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    Clinical Trial Results:
    A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee

    Summary
    EudraCT number
    2014-004996-22
    Trial protocol
    BE   HU   GB   CZ   ES  
    Global end of trial date
    29 Sep 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    29 Jul 2018
    First version publication date
    20 Jun 2018
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Results updated for consistency

    Trial information

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    Trial identification
    Sponsor protocol code
    7962-CL-0022
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02611466
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.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
    29 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study, conducted in participants with pain due to osteoarthritis (OA) of the knee, was to evaluate the analgesic efficacy of ASP7962 relative to placebo. The study consisted of a screening period (up to 3 weeks), a 1-week baseline period, a 4-week double-blind treatment period and a 4-week follow-up period.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Feb 2016
    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
    Belgium: 6
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Hungary: 67
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    215
    EEA total number of subjects
    215
    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)
    108
    From 65 to 84 years
    107
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants with pain due to OA of the knee were enrolled in sites in Western and Eastern Europe.

    Pre-assignment
    Screening details
    Participants who met the screening criteria entered a washout of all pain medication for at least 7 days and recorded daily average pain ratings for at least 5 days in an e-diary. After entry criteria were reassessed, eligible participants were randomized to receive ASP7962, placebo or naproxen treatment in a ratio of 2:2:1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received placebo orally twice daily for a period of 4 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
    Participants received matching placebo orally twice daily, in the morning and evening with or without food (approximately 12 hours).

    Arm title
    ASP7962
    Arm description
    Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP7962
    Investigational medicinal product code
    ASP7962
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ASP7962 100 mg orally twice daily, in the morning and evening with or without food (approximately 12 hours).

    Arm title
    Naproxen
    Arm description
    Participants received 500 mg of Naproxen orally twice daily for 4 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
    Participants received naproxen 500 mg orally twice daily, in the morning and evening with or without food (approximately 12 hours).

    Number of subjects in period 1
    Placebo ASP7962 Naproxen
    Started
    87
    85
    43
    Completed
    77
    79
    40
    Not completed
    10
    6
    3
         Protocol Deviation
    2
    2
    -
         Miscellaneous
    -
    1
    -
         Withdrawal by Subject
    3
    -
    -
         Did Not Receive Study Drug
    2
    -
    1
         Adverse Event
    3
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally twice daily for a period of 4 weeks.

    Reporting group title
    ASP7962
    Reporting group description
    Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

    Reporting group title
    Naproxen
    Reporting group description
    Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

    Reporting group values
    Placebo ASP7962 Naproxen Total
    Number of subjects
    87 85 43
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.0 ± 8.4 63.6 ± 8.4 65.7 ± 7.5 -
    Gender categorical
    Units:
        Male
    29 26 17 72
        Female
    58 59 26 143
    Race
    Units: Subjects
        White
    86 82 43 211
        Black or African American
    1 1 0 2
        Asian
    0 1 0 1
        Other
    0 1 0 1
    Index Knee Location
    Units: Subjects
        Right
    46 39 22 107
        Left
    41 46 21 108
    Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.63 ± 1.33 6.08 ± 1.37 5.83 ± 1.04 -
    WOMAC Stiffness Subscale Score
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.78 ± 1.71 6.20 ± 1.72 5.88 ± 1.76 -
    WOMAC Physical Function Subscale Score
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.82 ± 1.37 6.27 ± 1.40 5.99 ± 0.99 -
    WOMAC Walking Pain Score
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.54 ± 1.50 6.12 ± 1.61 6.02 ± 1.41 -
    WOMAC Total Score
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30.
    Units: units on a scale
        arithmetic mean (standard deviation)
    17.22 ± 4.07 18.54 ± 4.05 17.71 ± 3.36 -
    Mean Daily Average Numerical Rating Scale (NRS) Pain Score: Index Knee
    The NRS is an 11-point scale used to capture the participant’s average pain in the last 24 hours on a daily basis. This scale is composed of a single question and the score ranges from 0 to 10, where 0 anchors “no pain” and 10 anchors “pain as bad as you can imagine." The mean daily average NRS pain score was derived from the daily index knee pain ratings recorded by participants in an electronic diary (e-diary) on the last 4 days prior to randomization. Data only available for 214 participants [86, 85 43].
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.15 ± 1.39 6.26 ± 1.57 6.40 ± 1.29 -
    Patient Global Assessment Score
    The PGA is an 11-point NRS scale used to capture the participant’s overall impression at the time of the assessment in the index knee. This is a single question and the score ranges from 0 to 10, where 0 anchors “very good” and 10 anchors “very poor.” Data only available for 211 participants [84, 84 43].
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.98 ± 1.69 6.36 ± 1.71 6.23 ± 1.57 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally twice daily for a period of 4 weeks.

