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    Clinical Trial Results:
    A Safety and Efficacy Extension Study of ONO-4641 (MSC2430913A) in Patients with Relapsing-Remitting Multiple Sclerosis

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2010-018705-11
    Trial protocol
    BE   ES   CZ   DE   GR  
    Global end of trial date
    30 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ONO-4641POU007 (EMR200559-002)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01226745
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this active-drug Extension Study is to evaluate the continuing safety and efficacy of ONO-4641 (MSC2430913A) in subjects with relapsing-remitting multiple sclerosis (RRMS) who have completed an initial 26-week Core Study (ONO-4641POU006 [NCT01081782]).
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Oct 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Poland: 105
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    United States: 93
    Worldwide total number of subjects
    340
    EEA total number of subjects
    150
    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)
    340
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    One subject received 0.15 mg of ONO-4641 instead of placebo in error in the core trial and was subsequently re-randomised during the extension trial and received 0.10 mg of ONO-4641. This subject was not reported in the participant flow for the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ONO-4641 0.15 milligram (mg) - 0.15 mg
    Arm description
    Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

    Arm title
    ONO-4641 0.10 mg - 0.10 mg
    Arm description
    Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

    Arm title
    ONO-4641 0.05 mg - 0.05 mg
    Arm description
    Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of ONO4641 0.15mg in core as well as in extension study.

    Arm title
    Placebo - ONO4641 0.15 mg
    Arm description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of 0.15 mg once daily in extension study.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of Placebo 0.15 mg in core study.

    Arm title
    Placebo - ONO4641 0.10 mg
    Arm description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of ONO-4641 0.10 mg in the extension study.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of Placebo 0.10 mg in core study.

    Arm title
    Placebo - ONO4641 0.05 mg
    Arm description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ONO-4641
    Investigational medicinal product code
    Other name
    MSC2430913A, Ceralifimod
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of ONO-4641 0.05 mg at in the extension study.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily dose of Placebo 0.05 mg in core study.

    Number of subjects in period 1
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Started
    80
    87
    89
    29
    26
    29
    Completed
    63
    71
    69
    24
    22
    24
    Not completed
    17
    16
    20
    5
    4
    5
         Death
    1
    -
    -
    -
    -
    1
         Did not complete schedule of assessments
    8
    3
    6
    -
    -
    1
         Unspecified
    6
    7
    8
    4
    3
    1
         Lost to follow-up
    2
    6
    6
    1
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ONO-4641 0.15 milligram (mg) - 0.15 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.10 mg - 0.10 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.05 mg - 0.05 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.15 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.10 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.05 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg Total
    Number of subjects
    80 87 89 29 26 29 340
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    36.3 ± 8.47 36 ± 8.64 38.2 ± 8.66 35.6 ± 9.59 37 ± 6.96 38.7 ± 9.48 -
    Gender, Male/Female
    Units: Subjects
        Female
    53 74 66 18 17 24 252
        Male
    27 13 23 11 9 5 88

    End points

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    End points reporting groups
    Reporting group title
    ONO-4641 0.15 milligram (mg) - 0.15 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.10 mg - 0.10 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.05 mg - 0.05 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.15 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.10 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.05 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Subject analysis set title
    ONO-4641 0.15 mg - 0.15 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Subject analysis set title
    Placebo - ONO4641 0.10 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Primary: Number of subjects with clinically significant abnormal vital signs

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    End point title
    Number of subjects with clinically significant abnormal vital signs [1]
    End point description
    Vital signs included oral temperature, pulse, respiration rate and blood pressure (BP) (taken after 5 minutes in the sitting position). The abnormalities in vital signs were decided as clinically significant or not based on the clinical judgment of the investigator. Safety analysis set consisted of all the enrolled subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 255
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Forced Expiratory Volume in one Second (FEV1) (Percent (%) predicted value)

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    End point title
    Change From Baseline in Forced Expiratory Volume in one Second (FEV1) (Percent (%) predicted value) [2]
    End point description
    FEV1 was defined as the maximal volume of air exhaled in the 1st second of a forced expiration from a position of full inspiration. FEV1 was obtained from spirometry, performed before study treatment administration. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects. Here “n” signifies the number of subjects analysed for the individual time point in the outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 40, 52, 76, 100, 124, 148, early termination, Week 152, 200, early termination 2, Week 255
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: Percentage of predicted value
    arithmetic mean (standard deviation)
        Week 40 (n=77, 83, 82, 29, 24, 24)
    -0.227 ± 6.5379
    -0.741 ± 6.2026
    -0.062 ± 5.4947
    -1.5 ± 5.0115
    -1.555 ± 7.8424
    -1.146 ± 4.7952
        Week 52 (n=74, 84, 77, 25, 24, 21)
    -0.675 ± 7.7166
    -1.981 ± 6.8499
    -0.484 ± 6.0952
    -3.113 ± 5.4753
    -2.851 ± 6.7997
    -0.561 ± 5.504
        Week 76 (n=72, 78, 74, 24, 24, 21)
    1.148 ± 9.595
    -2.352 ± 6.1152
    0.65 ± 7.2084
    -1.574 ± 6.3645
    -2.3 ± 9.2869
    2.657 ± 8.928
        Week 100 (n=68, 70, 72, 24, 24, 18)
    -0.746 ± 8.3955
    -2.79 ± 8.2129
    -1.187 ± 7.8818
    -3.202 ± 6.7073
    -3.748 ± 8.5817
    -1.207 ± 7.74
        Week 124 (n=66, 70, 68, 21, 23, 18)
    -0.795 ± 9.6531
    -2.003 ± 7.7998
    0.197 ± 7.9068
    -2.178 ± 9.7656
    -1.968 ± 9.2415
    -0.874 ± 8.2237
        Week 148 (n=59, 67, 68, 20, 21, 18)
    -1.828 ± 10.8131
    -3.429 ± 8.4036
    -1.234 ± 6.527
    -0.459 ± 9.0302
    -3.052 ± 9.497
    -2.599 ± 10.3997
        Early termination (n=16, 17, 13, 7, 3, 8)
    -6.803 ± 6.7393
    0.443 ± 6.084
    -1.78 ± 11.6068
    -2.984 ± 13.8177
    -4.109 ± 21.4354
    2.108 ± 8.1682
        Week 152 (n=12, 12, 10, 4, 3, 8)
    -3.786 ± 7.3297
    4.515 ± 11.3809
    -1.725 ± 7.4166
    -11.929 ± 13.1156
    -11.525 ± 12.3316
    2.688 ± 5.5468
        Week 200 (n=18, 18, 19, 6, 6, 3)
    -0.024 ± 8.0705
    -0.354 ± 12.8489
    -2.144 ± 8.3421
    -2.299 ± 8.2038
    -4.557 ± 13.3731
    0.944 ± 7.8955
        Early termination 2(n=56, 63, 63, 19, 20, 16)
    -1.416 ± 9.4274
    -2.031 ± 10.6185
    -2.859 ± 9.6661
    -1.321 ± 8.7759
    -1.291 ± 10.4528
    -3.249 ± 11.5213
        Week 255 (n=47, 48, 47, 17, 16, 13)
    -0.368 ± 13.5515
    -1.374 ± 11.092
    -0.027 ± 13.0574
    -0.209 ± 12.1999
    -2.377 ± 11.6511
    -0.963 ± 14.2975
    No statistical analyses for this end point

