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    Clinical Trial Results:
    A Randomized, 18-Week, Placebo-Controlled, Double Blind, Parallel Group Study of the Safety and Efficacy of PF-05212377 (SAM-760) in Subjects With Mild to-Moderate Alzheimer's Disease With Existing Neuropsychiatric Symptoms on a Stable Daily Dose of Donepezil

    Summary
    EudraCT number
    		 2014-000830-42
    Trial protocol
    		 ES   GB  
    Global end of trial date
    15 Sep 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Feb 2017
    First version publication date
    11 Sep 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B2081011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer, Inc., Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer, Inc., Pfizer, Inc., 001 800-718-1021, 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
    17 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary Objective: To evaluate the efficacy of PF-05212377 (SAM 760) 30 milligram (mg) once daily (QD) as compared to placebo on the primary measure of cognition and memory, the Alzheimer’s Disease Assessment Scale cognitive subscale 13 item version (ADAS-cog13) 12 weeks after start of double blind study medication. Secondary Objective: To evaluate the efficacy of PF-05212377 30 mg QD as compared to placebo on a broad measure of behavior, the Neuropsychiatric Inventory (NPI) (12 item) at 12 weeks after start of double blind study medication.
    Protection of trial subjects
    This study was conducted in compliance with good clinical practice (GCP) guidelines and, where applicable, local country regulations relevant to the use of new therapeutic agents in the country/countries of conduct, including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Chile: 39
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 125
    Country: Number of subjects enrolled
    Canada: 16
    Worldwide total number of subjects
    195
    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)
    15
    From 65 to 84 years
    151
    85 years and over
    29

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was a multicenter Phase 2a, randomized, placebo controlled, safety and efficacy study of 18 weeks in duration in subjects with mild-to-moderate Alzheimer’s disease (AD) who were stable on treatment with 5 or 10 mg of donepezil and who had existing neuropsychiatric symptoms.

    Pre-assignment
    Screening details
    		 Before entering in the 12-week treatment period, participants were required to enter a 4-week placebo run-in period. 195 participants started the run-in period, of which 185 were eligible for the treatment period. One subject who discontinued during the placebo run-in was incorrectly enrolled into the double-blind period but was never treated.

    Period 1
    Period 1 title
    Placebo Run-in Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Placebo Run-in Period
    Arm description
    		 All subjects receiving placebo during the single-blind placebo run-in period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as capsule once daily in the morning.

    Number of subjects in period 1
    		Placebo Run-in Period
    Started
    195
    Completed
    185
    Not completed
    10
         Adverse event, non-fatal
    2
         No longer willing to participate in study
    1
         No longer met eligibility criteria
    5
         Unspecified
    1
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Double-blind treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-05212377 30 mg
    Arm description
    		 All subjects receiving PF-05212377 30 mg during double blind period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05212377
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    PF-05212377 was provided as 15 mg capsules once daily in the morning

    Arm title
    		 Placebo
    Arm description
    		 All subjects receiving placebo during the double blind period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as capsule once daily in the morning.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 for this study is considered the placebo run-in period.
    Number of subjects in period 2 [2]
    		PF-05212377 30 mg Placebo
    Started
    91
    94
    Completed
    77
    86
    Not completed
    15
    8
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    2
    1
         No longer meets eligibility criteria
    3
    -
         Randomized but not treated
    1
    -
         No longer willing to participate in study
    2
    4
         Unspecified
    4
    1
         Lost to follow-up
    2
    1
         Protocol deviation
    -
    1
    Joined
    1
    0
         Randomized but not treated
    1
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled in the trial includes all subjects included for safety reporting and enrolled in the placebo run-in period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-blind treatment period
    Reporting group description
    		 -

    Reporting group values
    		 Double-blind treatment period Total
    Number of subjects
    		 186 186
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 144 144
        85 years and over
    		 28 28
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 76 ± 7.7 -
    Gender Categorical
    Units: Subjects
        Female
    		 101 101
        Male
    		 85 85

    End points

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    End points reporting groups
    Reporting group title
    Placebo Run-in Period
    Reporting group description
    		 All subjects receiving placebo during the single-blind placebo run-in period
    Reporting group title
    PF-05212377 30 mg
    Reporting group description
    		 All subjects receiving PF-05212377 30 mg during double blind period.