    Reporting group title
    ASP7962
    Reporting group description
    Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

    Reporting group title
    Naproxen
    Reporting group description
    Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

    Primary: Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score

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    End point title
    Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the full analysis set (FAS), which included all randomized participants who took at least 1 dose of study drug and who had a baseline and at least 1 double-blind treatment value for the WOMAC pain subscale score. Only participants with data available at baseline and at each timepoint were included.
    End point type
    Primary
    End point timeframe
    Baseline and week 4
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    75
    77
    39
    Units: units on a scale
        least squares mean (standard error)
    -1.73 ± 0.21
    -1.87 ± 0.20
    -2.40 ± 0.28
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 and 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline and week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.316 [1]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    Least Squares Mean (LSM) Difference
    Point estimate
    -0.14
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [1] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 and 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline and week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.027 [2]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.67
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [2] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score

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    End point title
    Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
        least squares mean (standard error)
    -1.74 ± 0.20
    -1.91 ± 0.20
    -2.41 ± 0.27
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    Analysis of covariance (ANCOVA) model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.276 [3]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.17
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [3] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025 [4]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.66
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [4] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to EOT in WOMAC Physical Function Subscale Score

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    End point title
    Change from Baseline to EOT in WOMAC Physical Function Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
        least squares mean (standard error)
    -1.67 ± 0.19
    -1.81 ± 0.19
    -2.51 ± 0.26
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.306 [5]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.14
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.59
         upper limit
    0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [5] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [6]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.84
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.26
         upper limit
    -0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [6] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to EOT in WOMAC Stiffness Subscale Score

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    End point title
    Change from Baseline to EOT in WOMAC Stiffness Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
        least squares mean (standard error)
    -1.68 ± 0.20
    -1.89 ± 0.20
    -2.82 ± 0.28
    Statistical analysis title
    Difference ASP7962 vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.232 [7]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [7] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [8]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -1.14
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.58
         upper limit
    -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [8] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to EOT in WOMAC Total Score

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    End point title
    Change from Baseline to EOT in WOMAC Total Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
        least squares mean (standard error)
    -5.07 ± 0.56
    -5.65 ± 0.56
    -7.71 ± 0.77
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.232 [9]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.59
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.91
         upper limit
    0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [9] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [10]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -2.64
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -3.87
         upper limit
    -1.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95
    Notes
    [10] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to EOT in WOMAC Walking Pain Score

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    End point title
    Change from Baseline to EOT in WOMAC Walking Pain Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
        least squares mean (standard error)
    -1.56 ± 0.22
    -1.82 ± 0.21
    -2.53 ± 0.29
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.197 [11]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.26
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.77
         upper limit
    0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [11] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [12]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.96
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.44
         upper limit
    -0.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Notes
    [12] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score

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    End point title
    Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1 and 2
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=76, 79, 42]
    -1.13 ± 0.17
    -1.12 ± 0.17
    -1.90 ± 0.23
        Week 2 [N=75, 80, 41]
    -1.19 ± 0.19
    -1.49 ± 0.18
    -1.83 ± 0.25
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.516 [13]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.01
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [13] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [14]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.77
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [14] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.122 [15]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.31
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [15] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [16]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.64
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    -0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [16] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score