    Primary: Change From Baseline in Forced Vital Capacity (FVC)

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    End point title
    Change From Baseline in Forced Vital Capacity (FVC) [3]
    End point description
    FVC (% of predicted value) was the volume of air which was forcibly exhaled from the lungs after taking the deepest breath possible. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects. Here “n” signifies the number of subjects analysed for the individual time point in the outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 40, 52, 76, 100, 124, 148, early termination, Week 152, 200, early termination 2, Week 255
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: Percentage of predicted value
    arithmetic mean (standard deviation)
        Week 40 (n=77,83,82,29,24,24)
    -0.123 ± 6.9868
    -1 ± 6.406
    0.921 ± 6.9931
    -1.593 ± 5.052
    1.554 ± 7.9727
    -0.423 ± 5.5244
        Week 52 (n=74, 84, 77, 25, 24, 21)
    -0.681 ± 6.1396
    -1.175 ± 6.1523
    0.107 ± 7.7364
    -2.69 ± 5.2847
    -0.111 ± 6.2548
    -1.442 ± 6.8125
        Week 76 (n=72, 78, 74, 24, 24, 21)
    1.397 ± 8.1634
    -1.906 ± 6.0432
    1.828 ± 10.0612
    -2.487 ± 6.583
    0.568 ± 6.453
    -0.707 ± 11.3657
        Week 100 (n=68, 70, 72, 24, 24, 18)
    -0.308 ± 7.9759
    -2.433 ± 6.678
    0.118 ± 7.8025
    -2.683 ± 4.987
    -1.623 ± 8.3312
    -2.927 ± 7.867
        Week 124 (n=66, 70, 68, 21, 23, 18)
    -0.794 ± 7.8392
    -2.246 ± 6.5967
    0.89 ± 7.8545
    -2.582 ± 8.464
    -0.487 ± 8.2776
    -1.821 ± 7.7421
        Week 148 (n=59, 67, 68, 20, 21, 18)
    -0.909 ± 6.7009
    -3.078 ± 6.6149
    0.124 ± 7.7589
    -2.01 ± 7.8162
    -0.715 ± 6.7088
    -4.803 ± 9.3143
        Early termination(n=16, 17, 13, 7, 3, 8)
    -4.225 ± 8.2667
    -0.632 ± 5.1482
    979.704 ± 3533.962
    0.278 ± 9.2002
    0.459 ± 16.2506
    2.813 ± 6.3216
        Week 152 (n=12, 12, 10, 4, 3, 8)
    -4.256 ± 7.4403
    -0.074 ± 6.8982
    -2.829 ± 7.0313
    -3.748 ± 9.0311
    -2.726 ± 17.6042
    -1.283 ± 9.759
        Week 200 (n=18, 18, 19, 6, 6, 3)
    -0.316 ± 5.0212
    -3.057 ± 12.0551
    -1.59 ± 8.9426
    -1.109 ± 5.4668
    -1.152 ± 14.6922
    4.287 ± 8.1537
        Early termination (n=56, 63, 63, 19, 20, 16)
    -0.033 ± 6.5169
    -1.952 ± 9.6157
    -0.903 ± 10.0341
    -1.593 ± 8.6842
    -0.892 ± 5.6941
    -4.731 ± 12.9422
        Week 255 (n=47, 48, 47, 17, 16, 13)
    -0.717 ± 8.1437
    -1.686 ± 10.456
    1.386 ± 13.997
    -0.115 ± 13.4126
    -1.059 ± 10.2246
    -0.675 ± 11.1022
    No statistical analyses for this end point

    Primary: Change From Baseline in Diffusing Capacity of Lung for Carbon Monoxide (DLCO)

