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    Clinical Trial Results:
    A randomised, double-blind, placebo controlled, parallel group, multi-centre, study to evaluate the efficacy, safety, tolerability and pharmacokinetics of ONO-4474 in patients with pain due to osteoarthritis of the knee

    Summary
    EudraCT number
    		 2016-002675-97
    Trial protocol
    		 HU   DK   ES   PL   GB  
    Global end of trial date
    09 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Dec 2018
    First version publication date
    07 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ONO-4474-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02997696
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ono Pharmaceutical Co. Ltd.
    Sponsor organisation address
    8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka, Japan,
    Public contact
    Clinical Trial Information Desk, Ono Pharma UK Ltd, 44 207421 4920, ctinfo@ono-uk.co.uk
    Scientific contact
    Clinical Trial Information Desk, Ono Pharma UK Ltd, 44 207421 4920, ctinfo@ono-uk.co.uk
    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
    13 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Investigate the effects of ONO-4474 on walking pain
    Protection of trial subjects
    Before they were screened for the study, all subjects read the informed consent form, which contained information about the study design, investigational product, procedures, and risks. The investigator, or physician designated by the investigator, explained the benefits and risks of participation in the study to each subject, and obtained written informed consent before the subject entered the study. In obtaining and documenting informed consent, the investigator was required to comply with the applicable regulatory requirements and adhere to ICH-GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Each subject was free to withdraw from the study at any time without giving reasons. Rescue medication was permitted. Subjects were willing to discontinue use of all analgesic pharmacotherapy (aside from rescue medication) from Visit 2 to randomisation (Visit 3) and for the duration of the treatment and follow-up periods (Visit 8).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Hungary: 5
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    37
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was terminated early due to non-safety reasons.

    Pre-assignment
    Screening details
    		 247 of the 317 screened subjects failed screening, mostly due to not meeting inclusion/exclusion criteria (221 patients). Following screening (Visit 1), eligible patients entered a washout period (minimum 1 week) during which previous medications for OA analgesia were stopped (Visit 2). Randomization was performed at Visit 3 (Week 0; Baseline).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo BID, 12 hours apart
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were to be administered orally BID with water, immediately following a meal, at approximately 12-hour intervals, where possible. At Visit 3 (randomization visit), only the evening dose was to be taken and at Visit 7 (Week 4), only the morning dose was to be taken. At Visits 4 (Week 1), 5 (Week 2) and 7 (Week 4) the morning dose was to be taken at the study site, where a standard breakfast was provided. A combination of four tablets, either ONO-4474 or matching placebo, were to be administered on each dosing occasion (two tablets from each of the two bottles dispensed). At Visit 7, (Week 4) patients were to take the morning dose and then return all remaining study drug to site staff. No treatment was to be administered at Visit 6 (Week 3); this was a telephone call.

    Arm title
    		 ONO-4474 100 mg
    Arm description
    		 ONO-4474 100 mg BID, 12 hours apart
    Arm type
    		 Experimental

    Investigational medicinal product name
    ONO-4474 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ONO-4474, containing 50 mg of the free form of ONO-4474 TS (toluenesulfonate), was to be administered orally BID with water, immediately following a meal, at approximately 12-hour intervals, where possible. At Visit 3 (randomization visit), only the evening dose was to be taken and at Visit 7 (Week 4), only the morning dose was to be taken. At Visits 4 (Week 1), 5 (Week 2) and 7 (Week 4) the morning dose was to be taken at the study site, where a standard breakfast was provided. A combination of four tablets, either ONO-4474 or matching Placebo, were to be administered on each dosing occasion (two tablets from each of the two bottles dispensed). At Visit 7, (Week 4) patients were to take the morning dose and then return all remaining study drug to site staff. No treatment was to be administered at Visit 6 (Week 3); this was a telephone call.

    Arm title
    		 ONO-4474 200 mg
    Arm description
    		 ONO-4474 200 mg BID, 12 hours apart
    Arm type
    		 Experimental

    Investigational medicinal product name
    ONO-4474 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ONO-4474, containing 50 mg of the free form of ONO-4474 TS (toluenesulfonate), was to be administered orally BID with water, immediately following a meal, at approximately 12-hour intervals, where possible. At Visit 3 (randomization visit), only the evening dose was to be taken and at Visit 7 (Week 4), only the morning dose was to be taken. At Visits 4 (Week 1), 5 (Week 2) and 7 (Week 4) the morning dose was to be taken at the study site, where a standard breakfast was provided. A combination of four tablets, either ONO-4474 or matching Placebo, were to be administered on each dosing occasion (two tablets from each of the two bottles dispensed). At Visit 7, (Week 4) patients were to take the morning dose and then return all remaining study drug to site staff. No treatment was to be administered at Visit 6 (Week 3); this was a telephone call.