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    End point title
    Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, and 4
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=76, 79, 42]
    -1.00 ± 0.16
    -1.07 ± 0.16
    -1.87 ± 0.21
        Week 2 [N=75, 80, 41]
    -1.14 ± 0.18
    -1.42 ± 0.18
    -1.92 ± 0.24
        Week 4 [N=75, 77, 39]
    -1.65 ± 0.20
    -1.77 ± 0.20
    -2.48 ± 0.27
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.375 [17]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.07
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Notes
    [17] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [18]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.88
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.21
         upper limit
    -0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [18] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.132 [19]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.28
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [19] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.005 [20]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.77
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.16
         upper limit
    -0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [20] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.335 [21]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.12
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.58
         upper limit
    0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [21] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007 [22]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.83
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.26
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [22] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score

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    End point title
    Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, and 4
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=76, 79, 42]
    -1.20 ± 0.18
    -1.24 ± 0.18
    -2.11 ± 0.25
        Week 2 [N=75, 80, 41]
    -1.32 ± 0.19
    -1.52 ± 0.19
    -2.39 ± 0.26
        Week 4 [N=75, 77, 39]
    -1.66 ± 0.20
    -1.83 ± 0.20
    -2.81 ± 0.28
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.439 [23]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.04
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.46
         upper limit
    0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [23] - One-sided P-value for pairwise treatment comparison with placebo..
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [24]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.9
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    -0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [24] - One-sided P-value for pairwise treatment comparison with placebo..
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.217 [25]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.65
         upper limit
    0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [25] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [26]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -1.08
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.49
         upper limit
    -0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [26] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.278 [27]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.17
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.64
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [27] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [28]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -1.16
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Notes
    [28] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score

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    End point title
    Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, and 4
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=76, 79, 42]
    -3.30 ± 0.48
    -3.50 ± 0.47
    -5.84 ± 0.64
        Week 2 [N=75, 80, 41]
    -3.63 ± 0.52
    -4.50 ± 0.52
    -6.11 ± 0.71
        Week 4 [N=75, 77, 39]
    -5.02 ± 0.58
    -5.54 ± 0.57
    -7.66 ± 0.79
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.379 [29]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Notes
    [29] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [30]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -2.54
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -3.56
         upper limit
    -1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.79
    Notes
    [30] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.117 [31]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.88
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -2.09
         upper limit
    0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.73
    Notes
    [31] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [32]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -2.48
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -3.61
         upper limit
    -1.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87
    Notes
    [32] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.261 [33]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.52
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.86
         upper limit
    0.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.81
    Notes
    [33] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [34]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -2.64
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -3.89
         upper limit
    -1.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.97
    Notes
    [34] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score

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    End point title
    Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score
    End point description
    WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, and 4
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=76, 79, 42]
    -0.91 ± 0.20
    -0.90 ± 0.19
    -1.80 ± 0.26
        Week 2 [N=75, 80, 41]
    -0.95 ± 0.21
    -1.33 ± 0.21
    -1.92 ± 0.28
        Week 4 [N=75, 77, 39]
    -1.56 ± 0.23
    -1.78 ± 0.22
    -2.52 ± 0.31
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.518 [35]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.01
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [35] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [36]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.89
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    -0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [36] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.101 [37]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.38
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.86
         upper limit
    0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [37] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [38]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.97
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    -0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [38] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.243 [39]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [39] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [40]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.96
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.45
         upper limit
    -0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Notes
    [40] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale