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    End point title
    Change From Baseline in Diffusing Capacity of Lung for Carbon Monoxide (DLCO) [4]
    End point description
    DLCO was one of most clinically valuable tests of lung function. The DLCO measure the ability of lungs to transfer gas from inhaled air to red blood cells in pulmonary capillaries. Early termination visit was recorded when subject was early terminated from study during the first 2.5 year period, while early termination 2 visit was recorded when subject was early terminated from the study during the additional 2 year period with delay. Values for DLCO “% of predicted” defined as mean value of 2 test results that were within 10% variability of each other. Safety analysis set consisted of all enrolled subjects. Here “n” signifies number of subjects analysed for individual time point in outcome measure. Here "99999" in ONO-4641 0.10 mg - 0.10 mg and Placebo - ONO4641 0.15 mg arm for Standard deviation signifies data not evaluable as it is assessed only for 1 subject. "99999" in Placebo - ONO4641 0.05 mg arm signifies Zero subjects were assessed for this measure. Hence, no data available.
    End point type
    Primary
    End point timeframe
    Baseline, Week 40, 52, early termination, Week 152, 200, 255
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: Percentage of predicted value
    arithmetic mean (standard deviation)
        Week 40 (n=22, 21, 16, 8, 9, 4)
    2.4 ± 13.16
    -1 ± 10.98
    -2.4 ± 17.36
    -5.3 ± 16.02
    -2.7 ± 10.61
    3.3 ± 6.4
        Week 52 (n=20, 19, 19, 8, 9, 5)
    -3.7 ± 8.36
    -2.7 ± 10.74
    0.8 ± 20.01
    -5.3 ± 11.56
    -4.8 ± 8.04
    5.2 ± 6.34
        Early termination (n=2, 1, 2, 3, 0, 0)
    -6.5 ± 2.12
    -9 ± 99999
    -43 ± 46.67
    -16.3 ± 12.58
    99999 ± 99999
    99999 ± 99999
        Week 152 (n=3, 1, 2, 1, 0, 0)
    -1 ± 1
    11 ± 99999
    9.5 ± 3.54
    -14 ± 99999
    99999 ± 99999
    99999 ± 99999
        Week 200 (n=7, 5, 5, 2, 3, 2)
    3 ± 43.89
    2 ± 12.85
    35.8 ± 34.87
    9.5 ± 28.99
    25 ± 12
    5 ± 9.9
        Week 255 (n=14, 15, 12, 4, 6, 4)
    42.3 ± 40.41
    21 ± 29.4
    27.8 ± 37.38
    5.8 ± 32.79
    37.5 ± 40.78
    16.3 ± 19.52
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant abnormal electrocardiogram (ECG) measures

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    End point title
    Number of subjects with clinically significant abnormal electrocardiogram (ECG) measures [5]
    End point description
    The 12-lead ECG was recorded after the subject was in supine position for 5 minutes. ECGs were acquired on digital cardiographs. Abnormal findings were analysed as clinically significant or not clinically significant as per the discretion of the study investigator. Safety analysis set consisted of all the enrolled subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 255
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant abnormal ophthalmologic examination

