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    Clinical Trial Results:
    A PHASE 2A RANDOMIZED, DOUBLE-BLINDED, DOUBLE DUMMY, PLACEBO AND ACTIVE CONTROLLED, TWO-WAY CROSS-OVER, FLARE-ENRICHED MULTI-CENTRE CLINICAL TRIAL TO EXAMINE THE PAIN RELIEF PRODUCED BY 2 WEEKS OF DAILY ORAL ADMINISTRATION OF A FATTY ACID AMIDE HYDROLASE (FAAH) INHIBITOR PF-04457845 IN PATIENTS WITH OSTEOARTHRITIS OF THE KNEE.

    Summary
    EudraCT number
    		 2009-014734-16
    Trial protocol
    		 SE  
    Global end of trial date
    21 Jun 2010

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B0541004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00981357
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of PF-04457845 (administered once daily [QD]) versus placebo in relieving pain in subjects with osteoarthritis of the knee. To evaluate the safety and tolerability of PF-04457845 in patients with osteoarthritis.
    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
    02 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Canada: 14
    Worldwide total number of subjects
    74
    EEA total number of subjects
    1
    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)
    50
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study was conducted at 5 sites in 3 countries from 2 November 2009 to 21 June 2010.

    Pre-assignment
    Screening details
    		 74 of 76 randomised subjects were treated. Subjects had an initial 7 day pain assessment period (PAP) for baseline. Subjects then had 14 day double-blind treatment period (1), followed by a 14 day washout. A repeat PAP was then conducted followed by double-blind treatment period 2. 

    Period 1
    Period 1 title
    First Intervention Period (2 Week)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-04457845 then Placebo
    Arm description
    		 PF-04457845 tablet was administered once daily (QD) in the first intervention period and then matching placebo tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04457845
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PF-04457845 4 milligram (mg) tablet was administered QD for 14 days (First Intervention Period).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to PF-04457845 was administered QD for 14 days (First Intervention Period).

    Arm title
    		 Placebo then PF-04457845
    Arm description
    		 Placebo matched to PF-04457845 tablet was administered QD in the first intervention period and then PF-04457845 4 mg tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to PF-04457845 was administered QD for 14 days (First Intervention Period).

    Investigational medicinal product name
    PF-04457845
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PF-04457845 4 mg tablet was administered QD for 14 days (First Intervention Period).

    Arm title
    		 Naproxen then Placebo
    Arm description
    		 Naproxen tablet was administered twice daily (BID) in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Naproxen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naproxen 500 mg tablet was administered BID for 14 days (First Intervention Period).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Naproxen was administered BID for 14 days (First Intervention Period).

    Arm title
    		 Placebo then Naproxen
    Arm description
    		 Placebo matched to Naproxen was administered BID in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Naproxen was administered BID for 14 days (First Intervention Period).

    Investigational medicinal product name
    Naproxen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naproxen 500 mg tablet was administered BID for 14 days (First Intervention Period).

    Number of subjects in period 1
    		PF-04457845 then Placebo Placebo then PF-04457845 Naproxen then Placebo Placebo then Naproxen
    Started
    19
    19
    17
    19
    Completed
    15
    18
    17
    19
    Not completed
    4
    1
    0
    0
         'Protocol Violation '
    1
    1
    -
    -
         'Withdrawal by Subject '
    3
    -
    -
    -
    Period 2
    Period 2 title
    Repeat Pain Assessment Period (1 week)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-04457845 then Placebo
    Arm description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 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
    Placebo matched to PF-04457845 was administered QD for 7 days (Repeat Pain Assessment Period).

    Arm title
    		 Placebo then PF-04457845
    Arm description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 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
    Placebo matched to PF-04457845 was administered QD for 7 days (Repeat Pain Assessment Period).

    Arm title
    		 Naproxen then Placebo
    Arm description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 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
    Placebo matched to PF-04457845 was administered QD for 7 days (Repeat Pain Assessment Period ).