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    End point title
    Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale
    End point description
    The NRS is an 11-point scale used to capture the participant’s average pain in the last 24 hours on a daily basis. This scale is composed of a single question and the score ranges from 0 to 10, where 0 anchors “no pain” and 10 anchors “pain as bad as you can imagine." The mean daily average NRS pain score was derived from the daily index knee pain ratings recorded by participants in an electronic diary (e-diary) on the last 4 days prior to randomization. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4 and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=78, 81, 42]
    -0.61 ± 0.15
    -0.58 ± 0.15
    -1.38 ± 0.21
        Week 2 [N=77, 81, 42]
    -1.17 ± 0.17
    -0.96 ± 0.17
    -1.96 ± 0.23
        Week 3 [N=77, 80, 41]
    -1.40 ± 0.19
    -1.20 ± 0.19
    -2.22 ± 0.26
        Week 4 [N=77, 80, 40]
    -1.59 ± 0.20
    -1.42 ± 0.19
    -2.26 ± 0.27
        EOT [N=78, 81, 42]
    -1.60 ± 0.19
    -1.49 ± 0.19
    -2.30 ± 0.26
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.555 [41]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.03
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21
    Notes
    [41] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [42]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.77
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    -0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [42] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.807 [43]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [43] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [44]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.79
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.16
         upper limit
    -0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [44] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 3)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.775 [45]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [45] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 3)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [46]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.83
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    -0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [46] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.734 [47]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    0.17
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    0.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [47] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.023 [48]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.67
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    -0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [48] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (EOT)
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number analyzed is calculated incorrectly due to system limitation.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.653 [49]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    0.11
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.34
         upper limit
    0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [49] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (EOT)
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number analyzed is calculated incorrectly due to system limitation.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016 [50]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.71
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    -0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [50] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT

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    End point title
    Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT
    End point description
    The PGA is an 11-point NRS scale used to capture the participant’s overall impression at the time of the assessment in the index knee. This is a single question and the score ranges from 0 to 10, where 0 anchors “very good” and 10 anchors “very poor.” A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 4 and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: units on a scale
    least squares mean (standard error)
        Week 1 [N=75, 79, 42]
    -1.15 ± 0.20
    -1.27 ± 0.19
    -1.71 ± 0.26
        Week 2 [N=74, 80, 41]
    -1.25 ± 0.21
    -1.55 ± 0.20
    -2.02 ± 0.28
        Week 4 [N=73, 77, 39]
    -1.57 ± 0.24
    -1.97 ± 0.23
    -2.43 ± 0.32
        EOT [N=78, 81, 42]
    -1.56 ± 0.23
    -1.99 ± 0.22
    -2.48 ± 0.31
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.324 [51]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.13
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.58
         upper limit
    0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [51] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 1)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.042 [52]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.57
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.98
         upper limit
    -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [52] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.148 [53]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [53] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 2)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.013 [54]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.77
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.22
         upper limit
    -0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [54] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.112 [55]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.95
         upper limit
    0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [55] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (Week 4)
    Statistical analysis description
    MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.015 [56]
    Method
    Mixed-effect model, Repeated measures
    Parameter type
    LSM Difference
    Point estimate
    -0.87
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.38
         upper limit
    -0.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [56] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: ASP7962 vs. Placebo (EOT)
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number analyzed is calculated incorrectly due to system limitation.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.088 [57]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.44
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.97
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [57] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo (EOT)
    Statistical analysis description
    ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number analyzed is calculated incorrectly due to system limitation.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009 [58]
    Method
    ANCOVA
    Parameter type
    LSM Difference
    Point estimate
    -0.92
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    -0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [58] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

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    End point title
    Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score
    End point description
    Percentage of participants who had a reduction from baseline to EOT in WOMAC pain subscale score of ≥ 30% is reported. WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. The analysis population was the FAS. Only participants with data at baseline or EOT were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: percentage of participants
        number (confidence interval 90%)
    43 (33.6 to 52.9)
    53.1 (43.4 to 62.6)
    64.3 (50.5 to 76.5)
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    Differences of the percentages were calculated by subtracting the percentage of placebo group from the percentage of the active treatment group. Confidence interval for each treatment group and the difference of the percentage was an exact unconditional confidence interval based on Santner-Snell approach.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.133 [59]
    Method
    Fisher exact
    Parameter type
    Percentage Difference
    Point estimate
    10
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    23.2
    Notes
    [59] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    Differences of the percentages were calculated by subtracting the percentage of placebo group from the percentage of the active treatment group. Confidence interval for each treatment group and the difference of the percentage was an exact unconditional confidence interval based on Santner-Snell approach.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.021 [60]
    Method
    Fisher exact
    Parameter type
    Percentage Difference
    Point estimate
    21.2
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    8.8
         upper limit
    33.1
    Notes
    [60] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