    Number of subjects in period 1
    		Placebo ONO-4474 100 mg ONO-4474 200 mg
    Started
    21
    23
    26
    Completed
    18
    20
    22
    Not completed
    3
    3
    4
         Consent withdrawn by subject
    -
    1
    -
         Violation of eligibility
    1
    -
    -
         Adverse event, non-fatal
    2
    2
    2
         Intake of prohibited medications
    -
    -
    1
         Other (no further explanation)
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BID, 12 hours apart

    Reporting group title
    ONO-4474 100 mg
    Reporting group description
    		 ONO-4474 100 mg BID, 12 hours apart

    Reporting group title
    ONO-4474 200 mg
    Reporting group description
    		 ONO-4474 200 mg BID, 12 hours apart

    Reporting group values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg Total
    Number of subjects
    		 21 23 26 70
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 8 14 15 37
        From 65-84 years
    		 13 9 11 33
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ± 6.3 62.2 ± 6.7 61.5 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    		 15 12 18 45
        Male
    		 6 11 8 25
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set will comprise all randomised patients who had at least one dose of study drug and at least one valid post baseline efficacy endpoint.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    70
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    37
        From 65-84 years
    33
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.7 ± 6.8
    Gender categorical
    Units: Subjects
        Female
    45
        Male
    25

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BID, 12 hours apart

    Reporting group title
    ONO-4474 100 mg
    Reporting group description
    		 ONO-4474 100 mg BID, 12 hours apart

    Reporting group title
    ONO-4474 200 mg
    Reporting group description
    		 ONO-4474 200 mg BID, 12 hours apart

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set will comprise all randomised patients who had at least one dose of study drug and at least one valid post baseline efficacy endpoint.

    Primary: Change from Baseline in Mean Daily Average Index Knee Pain While Walking (24h recall) by Week, up to Week 4

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    End point title
    		 Change from Baseline in Mean Daily Average Index Knee Pain While Walking (24h recall) by Week, up to Week 4
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: Knee pain score
        arithmetic mean (standard deviation)
    -18.34 ± 23.34
    -21.92 ± 18.68
    -29.94 ± 22.06
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.841
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.21
         upper limit
    		 12.44
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.315
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -6.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.2
         upper limit
    		 6.62

    Secondary: Change from Baseline in Mean Daily Average Index Knee Pain While Walking (24h Recall) at Week 4, up to Follow-up Week 2

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    End point title
    		 Change from Baseline in Mean Daily Average Index Knee Pain While Walking (24h Recall) at Week 4, up to Follow-up Week 2
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 4, Follow-up Week 1 and Follow-up Week 2
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    19 [1]
    21 [2]
    24 [3]
    Units: Knee pain score
    arithmetic mean (standard deviation)
        Change from Baseline to Week 4
    -19.41 ± 23.08
    -21.21 ± 18.60
    -27.95 ± 22.99
        Change from Baseline to Follow-up Week 1
    -19.24 ± 23.64
    -17.52 ± 14.77
    -18.66 ± 26.45
        Change from Baseline to Follow-up Week 2
    -19.83 ± 25.73
    -14.42 ± 11.92
    -21.28 ± 20.61
    Notes
    [1] - n=19 at Week 4, n=19 at Follow-up Week 1, n=17 at Follow-up Week 2.
    [2] - n=21 at Week 4, n=20 at Follow-up Week 1, n=20 at Follow-up Week 2.
    [3] - n=24 at Week 4, n=23 at Follow-up Week 1, n=22 at Follow-up Week 2.
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Statistical analysis description
    Change from baseline to Week 4
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.873
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.78
         upper limit
    		 15.02
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Statistical analysis description
    Change from baseline to Week 4
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.471
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.41
         upper limit
    		 8.61

    Secondary: Change from Baseline in WOMAC Walking Pain (Q1), Pain (Q1-Q5), Stiffness (Q6-Q7), and Physical Function (Q8-Q24) Scores (48h Recall)