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    End point title
    Number of subjects with clinically significant abnormal ophthalmologic examination [6]
    End point description
    Subjects undergo comprehensive ophthalmic examination including best corrected visual acuity (Snellen),manifest refractions,pupil examination, ocular motility,nystagmus,confrontation visual fields,Ishihara color plates,Amsler grid; tonometry and biomicroscopy slit lamp examination ofconjunctiva,cornea,anterior chamber,iris andlens; and fundoscopic examination(with dilation) of vitreous,optic nerve,retinal vessels,macula, peripheralretina.Optical Coherence Tomography (OCT): Thicknesses of macularretinaand retinal nerve fiber layer atoptic nervehead in each eye assessed by OCTusing fast macular thickness mapscan andfast retinal nerve fiber layer scanfeatures. Abnormalities of ophthalmologic examination judged to beclinically significant or notas per investigatorsdiscretion. Ophthalmologic examination was performed for both right eye and left eye. Safety analysis set consisted of all enrolled subjects."n" signifies number of subjects analysed for individual time point in outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 255
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: subjects
        COE: RE: Baseline (n=80, 87, 89, 29, 26,29)
    1
    4
    3
    2
    0
    0
        COE: LE: Baseline (n=80, 87, 89, 29, 26, 29)
    0
    4
    3
    2
    0
    0
        COE: RE: Week 40 (n=78, 81, 82, 25, 23, 24)
    2
    2
    2
    1
    0
    0
        COE: LE: Week 40 (n=78, 81, 82, 25, 23, 24)
    5
    1
    2
    1
    0
    0
        COE: RE: Week 52 (n=76, 83, 77, 26, 24, 21)
    0
    2
    4
    1
    0
    0
        COE: LE: Week 52 (n=76, 83, 77, 26, 24, 21)
    2
    2
    3
    1
    0
    0
        COE: RE: Week 76 (n=72, 79, 72, 24, 24, 21)
    1
    2
    4
    1
    0
    1
        COE: LE: Week 76 (n=72, 79, 72, 24, 24, 21)
    3
    2
    5
    1
    0
    1
        COE: RE: Week 100 (n=67, 72, 71, 24, 23, 18)
    2
    2
    0
    1
    0
    0
        COE: LE: Week 100 (n=67, 72, 71, 24, 23, 18)
    5
    1
    1
    1
    0
    0
        COE: RE: Week 124 (n=65, 69, 67, 20, 22, 18)
    2
    2
    3
    1
    0
    0
        COE: LE: Week 124 (n=65, 69, 67, 20, 22, 18)
    2
    2
    1
    1
    1
    0
        COE: RE: Week 148 (n=58, 66, 67, 19, 21, 18)
    2
    2
    3
    1
    0
    0
        COE: LE: Week 148 (n=58, 66, 67, 19, 21, 18)
    3
    3
    4
    1
    0
    0
        COE: RE: Early termination (n=15, 14, 16, 6, 2, 8)
    0
    0
    1
    0
    0
    0
        COE: LE: Early termination (n=15, 14, 16, 6, 2, 8)
    1
    0
    1
    0
    0
    0
        COE: RE: Week 152 (n=12, 11, 11, 3, 2, 9)
    0
    0
    2
    0
    0
    0
        COE: LE: Week 152 (n=12, 11, 11, 3, 2, 9)
    1
    0
    1
    0
    0
    0
        COE: RE: Week 174 (n=57, 61, 63, 17, 21, 15)
    0
    2
    4
    1
    0
    0
        COE: LE: Week 174 (n=57, 61, 63, 17, 21, 15)
    2
    2
    2
    1
    0
    0
        COE: RE: Week 200 (n=19, 18, 19, 5, 5, 4)
    0
    1
    0
    1
    0
    0
        COE: LE: Week 200 (n=19, 18, 19, 5, 5, 4)
    0
    1
    0
    1
    0
    0
        COE: RE: Week 225 (n=3, 2, 0, 0, 0, 0)
    0
    0
    0
    0
    0
    0
        COE: LE: Week 225 (n=3, 2, 0, 0, 0, 0)
    0
    0
    0
    0
    0
    0
        COE: RE: Early termination 2(n=50,56,62,19,21,16)
    1
    2
    2
    1
    0
    0
        COE: LE: Early termination 2(n=50,56,62,19,21,16)
    1
    2
    3
    1
    0
    0
        COE: RE: Week 255 (n=43, 42, 44, 16, 14, 13)
    1
    0
    3
    1
    0
    0
        COE: LE: Week 255 (n=43, 42, 44, 16, 14, 13)
    1
    0
    3
    1
    0
    0
        OCT: RE: Baseline (n=80, 87, 89, 29, 26, 29)
    4
    2
    4
    1
    0
    1
        OCT: LE: Baseline (n=80, 87, 89, 29, 26, 29)
    4
    1
    2
    1
    0
    1
        OCT: RE: Week 40 (n=76, 80, 81, 25, 23, 24)
    2
    1
    3
    0
    0
    1
        OCT: LE: Week 40 (n=76, 80, 82, 25, 23, 24)
    2
    1
    3
    1
    0
    1
        OCT: RE: Week 52 (n=74, 82, 74, 25, 22, 20)
    1
    1
    2
    1
    0
    0
        OCT: LE: Week 52 (n=74, 82, 74, 25, 22, 20)
    1
    1
    2
    2
    0
    0
        OCT: RE: Week 76 (n=69, 77, 72, 24, 24, 21)
    2
    0
    1
    0
    0
    0
        OCT: LE: Week 76 (n=70, 77, 72, 24, 24, 21)
    2
    0
    1
    2
    0
    0
        OCT: RE: Week 100 (n=66, 71, 70, 23, 23, 18)
    3
    0
    1
    0
    0
    0
        OCT: LE: Week 100 (n=66, 71, 70, 23, 23, 18)
    2
    0
    1
    2
    0
    0
        OCT: RE: Week 124 (n=64, 68, 66, 19, 21, 18)
    3
    0
    1
    0
    0
    0
        OCT: LE: Week 124 (n=64, 68, 66, 19, 21, 18)
    2
    1
    1
    1
    0
    0
        OCT: RE: Week 148 (n=57, 67, 67, 20, 21, 18)
    2
    1
    2
    0
    0
    0
        OCT: LE: Week 148 (n=57, 67, 67, 20, 21, 18)
    2
    1
    2
    1
    0
    0
        OCT: RE: Early termination (n=14, 15, 15, 8, 2, 8)
    0
    0
    1
    1
    0
    1
        OCT: LE: Early termination (n=14, 15, 15, 8, 2, 8)
    0
    0
    1
    1
    0
    1
        OCT: RE: Week 152 (n=12, 11, 10, 3, 2, 9)
    0
    0
    2
    0
    0
    1
        OCT: LE: Week 152 (n=12, 11, 10, 3, 2, 9)
    0
    0
    0
    0
    0
    1
        OCT: RE: Week 174 (n=57, 60, 63, 17, 21, 15)
    2
    1
    3
    0
    0
    1
        OCT: LE: Week 174 (n=57, 60, 63, 17, 21, 15)
    3
    1
    2
    1
    1
    0
        OCT: RE: Week 200 (n=18, 15, 20, 5, 5, 4)
    1
    0
    0
    0
    1
    0
        OCT: LE: Week 200 (n=18, 15, 20, 5, 5, 4)
    0
    0
    0
    1
    0
    0
        OCT: RE: Week 225 (n=2, 2, 0, 0, 0, 0)
    0
    0
    0
    0
    0
    0
        OCT: LE: Week 225 (n=2, 2, 0, 0, 0, 0)
    0
    0
    0
    0
    0
    0
        OCT:RE:Early termination 2(n=51, 55, 62,19,21,16)
    4
    0
    2
    0
    0
    0
        OCT:LE:Early termination 2(n=51, 55, 62,19,21,16)
    2
    0
    1
    1
    0
    0
        OCT: RE: Week 255 (n=43, 42, 41, 15, 14, 13)
    2
    0
    2
    0
    0
    0
        OCT: LE: Week 255 (n=42, 42, 41, 15, 14, 13)
    2
    0
    1
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant abnormalities in dermatological examination

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    End point title
    Number of subjects with clinically significant abnormalities in dermatological examination [7]
    End point description
    A whole body examination, paying particular attention to identify precancerous or cancerous lesions was done by a dermatologist and based on the clinical judgment of the dermatologist the abnormalities were categorized as clinically significant or clinically not significant. Early termination visit was recorded when the subject was early terminated from the study during the first 2.5 year period, while early termination 2 visit was recorded when the subject early terminated from the study during the additional 2 year period with delay shall be defined. Safety analysis set consisted of all the enrolled subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to end of the treatment, assessed up to Week 255
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: subjects
        Baseline
    1
    0
    3
    1
    0
    1
        Week 40
    1
    2
    3
    1
    0
    0
        Week 52
    3
    4
    3
    0
    0
    1
        Week 76
    4
    4
    3
    2
    1
    0
        Week 100
    5
    2
    2
    2
    1
    1
        Week 124
    6
    7
    2
    2
    1
    1
        Week 148
    3
    5
    1
    2
    0
    2
        Early termination
    0
    1
    0
    1
    0
    0
        Week 152
    0
    1
    0
    0
    0
    0
        Week 174
    2
    1
    1
    0
    1
    1
        Week 200
    1
    1
    0
    1
    0
    0
        Early termination 2
    1
    0
    0
    1
    0
    1
        Week 255
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects with treatment emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to death and TEAEs leading to discontinuation