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    End point title
    Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score
    End point description
    Percentage of participants who had a reduction from baseline to EOT in WOMAC pain subscale score of ≥ 50% is reported. WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. The analysis population was the FAS. Only participants with data at baseline or EOT were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (up to 4 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    79
    81
    42
    Units: percentage of participants
        number (confidence interval 90%)
    22.8 (15.3 to 31.9)
    32.1 (23.6 to 41.7)
    45.2 (32.0 to 59.0)
    Statistical analysis title
    Difference: ASP7962 vs. Placebo
    Statistical analysis description
    Differences of the percentages were calculated by subtracting the percentage of placebo group from the percentage of the active treatment group. Confidence interval for each treatment group and the difference of the percentage was an exact unconditional confidence interval based on Santner-Snell approach.
    Comparison groups
    Placebo v ASP7962
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.127 [61]
    Method
    Fisher exact
    Parameter type
    Percentage Difference
    Point estimate
    9.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    22.2
    Notes
    [61] - One-sided P-value for pairwise treatment comparison with placebo.
    Statistical analysis title
    Difference: Naproxen vs. Placebo
    Statistical analysis description
    Differences of the percentages were calculated by subtracting the percentage of placebo group from the percentage of the active treatment group. Confidence interval for each treatment group and the difference of the percentage was an exact unconditional confidence interval based on Santner-Snell approach.
    Comparison groups
    Placebo v Naproxen
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [62]
    Method
    Fisher exact
    Parameter type
    Percentage Difference
    Point estimate
    22.5
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    10.1
         upper limit
    34.3
    Notes
    [62] - One-sided P-value for pairwise treatment comparison with placebo.

    Secondary: Number of Participants with Treatment-Emergent Adverse Events

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    End point title
    Number of Participants with Treatment-Emergent Adverse Events
    End point description
    A TEAE was defined as an adverse event (AE) which started or worsened after the first dose of study drug until 30 days after taking the last dose of study drug. This included abnormal laboratory tests, vital signs or electrocardiogram data that were defined as AEs if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study drug or was clinically significant in the investigator's opinion. The analysis population was the safety analysis set (SAF), which consisted of all randomized participants who took at least 1 dose of double-blind study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug (up to 8 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    85
    85
    42
    Units: participants
        TEAE
    24
    31
    13
        Drug-related TEAE
    10
    8
    7
        Serious TEAE
    0
    1
    0
        Drug-related serious TEAE
    0
    0
    0
        Deaths
    0
    0
    0
        TEAE leading to withdrawal of treatment
    3
    3
    2
        Drug-related TEAE leading to treatment withdrawal
    3
    1
    2
        Joint-related TEAE
    1
    3
    2
        Neurological-related TEAE
    2
    4
    0
        Hepatic-related TEAE
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation

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    End point title
    Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation
    End point description
    C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to questions: (1) Wish to be dead; (2) Non-specific active suicidal thoughts; (3) Active suicidal ideation with any methods (not plan) without intent to act; (4) Active suicidal ideation with some intent to act, without specific plan; and (5) Active suicidal ideation with specific plan and intent. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 8 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    85
    85
    42
    Units: participants
        Treatment period [N=79, 82, 42]
    0
    0
    0
        Follow-up period [N=77, 81, 42]
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior

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    End point title
    Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior
    End point description
    C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to questions: (1) Preparatory acts or behavior; (2) Aborted attempt; (3) Interrupted attempt; (4) Actual attempt; and (5) Completed suicide. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 8 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    85
    85
    42
    Units: participants
        Treatment period [N=79, 82, 42]
    0
    0
    0
        Follow-up period [N=77, 81, 42]
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior

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    End point title
    Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior
    End point description
    C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to any one of the ten suicidal ideation and behavior questions. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 8 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    85
    85
    42
    Units: participants
        Treatment period [N=79, 82, 42]
    0
    0
    0
        Follow-up period [N=77, 81, 42]
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent

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    End point title
    Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent
    End point description
    C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to the question "Has subject engaged in Non-Suicidal Self-Injurious Behavior?" The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 8 weeks)
    End point values
    Placebo ASP7962 Naproxen
    Number of subjects analysed
    85
    85
    42
    Units: participants
        Treatment period [N=79, 82, 42]
    0
    1
    0
        Follow-up period [N=77, 81, 42]
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug (up to 8 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo orally twice daily for a period of 4 weeks.