    Reporting group title
    Placebo
    Reporting group description
    		 All subjects receiving placebo during the double blind period

    Primary: Change From Baseline in ADAS-cog13 Total Score at Week 16

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    End point title
    		 Change From Baseline in ADAS-cog13 Total Score at Week 16
    End point description
    ADAS-cog13 (13-item ADAS cog) is a psychometric instrument that evaluates word recall, ability to follow commands,constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. The Full Analysis Set (FAS) is defined as all subjects who were randomized. The FAS was the primary analysis set for efficacy data.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2, Week 4) and Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    78
    86
    Units: scores on a scale
        least squares mean (standard error)
    0.111 ± 0.629
    -0.584 ± 0.5995
    Statistical analysis title
    		 Difference between PF-05212377 30 mg and placebo
    Statistical analysis description
    Mixed Models Analysis
    Comparison groups
    PF-05212377 30 mg v Placebo
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.695
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.424
         upper limit
    		 1.814
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8697

    Secondary: Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16

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    End point title
    		 Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 16
    End point description
    The NPI evaluates both frequency and severity of 12 neuropsychiatric disturbances including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, as well as appetite/eating. The NPI total score (for 12 behavioral domains) is calculated as the product of frequency and severity for each domain, and ranges from 0 to 144. An increase in score indicates a worsening of symptoms. The FAS is defined as all subjects who are randomized. The FAS was the primary analysis set for efficacy data.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2, Week 4) and Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    78
    87
    Units: scores on scale
        least squares mean (standard error)
    -3.99 ± 1.2441
    -6.184 ± 1.1801
    Statistical analysis title
    		 Difference between PF-05212377 30 mg and placebo
    Statistical analysis description
    Mixed Models Analysis
    Comparison groups
    PF-05212377 30 mg v Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Median difference (net)
    Point estimate
    2.194
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.013
         upper limit
    		 4.401
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7149

    Other pre-specified: Percentage of Subjects with Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation

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    End point title
    		 Percentage of Subjects with Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation
    End point description
    Proportion (%) of subjects with TEAEs leading to discontinuation over the 12 week double blind treatment period and washout. Adverse events (AEs) occurring following start of treatment or increasing in severity were counted as treatment emergent. Population analysis was defined as all subjects who received any treatment during double blind period.
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 18 (Visit 6)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    94
    Units: Percentage of Subjects
        number (not applicable)
    3.3
    0
    No statistical analyses for this end point

    Other pre-specified: Proportion of Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period

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    End point title
    		 Proportion of Laboratory Abnormalities of Potential Clinical Concern During Double Blind Period
    End point description
    Proportion of subjects with lab abnormalities of potential clinical concern over the double blind period. The following parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein/albumin, hemoglobin/blood, ketones/acetone, nitrites, leukocyte esterase, microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (only at screening or needed: urine drug screen, thyroid panel, VB12, methylmalonic acid, folate and HbA1). Analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    94
    Units: Percentage of Subjects
        number (not applicable)
    36
    52
    No statistical analyses for this end point

    Other pre-specified: Selected Electrocardiogram (ECG) Change from Baseline - PR Interval at Week 6 (Visit 3)

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    End point title
    		 Selected Electrocardiogram (ECG) Change from Baseline - PR Interval at Week 6 (Visit 3)
    End point description
    The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 6 (Visit 3)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    85
    89
    Units: milliseconds (msec)
        arithmetic mean (full range (min-max))
    -2.8 (-52 to 24)
    -3.6 (-82 to 35)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - PR Interval at Week 10 (Visit 4)

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    End point title
    		 Selected ECG Change from Baseline - PR Interval at Week 10 (Visit 4)
    End point description
    The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 10 (Visit 4)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    79
    87
    Units: msec
        arithmetic mean (full range (min-max))
    -0.1 (-42 to 23)
    -1.3 (-61 to 61)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - PR Interval at Week 16/Early Termination (Visit 5)

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    End point title
    		 Selected ECG Change from Baseline - PR Interval at Week 16/Early Termination (Visit 5)
    End point description
    The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 16/Early Termination (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    82
    85
    Units: msec
        arithmetic mean (full range (min-max))
    -2.5 (-69 to 24)
    -1.6 (-49 to 33)
    No statistical analyses for this end point

    Other pre-specified: Proportion of PR Interval Abnormalities of Potential Clinical Concern

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    End point title
    		 Proportion of PR Interval Abnormalities of Potential Clinical Concern
    End point description
    Proportion (%) of subjects with PR Interval abnormalities meeting categorical criteria over the 12 week double blind treatment period. The PR interval is the time from the onset of the P wave to the start of the QRS complex (the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Subjects with post-baseline PR absolute value>=300 msec , a PR increase of >=25% (for subjects with a baseline value>=200 msec), or with an increase >=50% (for subjects with a baseline value<200 msec) were counted. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    86
    90
    Units: Percentage of Subjects
    number (not applicable)
        Post-Baseline Maximum Absolute Value >=300 msec
    0
    4.4
        Post-Baseline Maximum Increase >=25/50%
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QRS complex at Week 6 (Visit 3)