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    End point title
    Number of subjects with treatment emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to death and TEAEs leading to discontinuation [8]
    End point description
    An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as the AEs that occur between first dose of study drug administration and 35 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pretreatment state. Safety analysis set consisted of all the enrolled subjects.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug administration up to 35 days after the last dose of study drug administration, assessed up to 5 years
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was presented for this endpoint.
    End point values
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Number of subjects analysed
    80
    87
    89
    29
    26
    29
    Units: subjects
        TEAEs
    75
    85
    82
    27
    22
    29
        Serious TEAEs
    16
    12
    21
    5
    9
    11
        TEAEs leading to death
    1
    0
    0
    0
    0
    1
        TEAEs leading to discontinuation
    6
    6
    7
    3
    2
    6
    No statistical analyses for this end point

    Secondary: Number of Gadolinium (Gd)-Enhanced Lesions

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    End point title
    Number of Gadolinium (Gd)-Enhanced Lesions [9]
    End point description
    Gd-enhanced lesions obtained by magnetic resonance imaging at each scheduled assessment visit over study period. Extension study baseline is defined as measurement most immediately prior to or on day of first dose day of extension study. End of treatment (EoT) lesion count is average number of lesion counts per scan, calculated by dividing the sum of all lesion counts by number of scans during extension treatment period. Early termination visit recorded when subject was early terminated from study during first 2.5 year period, while early termination 2 visit was recorded when subject early terminated from study during additional 2 year period with delay. Extension study baseline is defined as measurement most immediately prior to or on the day of first dose day of extension study.Full Analysis Set (FAS)included all subjects who provided any post baseline efficacy data. "n” signifies number of subjects analysed for individual time point in outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40, 52, 100, 148, early termination, Week 152, 200, early termination 2, Week 255 and end of treatment (5 years)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For Efficacy analysis for this outcome measure. ONO4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-randomised in the extension trial hence, presented in these two reporting groups.
    End point values
    ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.05 mg ONO-4641 0.15 mg - 0.15 mg Placebo - ONO4641 0.10 mg
    Number of subjects analysed
    87
    89
    28
    28
    81
    27
    Units: Lesions
    arithmetic mean (standard deviation)
        Baseline
    0 ± 0.18
    0.3 ± 0.65
    2.7 ± 3.88
    1.6 ± 3.74
    0.2 ± 0.57
    3.6 ± 10.46
        Week 40 (n=78, 84, 82, 28, 24, 25)
    0.1 ± 0.62
    0.4 ± 1.32
    0.2 ± 0.42
    0.2 ± 0.5
    0.2 ± 0.67
    0.3 ± 1
        Week 52 (n=77, 84, 77, 25, 24, 21)
    0.2 ± 1.23
    0.4 ± 0.93
    0.2 ± 0.65
    0.4 ± 0.68
    0.2 ± 0.86
    0.1 ± 0.34
        Week 100 (n=71, 73, 72, 22, 24, 18)
    0.2 ± 0.76
    0.4 ± 1.37
    0.2 ± 0.53
    0.1 ± 0.47
    0.1 ± 0.49
    0.1 ± 0.34
        Week 148 (n=61, 67, 68, 18, 22, 18)
    0.1 ± 0.99
    0.6 ± 1.85
    0 ± 0
    0.1 ± 0.47
    0 ± 0.22
    0.2 ± 0.66
        Early termination (n=16, 14, 13, 6, 3, 6)
    0.1 ± 0.36
    1.5 ± 4.68
    0.2 ± 0.41
    0.5 ± 0.84
    0.8 ± 2.76
    0 ± 0
        Week 152 (n=11, 10, 8, 4, 3, 6)
    0.6 ± 0.97
    2.5 ± 6.3
    0.8 ± 1.5
    0.3 ± 0.82
    0.2 ± 0.6
    0 ± 0
        Week 200 (n=20, 18, 21, 28, 27, 28)
    0.5 ± 1.29
    0.2 ± 0.89
    0 ± 0
    0 ± 0
    0 ± 0
    0.5 ± 1.22
        Early Termination 2 (n=58, 61, 60, 17, 21, 16)
    0.2 ± 0.87
    0.2 ± 0.38
    0.1 ± 0.33
    0.4 ± 1.26
    0.1 ± 0.34
    0.2 ± 0.51
        Week 255 (n=46, 48, 48, 16, 17, 13)
    0.3 ± 1.01
    0.4 ± 1.38
    1.6 ± 3.9
    0.3 ± 0.85
    1.1 ± 5.9
    0.2 ± 0.53
        End of treatment (n=80, 84, 85, 28, 24, 25)
    0.2 ± 0.64
    0.4 ± 0.93
    0.2 ± 0.39
    0.3 ± 0.5
    0.1 ± 0.39
    0.2 ± 0.53
    No statistical analyses for this end point

    Secondary: Change from Baseline in Lesion Volume at the end of the treatment (EoT)