    Arm title
    		 Placebo then Naproxen
    Arm description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 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
    Placebo matched to PF-04457845 was administered QD for 7 days (Repeat Pain Assessment Period).

    Number of subjects in period 2
    		PF-04457845 then Placebo Placebo then PF-04457845 Naproxen then Placebo Placebo then Naproxen
    Started
    15
    18
    17
    19
    Completed
    15
    18
    17
    19

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    PF-04457845 then Placebo
    Reporting group description
    		 PF-04457845 tablet was administered once daily (QD) in the first intervention period and then matching placebo tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then PF-04457845
    Reporting group description
    		 Placebo matched to PF-04457845 tablet was administered QD in the first intervention period and then PF-04457845 4 mg tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Naproxen then Placebo
    Reporting group description
    		 Naproxen tablet was administered twice daily (BID) in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then Naproxen
    Reporting group description
    		 Placebo matched to Naproxen was administered BID in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group values
    		 PF-04457845 then Placebo Placebo then PF-04457845 Naproxen then Placebo Placebo then Naproxen Total
    Number of subjects
    		 19 19 17 19 74
    Age categorical
    Units: Subjects
        Less than (<) 18 years
    		 0 0 0 0 0
        Between 18 and 44 years
    		 0 0 2 3 5
        Between 45 and 64 years
    		 12 13 12 8 45
        Greater than or equal to (>=) 65 years
    		 7 6 3 8 24
    Gender categorical
    Units: Subjects
        Female
    		 8 14 8 13 43
        Male
    		 11 5 9 6 31

    End points

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    End points reporting groups
    Reporting group title
    PF-04457845 then Placebo
    Reporting group description
    		 PF-04457845 tablet was administered once daily (QD) in the first intervention period and then matching placebo tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then PF-04457845
    Reporting group description
    		 Placebo matched to PF-04457845 tablet was administered QD in the first intervention period and then PF-04457845 4 mg tablet orally QD in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Naproxen then Placebo
    Reporting group description
    		 Naproxen tablet was administered twice daily (BID) in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then Naproxen
    Reporting group description
    		 Placebo matched to Naproxen was administered BID in the first intervention period and then matching placebo tablet BID in the second intervention period. A washout period of 2 weeks was maintained between each intervention period during which matching placebo were given orally QD. Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.
    Reporting group title
    PF-04457845 then Placebo
    Reporting group description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then PF-04457845
    Reporting group description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Naproxen then Placebo
    Reporting group description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Reporting group title
    Placebo then Naproxen
    Reporting group description
    		 Following the washout period, a 1 week repeat PAP was also maintained during which matching placebo were given orally QD along with the rescue medication. Subjects were further followed up for 3 weeks.

    Subject analysis set title
    PF-04457845
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PF-04457845 4mg tablet was administered orally QD for 2 weeks in first intervention period.

    Subject analysis set title
    Naproxen
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Naproxen 500mg tablet was administered orally BID for 2 weeks in first intervention period.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo matched to PF-04457845 or Naproxen was administered orally for 2 weeks in first intervention period QD and BID, respectively.

    Primary: Western Ontario and McMaster (WOMAC) Osteoarthritis (OA) Index Pain Subscale Score at End of Treatment

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    End point title
    		 Western Ontario and McMaster (WOMAC) Osteoarthritis (OA) Index Pain Subscale Score at End of Treatment
    End point description
    WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain experienced due to OA in the index joint (knee) in the past 48 hours. The WOMAC Pain subscale is calculated as the mean of the scores from the 5 individual questions, and it may not necessarily be a whole (integer) number. The WOMAC Pain subscale scores for each question range from 0 to 4, giving a possible score range of 0-20, with higher scores indicating higher pain. Full Analysis Set (FAS) included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    End of treatment (Day 14 of both the intervention period)
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    35 [1]
    36 [2]
    68 [3]
    Units: Units on a scale
        least squares mean (standard error)
    9.09 ( 0.452 )
    7.92 ( 0.445 )
    9.05 ( 0.326 )
    Notes
    [1] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [2] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [3] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 WOMAC Pain subscale: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect analysis of covariance (ANCOVA) model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.52
    Statistical analysis title
    		 WOMAC Pain subscale: Naproxen vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -1.13
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.79
         upper limit
    		 -0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.511