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    End point title
    		 Selected ECG Change from Baseline - QRS complex at Week 6 (Visit 3)
    End point description
    The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization.The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 6 (Visit 3)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    88
    92
    Units: msec
        arithmetic mean (full range (min-max))
    -0.3 (-22 to 43)
    -0.8 (-14 to 10)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QRS complex at Week 10 (Visit 4)

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    End point title
    		 Selected ECG Change from Baseline - QRS complex at Week 10 (Visit 4)
    End point description
    The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization). The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 10 (Visit 4)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    81
    90
    Units: msec
        arithmetic mean (full range (min-max))
    -0.1 (-13 to 45)
    0.1 (-15 to 22)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QRS complex at Week 16/Early Termination (Visit 5)

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    End point title
    		 Selected ECG Change from Baseline - QRS complex at Week 16/Early Termination (Visit 5)
    End point description
    The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 16/Early Termination (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    85
    89
    Units: msec
        arithmetic mean (full range (min-max))
    0.1 (-14 to 18)
    -0.3 (-21 to 14)
    No statistical analyses for this end point

    Other pre-specified: Proportion of Subjects with QRS Complex Abnormalities of Potential Clinical Concern

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    End point title
    		 Proportion of Subjects with QRS Complex Abnormalities of Potential Clinical Concern
    End point description
    Proportion (%) of subjects with QRS complex abnormalities meeting categorical criteria over the 12 week double blind treatment period. The QRS complex is the combination of the Q wave, R wave and S wave, representing ventricular depolarization). Subjects with post-baseline QRS complex absolute value>=100 msec , a QRS complex increase of >=25% (for subjects with a baseline value>=100 msec), or with an increase >=50% (for subjects with a baseline value<100 msec) were counted. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    93
    Units: Percentage of Subjects
    number (not applicable)
        Post-Baseline Maximum Absolute Value >=200 msec
    0
    0
        Post-Baseline Maximum Increase >=25/50%
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QTcF interval at Week 6 (Visit 3)

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    End point title
    		 Selected ECG Change from Baseline - QTcF interval at Week 6 (Visit 3)
    End point description
    The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 6 (Visit 3)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    88
    92
    Units: msec
        arithmetic mean (full range (min-max))
    -3 (-31 to 37)
    -4.9 (-35 to 35)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QTcF interval at Week 10 (Visit 4)

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    End point title
    		 Selected ECG Change from Baseline - QTcF interval at Week 10 (Visit 4)
    End point description
    The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 10 (Visit 4)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    81
    90
    Units: msec
        arithmetic mean (full range (min-max))
    -0.2 (-38 to 47)
    -5.5 (-40 to 48)
    No statistical analyses for this end point

    Other pre-specified: Selected ECG Change from Baseline - QTcF interval at Week 16/Early Termination (Visit 5)

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    End point title
    		 Selected ECG Change from Baseline - QTcF interval at Week 16/Early Termination (Visit 5)
    End point description
    The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 16/Early Termination (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    85
    89
    Units: msec
        arithmetic mean (full range (min-max))
    0.8 (-31 to 34)
    -2.2 (-62 to 30)
    No statistical analyses for this end point

    Other pre-specified: Proportion of Subjects with QTcF Interval Abnormalities of Potential Clinical Concern

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    End point title
    		 Proportion of Subjects with QTcF Interval Abnormalities of Potential Clinical Concern
    End point description
    Proportion (%) of subjects with QTcF Interval abnormalities meeting categorical criteria over the 12-week double blind treatment period. The QTcF interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, which is corrected for heart rate using Fridericia's formula. Subjects with a post-baseline QTcF absolute value of 450 - <480, 480 - <500, or >=500 mec, or with a post-baseline QTcF increase of 30 - <60 or >=60 msec were counted. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    93
    Units: Percentage of Subjects
    number (not applicable)
        Post-Baseline Absolute Value of 450-<480 msec
    15.4
    14
        Post-Baseline Absolute Value of 480-<500 msec
    4.4
    1.1
        Change from Baseline of 30 -<60 msec
    6.6
    3.2
        Change from Baseline >=60 msec
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Blood Pressure (BP) Changes from Baseline - Week 6 (Visit 3)