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    End point title
    Change from Baseline in Lesion Volume at the end of the treatment (EoT) [10]
    End point description
    Brain lesion volume was obtained by magnetic resonance imaging (MRI). Extension study baseline was defined as the measurement most immediately prior to or on the day of the first dose day of extension study. End of treatment (EOT) was defined as the last visit during the treatment period. Change from extension baseline to EOT = last treatment period value in extension study — extension baseline value. FAS included all subjects who provided any post baseline efficacy data. One randomised error subject was summarised in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period. FAS included all subjects who provided any post baseline efficacy data.One randomised error subject was summarized in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period.
    End point type
    Secondary
    End point timeframe
    Baseline, End of treatment (5 years)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For Efficacy analysis for this outcome measure. Ono4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-ransomised in the extension trial hence, presented in these two reporting groups.
    End point values
    ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.05 mg ONO-4641 0.15 mg - 0.15 mg Placebo - ONO4641 0.10 mg
    Number of subjects analysed
    87
    89
    28
    28
    81
    27
    Units: Cubic centimeter (cc)
        arithmetic mean (standard deviation)
    0.0294 ± 0.11275
    0.0197 ± 0.19925
    -0.4548 ± 0.96555
    -0.1105 ± 0.36973
    -0.0264 ± 0.15483
    -0.4465 ± 1.22881
    No statistical analyses for this end point

    Secondary: Percent Brain Volume Change (PBVC) from Baseline at the end of treatment

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    End point title
    Percent Brain Volume Change (PBVC) from Baseline at the end of treatment [11]
    End point description
    Brain volume was obtained by magnetic resonance imaging (MRI). Extension study baseline is defined as the measurement most immediately prior to or on the day of the first dose day of extension study. Brain volume changes very little over time. Hence, the PBVC at the end of treatment was calculated by adding up all the PBVC values from the scans performed during the extension treatment period. FAS included all subjects who provided any post baseline efficacy data. One randomised error subject was summarised in the sequence 0.15-0.15 as the subject received 0.15 in core study period and in the sequence Placebo-0.10 mg as the subject received 0.10 in the extension study period.
    End point type
    Secondary
    End point timeframe
    Baseline and at end of treatment (Week 255)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For Efficacy analysis for this outcome measure. ONO4641 0.15mg - 0.15mg, Placebo - ONO4641 0.10 mg were presented as one of the subject was wrongly re-randomised in the extension trial hence, presented in these two reporting groups.
    End point values
    ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.05 mg ONO-4641 0.15 mg - 0.15 mg Placebo - ONO4641 0.10 mg
    Number of subjects analysed
    87
    89
    28
    28
    81
    27
    Units: Percent brain volume
        arithmetic mean (standard deviation)
    -0.713 ± 0.8558
    -0.757 ± 0.7554
    -0.756 ± 0.8239
    -0.972 ± 0.8215
    -0.845 ± 0.8745
    -1.302 ± 0.9643
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the administration of study medication up to the final study visit, assessed up to 5 years
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    ONO-4641 0.15 milligram (mg) - 0.15 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.15 mg in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.10 mg - 0.10 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.10 mg in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    ONO-4641 0.05 mg - 0.05 mg
    Reporting group description
    Subjects who were administered with ONO-4641 at a dose of 0.05 mg in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.15 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.15 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.10 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.10 mg once daily in the extension study for a duration of 225 weeks.

    Reporting group title
    Placebo - ONO4641 0.05 mg
    Reporting group description
    Subjects who were administered with placebo in the core study were administered with ONO-4641 at a dose of 0.05 mg once daily in the extension study for a duration of 225 weeks.