    Primary: Number of Subjects With Treatment Emergent Adverse Event (AEs) or Serious Adverse Event (SAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Event (AEs) or Serious Adverse Event (SAEs) [4]
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. AE include both SAE and Non-SAE. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 14 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety data included all randomized subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to 14 days after last dose of study drug
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    37
    36
    70
    Units: Subjects
        AEs
    19
    21
    36
        SAEs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Western Ontario and McMaster (WOMAC) Stiffness Domain Score

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    End point title
    		 Western Ontario and McMaster (WOMAC) Stiffness Domain Score
    End point description
    WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of stiffness experienced in the index joint (knee) in the past 48 hours. Stiffness is defined as a sensation of decreased ease in with which the patient moves the index joint. The WOMAC Stiffness subscale is calculated as the mean of the scores from the 2 individual questions, and it may not necessarily be a whole (integer) number. The WOMAC Stiffness subscale scores range from 0 to 4 giving a possible score range of 0-8, with higher scores indicating more stiffness. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment (Day 14 of both the intervention period)
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    35 [5]
    36 [6]
    69 [7]
    Units: Units on a scale
        least squares mean (standard error)
    3.87 ( 0.231 )
    3.26 ( 0.228 )
    3.85 ( 0.165 )
    Notes
    [5] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [6] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [7] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 WOMAC Stiffness subscale: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    0.03
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.264
    Statistical analysis title
    		 WOMAC Stiffness subscale: Naproxen vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -0.59
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.261

    Secondary: Western Ontario and McMaster (WOMAC) Physical Function Domain Score

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    End point title
    		 Western Ontario and McMaster (WOMAC) Physical Function Domain Score
    End point description
    WOMAC Physical Function subscale is comprised of 17 questions regarding the degree of difficulty experienced due to arthritis in the index joint (knee) in the past 48 hours. The WOMAC Physical Function subscale refers to the subject’s ability to move around and perform usual activities of daily living. The WOMAC Physical Function subscale is calculated as the mean of the scores from the 17 individual questions, and it may not be necessarily a whole (integer) number. The WOMAC Physical Function subscale scores for each question, range from 0 to 4 giving a possible score range of 0-68, with higher scores indicating worse function. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment (Day 14 of both the intervention period)
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    35 [8]
    34 [9]
    68 [10]
    Units: Units on a scale
        least squares mean (standard error)
    33.4 ( 1.523 )
    28.62 ( 1.528 )
    33.1 ( 1.119 )
    Notes
    [8] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [9] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [10] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 WOMAC Physical Function subscale
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    0.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.628
    Statistical analysis title
    		 WOMAC Physical Function subscale
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -4.49
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.56
         upper limit
    		 -2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.604

    Secondary: Western Ontario and McMaster (WOMAC) Total Score

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    End point title
    		 Western Ontario and McMaster (WOMAC) Total Score
    End point description
    WOMAC Total score was calculated as the sum of all 24 individual questions including sum of the first 5 questions of the WOMAC index (WOMAC pain score) assessing pain with a score range of 0-4, giving a range of 0-20; sum of questions 6 and 7 of the WOMAC index (WOMAC stiffness score) assessing stiffness giving a range from 0-8; and sum of questions 8-24 of the WOMAC index (WOMAC physical function score) assessing physical function with a score range of 0-68 the subjects experienced due to OA in the knee in the past 48 hours. The WOMAC Total score ranges from 0-96, with higher scores indicating more pain, stiffness, and/or worsening of function. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment (Day 14 of both the intervention period)
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    35 [11]
    34 [12]
    68 [13]
    Units: Units on a scale
        least squares mean (standard error)
    46.59 ( 2.116 )
    39.91 ( 2.127 )
    46.07 ( 1.56 )
    Notes
    [11] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [12] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [13] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 WOMAC Total score: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    0.52
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 3.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.259
    Statistical analysis title
    		 WOMAC Total score: Naproxen vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -6.15
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -9.04
         upper limit
    		 -3.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.231