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    End point title
    		 Change from Baseline in WOMAC Walking Pain (Q1), Pain (Q1-Q5), Stiffness (Q6-Q7), and Physical Function (Q8-Q24) Scores (48h Recall)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: WOMAC score
    arithmetic mean (standard deviation)
        Walking pain score (Q1)
    -2.50 ± 2.20
    -2.50 ± 1.99
    -3.45 ± 2.50
        Pain score (Q1-Q5)
    -2.22 ± 2.28
    -2.54 ± 2.06
    -3.48 ± 2.49
        Stiffness score (Q6-Q7)
    -1.33 ± 1.96
    -2.45 ± 2.46
    -3.50 ± 3.00
        Physical function score (Q8-Q24)
    -2.04 ± 2.30
    -2.70 ± 2.03
    -3.28 ± 2.22
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Statistical analysis description
    Walking pain
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.884
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 1.48
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Statistical analysis description
    Pain
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.938
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 1.34
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Statistical analysis description
    Stiffness
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.323
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 0.73
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Statistical analysis description
    Physical function
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.685
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 1.05
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Statistical analysis description
    Walking pain
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.247
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.13
         upper limit
    		 0.56
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Statistical analysis description
    Pain
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.175
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.31
         upper limit
    		 0.43
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Statistical analysis description
    Stiffness
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.23
         upper limit
    		 -0.4
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Statistical analysis description
    Physical function
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.176
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 0.41

    Secondary: Change from Baseline in Mean Daily Average Index Knee Pain (24h Recall) at Week 4

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    End point title
    		 Change from Baseline in Mean Daily Average Index Knee Pain (24h Recall) at Week 4
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: Knee pain score
        arithmetic mean (standard deviation)
    -17.99 ± 21.88
    -23.08 ± 18.79
    -32.81 ± 23.13
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.764
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.68
         upper limit
    		 11.56
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.173
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.3
         upper limit
    		 4.1

    Secondary: Change from Baseline in Patient Global Assessment by Week, up to Follow-up Visit

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    End point title
    		 Change from Baseline in Patient Global Assessment by Week, up to Follow-up Visit
    End point description
    End point type
    Secondary
    End point timeframe
    Change from Baseline to Follow-up Visit
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: Patient Global Assessment Score
    arithmetic mean (standard deviation)
        Baseline to Week 4
    -17.83 ± 23.79
    -25.20 ± 17.08
    -36.41 ± 25.28
    Statistical analysis title
    		 LS Mean Difference ONO-4474 100 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 100 mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.891
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.1
         upper limit
    		 12.28
    Statistical analysis title
    		 LS Mean Difference ONO-4474 200 mg vs Placebo
    Comparison groups
    Placebo v ONO-4474 200 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.079
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.79
         upper limit
    		 1.4

    Secondary: Change from Baseline in Clinical Global Impression by Week, up to Follow-up Visit

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    End point title
    		 Change from Baseline in Clinical Global Impression by Week, up to Follow-up Visit
    End point description
    Change from Baseline to Week 4 is presented.
    End point type
    Secondary
    End point timeframe
    Change from Baseline to Follow-up Visit
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    21
    23
    26
    Units: Number of patients
        Any improvement
    12
    19
    20
        Very much improved
    3
    1
    5
        Much improved
    4
    11
    10
        Minimally improved
    5
    7
    5
        No change
    4
    0
    2
        Any worsening
    2
    1
    0
        Minimally worse
    2
    1
    0
        Much worse
    0
    0
    0
        Very much worse
    0
    0
    0
    No statistical analyses for this end point

    Secondary: EuroQoL EQ-5D-5L Five Domains from Baseline to Week 4

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    End point title
    		 EuroQoL EQ-5D-5L Five Domains from Baseline to Week 4
    End point description
    The proportion of patients with favourable shifts in the EuroQoL EQ-5D-5L domains (mobility, self-care, usual activity, pain or discomfort, anxiety or depression) was generally greater in the ONO-4474 treatment groups compared to placebo.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Full analysis set
    Number of subjects analysed
    70
    Units: Number of patients
    70
    No statistical analyses for this end point