    Serious adverse events
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 80 (20.00%)
    12 / 87 (13.79%)
    21 / 89 (23.60%)
    5 / 29 (17.24%)
    9 / 26 (34.62%)
    11 / 29 (37.93%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Venous insufficiency
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Female sterilisation
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rectal cancer
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Autism spectrum disorder
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic prolapse
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical poisoning
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood human chorionic gonadotropin increased
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 80 (5.00%)
    8 / 87 (9.20%)
    11 / 89 (12.36%)
    1 / 29 (3.45%)
    6 / 26 (23.08%)
    6 / 29 (20.69%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 11
    0 / 1
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colonic polyp
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Connective tissue disorder
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitic infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ONO-4641 0.15 milligram (mg) - 0.15 mg ONO-4641 0.10 mg - 0.10 mg ONO-4641 0.05 mg - 0.05 mg Placebo - ONO4641 0.15 mg Placebo - ONO4641 0.10 mg Placebo - ONO4641 0.05 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 80 (83.75%)
    80 / 87 (91.95%)
    72 / 89 (80.90%)
    21 / 29 (72.41%)
    21 / 26 (80.77%)
    27 / 29 (93.10%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 80 (7.50%)
    2 / 87 (2.30%)
    3 / 89 (3.37%)
    1 / 29 (3.45%)
    4 / 26 (15.38%)
    5 / 29 (17.24%)
         occurrences all number
    6
    2
    3
    1
    4
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 87 (3.45%)
    5 / 89 (5.62%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    2 / 29 (6.90%)
         occurrences all number
    2
    3
    5
    1
    2
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 80 (3.75%)
    5 / 87 (5.75%)
    6 / 89 (6.74%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    5
    6
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 80 (7.50%)
    10 / 87 (11.49%)
    9 / 89 (10.11%)
    1 / 29 (3.45%)
    3 / 26 (11.54%)
    3 / 29 (10.34%)
         occurrences all number
    6
    10
    9
    1
    3
    3
    Pyrexia
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 87 (4.60%)
    6 / 89 (6.74%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    3
    4
    6
    0
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 80 (5.00%)
    10 / 87 (11.49%)
    6 / 89 (6.74%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    2 / 29 (6.90%)
         occurrences all number
    4
    10
    6
    2
    1
    2
    Depression
         subjects affected / exposed
    4 / 80 (5.00%)
    7 / 87 (8.05%)
    5 / 89 (5.62%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    4
    7
    5
    1
    0
    4
    Reproductive system and breast disorders
    Anxiety
         subjects affected / exposed
    7 / 80 (8.75%)
    2 / 87 (2.30%)
    2 / 89 (2.25%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    7
    2
    2
    1
    0
    2
    Dysmenorrhoea
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 80 (3.75%)
    8 / 87 (9.20%)
    3 / 89 (3.37%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    5 / 29 (17.24%)
         occurrences all number
    3
    8
    3
    1
    2
    5
    Fall
         subjects affected / exposed
    4 / 80 (5.00%)
    3 / 87 (3.45%)
    3 / 89 (3.37%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    3 / 29 (10.34%)
         occurrences all number
    4
    3
    3
    1
    2
    3
    Procedural pain
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 87 (4.60%)
    1 / 89 (1.12%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    4
    4
    1
    1
    1
    0
    Muscle strain
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 87 (4.60%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    4
    1
    0
    0
    1
    Excoriation
         subjects affected / exposed
    0 / 80 (0.00%)
    4 / 87 (4.60%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    2 / 29 (6.90%)
         occurrences all number
    0
    4
    1
    0
    2
    2
    Joint sprain
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 87 (2.30%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    1
    0
    1
    2
    Foreign body in eye
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 80 (10.00%)
    8 / 87 (9.20%)
    12 / 89 (13.48%)
    6 / 29 (20.69%)
    3 / 26 (11.54%)
    6 / 29 (20.69%)
         occurrences all number
    8
    8
    12
    6
    3
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 80 (8.75%)
    9 / 87 (10.34%)
    9 / 89 (10.11%)
    4 / 29 (13.79%)
    3 / 26 (11.54%)
    5 / 29 (17.24%)
         occurrences all number
    7
    9
    9
    4
    3
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 87 (4.60%)
    4 / 89 (4.49%)
    3 / 29 (10.34%)
    0 / 26 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    3
    4
    4
    3
    0
    4
    Activated partial thromboplastin time
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 87 (3.45%)
    2 / 89 (2.25%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    1 / 29 (3.45%)
         occurrences all number
    2
    3
    2
    0
    2
    1
    Blood cholesterol increased
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 87 (2.30%)
    3 / 89 (3.37%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    1 / 29 (3.45%)
         occurrences all number
    2
    2
    3
    0
    2
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 87 (1.15%)
    4 / 89 (4.49%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    3
    1
    4
    0
    2
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 87 (5.75%)
    2 / 89 (2.25%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    5
    2
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 87 (3.45%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    1
    3
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 80 (5.00%)
    6 / 87 (6.90%)
    8 / 89 (8.99%)
    2 / 29 (6.90%)
    2 / 26 (7.69%)
    3 / 29 (10.34%)
         occurrences all number
    4
    6
    8
    2
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    7 / 80 (8.75%)
    3 / 87 (3.45%)
    2 / 89 (2.25%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    2 / 29 (6.90%)
         occurrences all number
    7
    3
    2
    1
    1
    2
    Sinus congestion
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 87 (1.15%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    5
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 87 (5.75%)
    2 / 89 (2.25%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    5
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 80 (16.25%)
    13 / 87 (14.94%)
    13 / 89 (14.61%)
    7 / 29 (24.14%)
    5 / 26 (19.23%)
    2 / 29 (6.90%)
         occurrences all number
    13
    13
    13
    7
    5
    2
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 80 (5.00%)
    9 / 87 (10.34%)
    12 / 89 (13.48%)
    1 / 29 (3.45%)
    7 / 26 (26.92%)
    7 / 29 (24.14%)
         occurrences all number
    4
    9
    12
    1
    7
    7
    Dizziness
         subjects affected / exposed
    4 / 80 (5.00%)
    8 / 87 (9.20%)
    3 / 89 (3.37%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    1 / 29 (3.45%)
         occurrences all number
    4
    8
    3
    2
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    5 / 80 (6.25%)
    3 / 87 (3.45%)
    5 / 89 (5.62%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    5
    3
    5
    2
    0
    2
    Migraine
         subjects affected / exposed
    5 / 80 (6.25%)
    4 / 87 (4.60%)
    3 / 89 (3.37%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    5
    4
    3
    0
    2
    0
    Muscle spasticity
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 87 (5.75%)
    2 / 89 (2.25%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 29 (3.45%)
         occurrences all number
    1
    5
    2
    0
    1
    1
    Paraesthesia
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 87 (2.30%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    2
    1
    0
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 87 (2.30%)
    3 / 89 (3.37%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    3
    1
    0
    2
    Tremor
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 87 (2.30%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    1
    0
    0
    2
    Memory impairment
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 87 (1.15%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 87 (1.15%)
    6 / 89 (6.74%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    2
    1
    6
    0
    1
    0
    Retinal disorder
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 87 (2.30%)