    Secondary: Importance Weighted Total Western Ontario and McMaster (WOMAC) Score

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    End point title
    		 Importance Weighted Total Western Ontario and McMaster (WOMAC) Score
    End point description
    Importance Weighted WOMAC Total score was calculated as the WOMAC Total score using all subscales including Pain, Stiffness and Physical Function subscales (24 questions in total,score range: 0=none to 4= extreme,giving a possible overall score range of 0-96) with higher scores indicating more pain, stiffness, and/or worsening of function. Different weights are given according to the importance of each category which was Pain = 42 percentage (%), Stiffness = 21%, and Physical Function = 37%. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment (Day 14 of both the intervention period)
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    35 [14]
    34 [15]
    68 [16]
    Units: Units on a scale
        least squares mean (standard error)
    47.78 ( 2.245 )
    41.15 ( 2.263 )
    47.31 ( 1.652 )
    Notes
    [14] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [15] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [16] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 PF-04457845 vs Placebo
    Statistical analysis description
    Importance Weighted WOMAC Total score: A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    0.48
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 3.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.424
    Statistical analysis title
    		 Naproxen vs Placebo
    Statistical analysis description
    Importance Weighted WOMAC Total score: A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline scores as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -6.16
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -9.27
         upper limit
    		 -3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.408

    Secondary: Number of Subjects With Rescue Medication Usuage

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    End point title
    		 Number of Subjects With Rescue Medication Usuage
    End point description
    Rescue medication use was collected daily in a daily diary, in which subjects noted the amount of rescue medication (number of pills) taken each day. Subjects were provided with rescue medication paracetamol/acetaminophen throughout the study including the Washout Period and the Initial Pain Assessment Period. Paracetamol/acetaminophen was taken as needed to a maximum of 8 caplets per day or maximum of 4000 mg per day, but must be discontinued 48 hours prior to the Baseline (Day 1). From day 1 onwards, subjects might take up to 4000 mg of acetaminophen per day up to 3 days per week. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 7 up to Day 49
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    37
    36
    70
    Units: Subjects
    22
    14
    41
    No statistical analyses for this end point

    Secondary: Average Daily Pain Score During Week 1, 2

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    End point title
    		 Average Daily Pain Score During Week 1, 2
    End point description
    Daily pain scale in subjects recorded their daily pain level during the past 24 hours, using an 11-point numeric rating scale (NRS) subjects would record a daily pain score in their diary (0 was no pain and 10 was worst pain possible). Average of daily score for each week was reported. FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 1, week 2
    End point values
    		 PF-04457845 Naproxen Placebo
    Number of subjects analysed
    37
    36
    70
    Units: Units on a scale
    least squares mean (standard error)
        Week 1
    5.36 ( 0.178 )
    4.88 ( 0.181 )
    5.59 ( 0.129 )
        Week 2
    5.19 ( 0.208 )
    4.49 ( 0.212 )
    5.38 ( 0.157 )
    Statistical analysis title
    		 Week 1: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline average daily pain scores at week 1 as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.215
    Statistical analysis title
    		 Week 1: Naproxen vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline average daily pain scores at week 1 as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -0.71
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 -0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.217
    Statistical analysis title
    		 Week 2: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline average daily pain scores at week 2 as inter- and intra-subject covariates.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -0.19
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.226
    Statistical analysis title
    		 Week 2: Naproxen vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with random subject effect, period and treatment as fixed effects, utilizing the baseline average daily pain scores at week 2 as inter- and intra-subject covariates.
    Comparison groups
    Naproxen v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 L S mean difference
    Point estimate
    -0.89
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.225