    Reporting group title
    Naproxen
    Reporting group description
    Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

    Reporting group title
    ASP7962
    Reporting group description
    Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

    Serious adverse events
    Placebo Naproxen ASP7962
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 42 (0.00%)
    1 / 85 (1.18%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 42 (0.00%)
    1 / 85 (1.18%)
         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: 4%
    Non-serious adverse events
    Placebo Naproxen ASP7962
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 85 (9.41%)
    5 / 42 (11.90%)
    8 / 85 (9.41%)
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 42 (0.00%)
    4 / 85 (4.71%)
         occurrences all number
    9
    0
    4
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 42 (4.76%)
    0 / 85 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 42 (4.76%)
    2 / 85 (2.35%)
         occurrences all number
    1
    2
    2
    Constipation
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 42 (4.76%)
    0 / 85 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 42 (0.00%)
    3 / 85 (3.53%)
         occurrences all number
    4
    0
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2015
    The substantial changes include: 1) The procedure for obtaining radiographic images was changed. A radiograph image of the index knee was added to the follow-up period to assess for potential changes in the index knee poststudy drug treatment. The requirement for a lateral view of hips was removed because it was considered not essential to the assessment of the progression of hip OA. 2) Inclusion Criteria 12 and 14 were revised. The list of highly effective forms of birth control was updated, and Inclusion Criteria 12 and 14 were updated to reflect current recommendations by the Clinical Trials Facilitation Group related to contraception in clinical trials. 3) The gastrointestinal protective strategy was expanded, adding explicit language to state that gastroprotective agents could be used at the investigators’ discretion, considering the risk of serious gastrointestinal toxicity of naproxen, especially in older adults and patients treated with low dose aspirin for cardioprophylaxis. 4) Text was added regarding the absence of any evaluation of the test drug's phototoxic potential because specific phototoxicity studies have not been conducted for ASP7962. Although ASP7962 did not contain typical phototoxic structural moieties and the nonclinical data did not indicate a photosafety concern, based on the absorption peak at 305 nm, a phototoxicity potential for ASP7962 could not be excluded. Nonsubstantial changes were made: 1) To update Sponsor contact information 2) To update footnote in schedule of assessments 3) To update Appendix 12.6.
    26 Jul 2016
    The substantial changes include: (continued from above) 5) Specification for exclusion of participants with severe knee malalignment or another jointrelated condition was updated. Due to the change of Inclusion Criterion 4, it was considered relevant to add severe malalignment to the exclusion criteria. Although malalignment does not appear to be an independent risk factor for RPOA, out of an abundance of caution, the Osteo IAC members recommended that patients with severe malalignment be excluded from the study. This was assessed through centrally read radiographs as well as clinical evaluation of the participant. It was recommended that, in case of acute subchondral insufficiency fracture, additional medical evaluation would be required before considering a participant for enrollment into this study. 6) The specification for exclusion of participants with specific shoulder medical history was updated. Based on a few cases of RPOA of the shoulder reported in the anti-NGF programs, there was a theoretical concern of RPOA of the shoulder. However, there is a lack of evidence to indicate which participants this might affect. As a history of conditions, such as rotator cuff diseases, was expected to be common among the patients, these types of condition were not to prohibit enrollment. 7) Exclusion Criterion12 was revised, stating that participants with intolerance or hypersensitivity to tramadol were allowed to enter the study if the participants accepted to limiting rescue medication to paracetamol. 8) Exclusion Criterion 17 was revised to allow the enrollment of participants with a history of cardiovascular disease whose condition was stable. Unexplained syncope was removed from the exclusion criterion. PR interval was increased from 210 to 240 ms.
    26 Jul 2016