    2 / 89 (2.25%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    2
    2
    2
    0
    0
    Blepharospasm
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 80 (6.25%)
    5 / 87 (5.75%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 29 (3.45%)
         occurrences all number
    5
    5
    5
    0
    1
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 80 (10.00%)
    10 / 87 (11.49%)
    4 / 89 (4.49%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    1 / 29 (3.45%)
         occurrences all number
    8
    10
    4
    1
    2
    1
    Nausea
         subjects affected / exposed
    8 / 80 (10.00%)
    7 / 87 (8.05%)
    4 / 89 (4.49%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    8
    7
    4
    0
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    3 / 80 (3.75%)
    5 / 87 (5.75%)
    4 / 89 (4.49%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    5
    4
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 87 (2.30%)
    4 / 89 (4.49%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    2
    4
    0
    0
    1
    Vomiting
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 87 (4.60%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    4
    1
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 87 (2.30%)
    2 / 89 (2.25%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    4
    2
    2
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 87 (1.15%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    0
    1
    5
    0
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 80 (6.25%)
    5 / 87 (5.75%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    5
    5
    5
    0
    0
    0
    Eczema
         subjects affected / exposed
    7 / 80 (8.75%)
    4 / 87 (4.60%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    7
    4
    1
    0
    0
    2
    Increased tendency to bruise
         subjects affected / exposed
    2 / 80 (2.50%)
    7 / 87 (8.05%)
    0 / 89 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    7
    0
    1
    0
    0
    Ecchymosis
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 87 (2.30%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    1
    0
    1
    2
    Rash
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 87 (5.75%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    5
    1
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    2 / 29 (6.90%)
         occurrences all number
    2
    0
    1
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 80 (13.75%)
    8 / 87 (9.20%)
    12 / 89 (13.48%)
    1 / 29 (3.45%)
    5 / 26 (19.23%)
    2 / 29 (6.90%)
         occurrences all number
    11
    8
    12
    1
    5
    2
    Arthralgia
         subjects affected / exposed
    7 / 80 (8.75%)
    8 / 87 (9.20%)
    6 / 89 (6.74%)
    1 / 29 (3.45%)
    3 / 26 (11.54%)
    5 / 29 (17.24%)
         occurrences all number
    7
    8
    6
    1
    3
    5
    Pain in extremity
         subjects affected / exposed
    11 / 80 (13.75%)
    4 / 87 (4.60%)
    8 / 89 (8.99%)
    3 / 29 (10.34%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    4
    8
    3
    0
    2
    Muscle spasms
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 87 (4.60%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    4
    4
    5
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 87 (3.45%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    3
    5
    0
    0
    2
    Neck pain
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 87 (2.30%)
    3 / 89 (3.37%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    3 / 29 (10.34%)
         occurrences all number
    2
    2
    3
    1
    1
    3
    Muscular weakness
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 87 (2.30%)
    6 / 89 (6.74%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    2
    6
    0
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    1 / 89 (1.12%)
    2 / 29 (6.90%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 87 (1.15%)
    5 / 89 (5.62%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    5
    0
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 80 (22.50%)
    21 / 87 (24.14%)
    22 / 89 (24.72%)
    3 / 29 (10.34%)
    8 / 26 (30.77%)
    7 / 29 (24.14%)
         occurrences all number
    18
    21
    22
    3
    8
    7
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 80 (17.50%)
    21 / 87 (24.14%)
    15 / 89 (16.85%)
    4 / 29 (13.79%)
    5 / 26 (19.23%)
    6 / 29 (20.69%)
         occurrences all number
    14
    21
    15
    4
    5
    6
    Urinary tract infection
         subjects affected / exposed
    7 / 80 (8.75%)
    16 / 87 (18.39%)
    13 / 89 (14.61%)
    2 / 29 (6.90%)
    4 / 26 (15.38%)
    6 / 29 (20.69%)
         occurrences all number
    7
    16
    13
    2
    4
    6
    Bronchitis
         subjects affected / exposed
    12 / 80 (15.00%)
    8 / 87 (9.20%)
    8 / 89 (8.99%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    12
    8
    8
    2
    0
    0
    Oral herpes
         subjects affected / exposed
    2 / 80 (2.50%)
    9 / 87 (10.34%)
    7 / 89 (7.87%)
    0 / 29 (0.00%)
    5 / 26 (19.23%)
    0 / 29 (0.00%)
         occurrences all number
    2
    9
    7
    0
    5
    0
    Pharyngitis
         subjects affected / exposed
    3 / 80 (3.75%)
    9 / 87 (10.34%)
    6 / 89 (6.74%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    3
    9
    6
    2
    0
    3
    Sinusitis
         subjects affected / exposed
    8 / 80 (10.00%)
    6 / 87 (6.90%)
    7 / 89 (7.87%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 29 (0.00%)
         occurrences all number
    8
    6
    7
    0
    2
    0
    Influenza
         subjects affected / exposed
    3 / 80 (3.75%)
    6 / 87 (6.90%)
    5 / 89 (5.62%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    3 / 29 (10.34%)
         occurrences all number
    3
    6
    5
    1
    1
    3
    Gastroenteritis viral
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 87 (2.30%)
    6 / 89 (6.74%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 29 (0.00%)
         occurrences all number
    4
    2
    6
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 87 (3.45%)
    1 / 89 (1.12%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    3
    1
    1
    0
    2
    Cystitis
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 87 (1.15%)
    2 / 89 (2.25%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    2
    0
    2
    1
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 87 (0.00%)
    2 / 89 (2.25%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    2
    1
    0
    2
    Onychomycosis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 87 (0.00%)
    0 / 89 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2010
    The following changes were made in this amended protocol: - The number of sites was increased. - Added the US as an additional country to enroll patients. - Adjusted enrollment figures. - Study Investigators must be blinded to magnetic resonance imaging (MRI) results after a schedule visit. - Further clarification was made for the Unscheduled Visit for Patients with delayed Entry into the Extension Study. - Blinding of WBC, Neutrophil, and Lymphocyte Count. - Laboratory values were also done for the investigator.
    30 Nov 2010
    The following changes were made in this amended protocol - Increased the extension study period from 26 weeks to 122 weeks. - Added an additional 96 weeks to the study. - Adjusted the dose-blinded extension from 6 months to 2.5 years. - Clarification was made when subjects should return for an Early Termination visit.
    02 Apr 2012
    The following changes were made in the amended protocol: - Change in the interim analysis; there was an interim database lock at the time point of Interim Analysis. The clinical team directly involved in the conduct of the study was remain blinded to the interim analysis results. Details of the maintenance of the blind was documented in a separate document. The final database lock was occurred at the end of the trial. - Changes in Population Pharmacokinetic (PK)/Pharmacodynamic (PD) analysis.
    05 Feb 2013
    The following changes were made in the amended protocol: - Study duration was changed from 122 weeks to 225 weeks (4.5 years). - Update on number of subjects enrolled; 343 patients were enrolled in the extension trial. - Withdrawal criteria for the subject was updated. - Management of Infections, Lymphopenia, and Arrhythmias, Bradycardia, and Precaution for Patients with Impaired Renal Function section was updated for the lymchocyte count criteria. - PK sampling was elaborately defined.

    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.
    Company decided to not pursue phase 3 development of ceralifimod (ONO-4641). The decision was not related to any safety and efficacy findings.
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