    Secondary: Plasma Concentration of PF-04457845

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    End point title
    		 Plasma Concentration of PF-04457845
    End point description
    Plasma concentration for only PF-04457845 arm group has been reported. Plasma concentrations have been calculated by setting concentration values below the lower limit of quantification to zero. The lower limit of quantification is 0.100 nanaogram per millilitre (ng/mL). All subjects who received 1 dose of study drug. 'n' signifies those subjects who were evaluable for this measure at given time points for each group, respectively. 99999 here indicates arithmetic mean and standard deviation as it was not analysed since, no subject was observed above lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Predose, at 1, 2, 4 hours postdose at Day 1, predose at Day 8, 2 hours post dose at Day 14 post dose any time on Day 22, Day 36
    End point values
    		 PF-04457845
    Number of subjects analysed
    37
    Units: ng/mL
    arithmetic mean (standard deviation)
        Predose Day 1 (n= 37)
    99999 ( 99999 )
        1 hour post dose Day 1 (n= 37)
    25.25 ( 15.118 )
        2 hours post dose Day 1 (n= 37)
    20.52 ( 8.2022 )
        4 hours post dose Day 1 (n= 37)
    17.6 ( 6.2973 )
        Pre dose Day 8 (n= 18)
    13.58 ( 5.3083 )
        2 hours post dose Day 14 (n= 35)
    37.13 ( 12.598 )
        Post dose Day 22 (n= 17)
    0.7299 ( 1.0448 )
        Post dose Day 36 (n= 18)
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Residual Fatty Acid Amide Hydrolase (FAAH) Activity in Leucocytes

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    End point title
    		 Residual Fatty Acid Amide Hydrolase (FAAH) Activity in Leucocytes
    End point description
    FAS included all subjects randomized who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose at Day 1, Day 36, 2 hours post dose at Day 14, Day 49
    End point values
    		 PF-04457845 Placebo
    Number of subjects analysed
    35 [17]
    33 [18]
    Units: nanoMole (nM)
        least squares mean (standard error)
    3.45 ( 0.1 )
    6.75 ( 0.103 )
    Notes
    [17] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [18] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 FAAH activity: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with LS mean adjusted for period and treatment as fixed effects, subjects as a random effect and baseline FAAH scores as covariates (inter and intra subject). The analysis is on the log transformed data; the end of treatment adjusted means, difference and standard error are on the log scale, but the Contrast of Treatments difference and confidence interval have been back transformed for presentation.
    Comparison groups
    Placebo v PF-04457845
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Back Transformed Difference
    Point estimate
    0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.0304
         upper limit
    		 0.0442
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.144