    The substantial changes include: (continued from above) 9) Exclusion Criterion 21 was revised, removing hepatitis B core antibodies (anti-HBc) test result from the exclusion criterion. HBsAg was considered a sufficient serologic test to assess presence of infection. A positive test result for anti-HBc in the presence of negative HBsAg suggests immunity due to natural infection. Active disease would be associated with increased liver tests and would be excluded due to Exclusion Criterion 19. 10) Exclusion Criterion 23 was revised, limiting the exclusion of participants having previously received antibodies to NGF to 3 months prior to screening. A 3-month washout was considered sufficient not to interfere with any study endpoints or cause any safety concerns. 11) Exclusion Criterion 23 and Prohibited Medications and Nonmedication Therapies were revised, reducing the use of intraarticular local anesthetics from 12 months to 3 months before screening. The reason was that there is no evidence that participants undergoing local anesthetic injection, such as lidocaine during a related single injection procedure, are at high risk of presentation of clinical chondral toxicity. 12) The strength and use of cytochrome P450 inducers were specified, adding "strong" to cytochrome P450 inducers and "regularly" to be consistent with the wording of Exclusion Criterion 32. 13) Study design was slightly revised, adding a section to allow reevaluation of participants who were not eligible under Version 2.0 of the protocol, but would be eligible based on the revised inclusion and exclusion criteria in Version 3.0 of the protocol. In case new radiographic assessments were deemed inappropriate, this was to be discussed first with the Medical Monitor. 14) Laboratory assessments were modified, deleting benzodiazepines from drug and alcohol urine screening. Assessment of benzodiazepine use was not considered to impact participant safety or adherence to the protocol.
    26 Jul 2016
    Nonsubstantial changes were made: (continued from above) 1) To update the contact details of key study personnel 2) To update the abbreviations list 3) To extend the planned study period 4) To update the planned number of study centers 5) To clarify the process for radiographic imaging 6) To update the order of the secondary safety endpoints 7) To update the statistical presentation of treatment-emergent adverse events (TEAEs) 8) To add text regarding educational material for participants 9) To update the schedule of assessments 10) To update the Hospital Anxiety and Depression Scale (HADS) 11) To update the physical examination section 12) To update the Neuropathic Pain Symptom Inventory (NPSI) 13) To update the reporting of serious adverse events (SAEs) 14) To update the analysis of exploratory endpoints 15) To update the statistical section on physical examination 16) To delete a reference 17) To update the table of questionnaires 18) To include minor administrative-type changes.
    26 Jul 2016
    The substantial changes include: 1) Inclusion Criterion 2 was revised, increasing the upper age limit from 75 to 80 years to allow participants aged 76 to 80 years to be entered in the study. The reason was that OA becomes increasingly prevalent with aging, and symptomatic OA affects many in their eighth decade. There was no evidence that ASP7962 should benefit older individuals to a lesser extent than those who are younger. 2) Inclusion Criterion 8 was removed. This inclusion criterion required participants to have a mean daily index knee average pain score between ≥ 4 and ≤ 9 (on a 0 to10 NRS). Pain criteria to enter the study were thus limited to the well-established WOMAC criteria for pain that are the standard for OA pain studies. 3) Inclusion Criterion 6 was revised. The Kellgren-Lawrence grade at screening (based on central reading) was increased such that participants with Kellgren-Lawrence grade 4 were included as well. After a review of publically available information from the anti-NGF monoclonal antibody programs and discussion with external experts and key opinion leaders (with expertise in rheumatology, radiology and RPOA), the exclusion of Kellgren-Lawrence grade 4 was considered unnecessary as there was no evidence suggesting an increased risk of RPOA with Kellgren-Lawrence grade 4. 4) Exclusion Criterion 4 was revised. If a participant was stable, treated and not experiencing clinical signs of concomitant diseases, the participant could be suitable as this should not impact safety or assessments within the study. For participants with diabetes mellitus, attaining a target HbA1c of < 6.5% to 7% can be challenging. For some participants the risks of intensive glycemic control may have outweighed the benefits and a less strict HbA1c cutoff seemed reasonable provided that, in the investigator’s judgment, the participant was clinically stable. HbA1c was increased from 7.1% to 8.0% to allow a less strict surrogate for diabetes control.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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