791 20 mg
    Number of subjects analysed
    64
    192
    Units: subjects
        AEs
    36
    105
        SAEs
    6
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs/SAEs: recorded from Week 0 to Week 16
    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 1 subject and as nonserious in another, or 1 subject may have experienced both serious, nonserious event during study. EU BR specific AE tables were generated separately as per EU format using latest coding.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to PF-00489791 tablet orally once daily for 12 weeks.

    Reporting group title
    PF-00489791 20 mg
    Reporting group description
    		 PF-00489791 20 mg tablet orally once daily for 12 weeks.

    Serious adverse events
    		 Placebo PF-00489791 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 64 (9.38%)
    13 / 192 (6.77%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Prostatectomy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Procedural hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo PF-00489791 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 64 (54.69%)
    104 / 192 (54.17%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Flushing
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 64 (3.13%)
    9 / 192 (4.69%)
         occurrences all number
    2
    9
    Hypotension
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 192 (0.00%)
         occurrences all number
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Peripheral venous disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    3
    Fatigue
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 192 (1.04%)
         occurrences all number
    1
    2
    Oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 192 (1.56%)
         occurrences all number
    1
    3
    Feeling hot
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    6 / 64 (9.38%)
    10 / 192 (5.21%)
         occurrences all number
    6
    12
    Pyrexia
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 192 (2.08%)
         occurrences all number
    0
    4
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    2
    Social circumstances
    Immobile
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    2
    0
    Spontaneous penile erection
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    5
    Sinus congestion
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Blood calcium decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 64 (4.69%)
    6 / 192 (3.13%)
         occurrences all number
    3
    6
    Blood creatinine increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    2
    Blood glucose abnormal
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 192 (1.56%)
         occurrences all number
    0
    3
    Blood pressure abnormal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Blood uric acid increased
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 192 (0.00%)
         occurrences all number
    3
    0
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Liver function test normal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Weight increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Humerus fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Coronary artery disease
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Diabetic neuropathy
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 64 (1.56%)
    7 / 192 (3.65%)
         occurrences all number
    1
    7
    Drooling
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    6 / 64 (9.38%)
    12 / 192 (6.25%)
         occurrences all number
    7
    13
    Paraesthesia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Tremor
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 192 (2.08%)
         occurrences all number
    0
    4
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Neutrophilia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Lacrimation increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 192 (1.04%)
         occurrences all number
    2
    2
    Dry mouth
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 64 (3.13%)
    17 / 192 (8.85%)
         occurrences all number
    2
    22
    Dyspepsia
         subjects affected / exposed
    1 / 64 (1.56%)
    12 / 192 (6.25%)
         occurrences all number
    1
    13
    Flatulence
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Gastritis erosive
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gastroduodenitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 192 (1.56%)
         occurrences all number
    0
    3
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 192 (2.08%)
         occurrences all number
    0
    4
    Nausea
         subjects affected / exposed
    2 / 64 (3.13%)
    4 / 192 (2.08%)
         occurrences all number
    2
    4
    Large intestine polyp
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Oesophageal ulcer
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 64 (3.13%)
    7 / 192 (3.65%)
         occurrences all number
    2
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 192 (0.00%)
         occurrences all number
    2
    0
    Neuropathic ulcer
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Neurodermatitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 192 (1.56%)
         occurrences all number
    0
    4
    Pruritus generalised
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Polyuria
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Proteinuria
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Renal cyst
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 192 (1.56%)
         occurrences all number
    1
    3
    Arthritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    2 / 64 (3.13%)
    5 / 192 (2.60%)
         occurrences all number
    2
    7
    Joint swelling
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    3
    Muscle spasms
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 192 (0.52%)
         occurrences all number
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Osteoarthritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 192 (1.56%)
         occurrences all number
    0
    3
    Osteopenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 192 (0.52%)
         occurrences all number
    2
    1
    Eye infection bacterial
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 192 (1.56%)
         occurrences all number
    0
    4
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Mastitis fungal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 64 (1.56%)
    9 / 192 (4.69%)
         occurrences all number
    1
    9
    Onychomycosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    6 / 192 (3.13%)
         occurrences all number
    1
    8
    Urinary tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Gout
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 192 (1.04%)
         occurrences all number
    0
    2
    Hyperamylasaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    4 / 192 (2.08%)
         occurrences all number
    1
    4
    Hyperuricaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 192 (1.56%)
         occurrences all number
    1
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 192 (1.04%)
         occurrences all number
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 192 (0.52%)
         occurrences all number
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 192 (0.52%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 192 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2011
    1)Entry criterion of UACR lowered to 300 milligram per gram (mg/g) in order to allow assessment of the effects of PF-00489791 in the lower part of the macroalbuminuric range. This revised range more fully represented the patient population at risk of disease progression. 2)Blood pressure at entry amended to 150/100 mmHg as this was more reflective of the at-risk patient population and allowed the study population to reflect this. 3)Estimated glomerular filtration rate (eGFR), which takes gender, age and African/Caribbean status into account remained as the determinant of renal function at study entry. Serum creatinine was continued to be monitored in subjects throughout study participation.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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