    Secondary: Plasma Fatty Acid Amide Levels

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    End point title
    		 Plasma Fatty Acid Amide Levels
    End point description
    Plasma fatty acid amide levels including 9(Z) octadecenamide (OEA), N-palmitoyl ethanolamine (PEA), N-linoleoyl ethanolamide (LEA) and N-arachidonyl ethanolamine (AEA) was estimated from blood plasma samples. FAS included all subjects randomized who have received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose, at 1, 2 and 4 hours post dose at Day 1, predose at Day 8, 2 hours post dose at Day 14, Day 22, Day 36
    End point values
    		 PF-04457845 Placebo
    Number of subjects analysed
    35 [19]
    33 [20]
    Units: ng/mL
    least squares mean (standard error)
        OEA
    1.87 ( 0.047 )
    -0.32 ( 0.049 )
        PEA
    1.24 ( 0.03 )
    0.02 ( 0.031 )
        LEA
    2.02 ( 0.068 )
    -0.58 ( 0.07 )
        AEA
    1.19 ( 0.055 )
    -1.29 ( 0.056 )
    Notes
    [19] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    [20] - ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    Statistical analysis title
    		 OEA: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with LS mean adjusted for period and treatment as fixed effects, subjects as a random effect and baseline OEA as covariates (inter and intra subject). The analysis is on the log transformed data; the end of treatment adjusted means, difference and standard error are on the log scale, but the Contrast of Treatments difference and confidence interval have been back transformed for presentation.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Back Transformed Difference
    Point estimate
    8.93
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 8.27
         upper limit
    		 9.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Statistical analysis title
    		 PEA: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with LS mean adjusted for period and treatment as fixed effects, subjects as a random effect and baseline PEA as covariates (inter and intra subjects). The analysis is on the log transformed data; the end of treatment adjusted means, difference and standard error are on the log scale, but the Contrast of Treatments difference and confidence interval have been back transformed for presentation.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Back Transformed Difference
    Point estimate
    3.38
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 3.19
         upper limit
    		 3.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.043
    Statistical analysis title
    		 LEA: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with LS mean adjusted for period and treatment as fixed effects, subjects as a random effect and baseline LEA as covariates (inter and intra subjects). The analysis is on the log transformed data; the end of treatment adjusted means, difference and standard error are on the log scale, but the Contrast of Treatments difference and confidence interval have been back transformed for presentation.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Back Transformed Difference
    Point estimate
    13.45
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 11.86
         upper limit
    		 15.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.097
    Statistical analysis title
    		 AEA: PF-04457845 vs Placebo
    Statistical analysis description
    A mixed effect ANCOVA model was fitted with LS mean adjusted for period and treatment as fixed effects, subjects as a random effect and baseline AEA as covariates (inter and intra subjects). The analysis is on the log transformed data; the end of treatment adjusted means, difference and standard error are on the log scale, but the Contrast of Treatments difference and confidence interval have been back transformed for presentation.
    Comparison groups
    PF-04457845 v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Back Transformed Difference
    Point estimate
    11.99
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 11.12
         upper limit
    		 12.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 14 days after last dose of study drug
    Adverse event reporting additional description
    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
    PF-04457845
    Reporting group description
    		 PF-04457845 4mg tablet was administered oralyl QD for 2 weeks in first intervention period.

    Reporting group title
    NAPROXEN
    Reporting group description
    		 Naproxen 500mg tablet was administered orally BID for 2 weeks in first intervention period.

    Reporting group title
    PLACEBO
    Reporting group description
    		 Placebo matched to PF-04457845 or Naproxen was administered orally for 2 weeks in first intervention period QD and BID, respectively.

    Serious adverse events
    		 PF-04457845 NAPROXEN PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 PF-04457845 NAPROXEN PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 37 (51.35%)
    21 / 36 (58.33%)
    36 / 70 (51.43%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    4 / 70 (5.71%)
         occurrences all number
    0
    1
    4
    Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Vessel puncture site pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    2 / 70 (2.86%)
         occurrences all number
    0
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences all number
    1
    1
    1
    Nightmare
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Hand fracture
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Lower limb fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 36 (5.56%)
    1 / 70 (1.43%)
         occurrences all number
    3
    4
    1
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 36 (5.56%)
    10 / 70 (14.29%)
         occurrences all number
    3
    3
    12
    Hypoaesthesia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Speech disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    2
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Ocular discomfort
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    1
    Photopsia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    3
    Abdominal distension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 36 (8.33%)
    0 / 70 (0.00%)
         occurrences all number
    1
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 36 (5.56%)
    3 / 70 (4.29%)
         occurrences all number
    1
    2
    4
    Dyspepsia
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 36 (8.33%)
    0 / 70 (0.00%)
         occurrences all number
    0
    3
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    2
    Toothache
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    2
    Bursitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    2
    0
    Chondritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    0
    Pyuria
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 37 (16.22%)
    3 / 36 (8.33%)
    6 / 70 (8.57%)
         occurrences all number
    6
    3
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2009
    Addition of fasting requirements before site visits when blood and urine samples would be collected for safety laboratory testing.

    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.
    On 26 May 2010, the study was stopped due to statistical evidence of pre-defined futility.
    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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