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    End point title
    		 Blood Pressure (BP) Changes from Baseline - Week 6 (Visit 3)
    End point description
    The BP changes from baseline at Week 6 (Visit 3) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP.The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 6 (Visit 3)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    89
    93
    Units: millimeters of mercury (mm Hg)
    arithmetic mean (full range (min-max))
        Supine Systolic BP
    -3.6 (-38 to 19)
    -3.9 (-52 to 30)
        Standing Systolic BP
    -4.1 (-49 to 20)
    -3 (-38 to 22)
        Supine Diastolic BP
    -2.2 (-37 to 26)
    -1.8 (-33 to 20)
        Standing Diastolic BP
    -1.1 (-23 to 17)
    -1 (-23 to 21)
    No statistical analyses for this end point

    Other pre-specified: Pulse Rate Changes from Baseline - Week 6 (Visit 3)

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    End point title
    		 Pulse Rate Changes from Baseline - Week 6 (Visit 3)
    End point description
    The pulse rate changes from baseline at Week 6 (Visit 3) including supine pulse rate, and standing pulse rate. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 6 (Visit 3)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    89
    93
    Units: beats per minute (bpm)
    arithmetic mean (full range (min-max))
        Supine Pulse Rate
    -1.4 (-30 to 30)
    1.4 (-21 to 20)
        Standing Pulse Rate
    -0.3 (-20 to 30)
    1.3 (-12 to 27)
    No statistical analyses for this end point

    Other pre-specified: BP Changes from Baseline - Week 10 (Visit 4)

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    End point title
    		 BP Changes from Baseline - Week 10 (Visit 4)
    End point description
    The BP changes from baseline at Week 10 (Visit 4) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 10 (Visit 4)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    81
    91
    Units: mm Hg
    arithmetic mean (full range (min-max))
        Supine Systolic BP
    -3.4 (-36 to 20)
    -0.3 (-68 to 34)
        Standing Systolic BP
    -3.8 (-33 to 32)
    0.8 (-49 to 49)
        Supine Diastolic BP
    -2.4 (-32 to 20)
    -0.7 (-39 to 25)
        Standing Diastolic BP
    -1.2 (-20 to 20)
    0.3 (-26 to 39)
    No statistical analyses for this end point

    Other pre-specified: Pulse Rate Changes from Baseline - Week 10 (Visit 4)

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    End point title
    		 Pulse Rate Changes from Baseline - Week 10 (Visit 4)
    End point description
    The pulse rate changes from baseline at Week 10 (Visit 4) including supine pulse rate, and standing pulse rate. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 10 (Visit 4)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    81
    91
    Units: bpm
    arithmetic mean (full range (min-max))
        Supine Pulse Rate
    -0.4 (-26 to 22)
    0.5 (-24 to 17)
        Standing Pulse Rate
    -0.7 (-20 to 24)
    1.8 (-19 to 21)
    No statistical analyses for this end point

    Other pre-specified: BP Changes from Baseline - Week 16/Early Termination (Visit 5)

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    End point title
    		 BP Changes from Baseline - Week 16/Early Termination (Visit 5)
    End point description
    The BP changes from baseline at Week 16/Early Termination (Visit 5) including supine systolic BP, standing systolic BP, standing systolic BP, supine diastolic BP, standing diastolic BP. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 16/Early Termination (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    85
    90
    Units: mmHg
    arithmetic mean (full range (min-max))
        Supine Systolic BP
    -1.4 (-30 to 27)
    -1.1 (-30 to 72)
        Standing Systolic BP
    -1 (-30 to 32)
    -1.1 (-26 to 66)
        Supine Diastolic BP
    -2.1 (-39 to 22)
    -0.3 (-18 to 35)
        Standing Diastolic BP
    -0.8 (-23 to 23)
    0 (-20 to 36)
    No statistical analyses for this end point

    Other pre-specified: Pulse Rate Changes from Baseline - Week 16/Early Termination (Visit 5)

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    End point title
    		 Pulse Rate Changes from Baseline - Week 16/Early Termination (Visit 5)
    End point description
    The pulse rate changes from baseline at Week 16/Early Termination (Visit 5) including supine pulse rate, and standing pulse rate. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 16/Early Termination (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    85
    90
    Units: bpm
    arithmetic mean (full range (min-max))
        Supine Pulse Rate
    -0.8 (-29 to 31)
    0.6 (-22 to 20)
        Standing Pulse Rate
    -1.9 (-24 to 39)
    0.8 (-17 to 17)
    No statistical analyses for this end point

    Other pre-specified: Proportion of Subjects with Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern

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    End point title
    		 Proportion of Subjects with Post-Baseline Vital Signs Abnormalities of Potential Clinical Concern
    End point description
    Proportion (%) of subjects with vital signs abnormalities (absolute and change from baseline) meeting categorical criteria over the 12-week double blind treatment period were counted. Vital signs data included BP and pulse rate. The analysis population was defined as all subjects who received any treatment during Week 4 (Visit 2) to Week 16 (Visit 5).
    End point type
    Other pre-specified
    End point timeframe
    Week 4 (Visit 2) to Week 16 (Visit 5)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    94
    Units: Percentage of Subjects
    number (not applicable)
        Absolute Supine Systolic BP<90 mmHg
    0
    1.1
        Absolute Standing Systolic BP<90 mmHg
    0
    1.1
        Absolute Supine Diastolic BP<50 mmHg
    0
    2.1
        Absolute Standing Diastolic BP <50 mmHg
    0
    0
        Absolute Supine Pulse Rate <40 bpm
    0
    0
        Absolute Supine Pulse Rate >120 bpm
    0
    0
        Absolute Standing Pulse Rate <40 bpm
    0
    0
        Absolute Standing Pulse Rate >140 bpm
    0
    0
        Increase in Supine Systolic BP>=30 mmHg
    0
    5.3
        Increase in Standing Systolic BP>=30 mmHg
    2.2
    3.2
        Increase in Supine Diastolic BP >=20 mmHg
    4.4
    4.3
        Increase in Standing Diastolic BP >=20 mmHg
    3.3
    5.3
        Decrease in Supine Systolic BP>=30 mmHg
    5.5
    5.3
        Decrease in Standing Systolic BP>=30 mmHg
    5.5
    5.3
        Decrease in Supine Diastolic BP >=20 mmHg
    8.8
    5.3
        Decrease in Standing Diastolic BP >=20 mmHg
    4.4
    6.4
    No statistical analyses for this end point

    Other pre-specified: Subjects in Each Category of C-CASA Mapped from the C-SSRS Responses

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    End point title
    		 Subjects in Each Category of C-CASA Mapped from the C-SSRS Responses
    End point description
    Subjects in each category of the Columbia Classification Algorithm of Suicide Assessment (C-CASA) mapped from the Columbia-Suicide Severity Rating Scale (C-SSRS) responses were reported. C-CASA Event Code: <1> Completed suicide; <2> Suicide attempt; <3> Preparatory acts towards imminent suicidal behavior; <4> Suicidal Ideation; <7> Self-injurious behavior, no suicidal intent. The suicidality assessments were performed at Screening, Week 0 (Visit 1), Week 4 (Visit 2), Week 6, (Visit 3), Week 10 (Visit 4), Week 16 (Visit 5), and Week 18 (Visit 6). Only subjects falling any category of C-CASA events were listed below. Analysis population was defined as all subjects screened and assigned.
    End point type
    Other pre-specified
    End point timeframe
    From Screening to Week 18/Early Termination (Visit 6)
    End point values
    		 PF-05212377 30 mg Placebo
    Number of subjects analysed
    91
    94
    Units: subjects
    number (not applicable)
        Week 4 (Visit 2): <4>
    2
    1
        Week 6 (Visit 3): <4>
    0
    1
        Week 10 (Visit 4): <4>
    2
    0
        Week 16/Early Termination (Visit 5): <4>
    1
    0
        Week 4 (Visit 2): <7>
    0
    1
        Week 6 (Visit 3): <7>
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 18
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo Run-in
    Reporting group description
    		 Subjects who received placebo during the single blind placebo-run in period

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo once daily in the morning during the double blind period.

    Reporting group title
    PF-05212377 30 mg
    Reporting group description
    		 Subjects who received PF-05212377 30 mg once daily in the morning during the double blind period.

    Serious adverse events
    		 Placebo Run-in Placebo PF-05212377 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 195 (0.51%)
    3 / 94 (3.19%)
    5 / 91 (5.49%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 94 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Run-in Placebo PF-05212377 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 195 (6.67%)
    20 / 94 (21.28%)
    25 / 91 (27.47%)
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 195 (0.51%)
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 195 (1.03%)
    3 / 94 (3.19%)
    3 / 91 (3.30%)
         occurrences all number
    2
    3
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences all number
    0
    2
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 195 (3.08%)
    3 / 94 (3.19%)
    8 / 91 (8.79%)
         occurrences all number
    6
    3
    9
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Insomnia
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences all number
    0
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 195 (2.05%)
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences all number
    4
    2
    2
    Pneumonia
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    4 / 94 (4.26%)
    5 / 91 (5.49%)
         occurrences all number
    0
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2013
    The inclusion and exclusion criteria were amended and some more efficacy evaluations were added
    02 Jan 2014
    Numbering of Days for Screening Period was revised. Some sections were reworded

    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
    For support, Contact us.
    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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