    Secondary: Rescue Medication for OA Symptoms

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    End point title
    		 Rescue Medication for OA Symptoms
    End point description
    There was no clear difference between treatment groups in use of rescue medication and the time to first use of rescue medication for OA symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Follow-up visit
    End point values
    		 Full analysis set
    Number of subjects analysed
    70
    Units: Number of patients
    70
    No statistical analyses for this end point

    Secondary: Pre-Dose Plasma Concentration (ng/mL) of ONO-4474 by Week

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    End point title
    		 Pre-Dose Plasma Concentration (ng/mL) of ONO-4474 by Week
    End point description
    End point type
    Secondary
    End point timeframe
    Week 1 to Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    0 [4]
    20 [5]
    24 [6]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1
    ±
    27.755 ± 21.373
    77.347 ± 80.061
        Week 2
    ±
    25.579 ± 25.231
    80.932 ± 120.372
        Week 4
    ±
    21.218 ± 16.238
    64.209 ± 95.117
    Notes
    [4] - Not applicable; PK could not be assessed in patients receiving placebo
    [5] - Pharmacokinetic analysis set (n=15 at Week 1, n=19 at Week 2, n=18 at Week 4)
    [6] - Pharmacokinetic analysis set (n=17 at Week 1, n=22 at Week 2, n=22 at Week 4)
    No statistical analyses for this end point

    Other pre-specified: OMERACT-OARSI Responders

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    End point title
    		 OMERACT-OARSI Responders
    End point description
    Data presented for Week 4
    End point type
    Other pre-specified
    End point timeframe
    Week 1, Week 2, Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: percent
        number (not applicable)
    44.4
    70.0
    86.4
    No statistical analyses for this end point

    Other pre-specified: Proportional Changes of Mean Daily Walking Pain Score by Improvement Rate (30%, 50%, and 70%) at Week 4

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    End point title
    		 Proportional Changes of Mean Daily Walking Pain Score by Improvement Rate (30%, 50%, and 70%) at Week 4
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Week 4
    End point values
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg
    Number of subjects analysed
    18
    20
    22
    Units: percent
    number (not applicable)
        ≥ 30% decrease
    44.4
    55.0
    54.5
        ≥ 50% decrease
    22.2
    25.0
    54.5
        ≥ 70% decrease
    11.1
    15.0
    27.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At all visits from Screening (Visit 1) to follow-up (Visit 8)
    Adverse event reporting additional description
    Data for the number of occurrences of each TEAE were not collected as the study was not designed to collect for the number of events in each subject group. Therefore, the number of occurrences of each TEAE have been reported as 0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Only treatment-emergent AEs are reported.

    Reporting group title
    ONO-4474 100 mg
    Reporting group description
    		 Only treatment-emergent AEs are reported.

    Reporting group title
    ONO-4474 200 mg
    Reporting group description
    		 Only treatment-emergent AEs are reported.

    Reporting group title
    Total
    Reporting group description
    		 Only treatment-emergent AEs are reported.

    Serious adverse events
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    1 / 26 (3.85%)
    2 / 70 (2.86%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    0 / 26 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    1 / 26 (3.85%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ONO-4474 100 mg ONO-4474 200 mg Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    17 / 23 (73.91%)
    19 / 26 (73.08%)
    46 / 70 (65.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 23 (0.00%)
    0 / 26 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 23 (8.70%)
    3 / 26 (11.54%)
    6 / 70 (8.57%)
         occurrences all number
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    0 / 26 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    0 / 26 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    2 / 26 (7.69%)
    2 / 70 (2.86%)
         occurrences all number
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    2 / 26 (7.69%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    1 / 26 (3.85%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    3 / 26 (11.54%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    5 / 26 (19.23%)
    6 / 70 (8.57%)
         occurrences all number
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    3 / 26 (11.54%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    1 / 26 (3.85%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 23 (4.35%)
    0 / 26 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 23 (0.00%)
    1 / 26 (3.85%)
    4 / 70 (5.71%)
         occurrences all number
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2017
    Amendment No.02. Global substantial amendment of the protocol to provide clarification on inclusion criterion #2 relating to the definition of females of non-child-bearing potential. To allow investigator sites to re-screen patients in limited circumstances, judged on a case by case basis, following approval by Medical Monitor.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Oct 2017
    Early termination of the study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the small sample size as a result of early study discontinuation, it is not possible to reach a definitive conclusion regarding the efficacy and safety of ONO-4474 in Study ONO-4474-02.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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