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    Clinical Trial Results:
    A Phase 2, multi-center, randomized, double-blind, placebo-controlled parallel-group study to evaluate the clinical efficacy and safety of induction therapy with RPC1063 in patients with moderately to severely active ulcerative colitis

    Summary
    EudraCT number
    2012-003123-38
    Trial protocol
    BE   HU   PL   SK   BG   GR   NL  
    Global end of trial date
    30 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Sep 2020
    First version publication date
    13 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPC01-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01647516
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene International II Sàrl
    Sponsor organisation address
    Rue du Pré-Jorat 14, Couvet, Switzerland, 2108
    Public contact
    Clinical Trial Disclosure, Celgene International II Sàrl, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Ernesto Oviedo-Orta, MD, PhD, MBA, Celgene International II Sàrl, 01 908-673-2861, Ernesto.Oviedo-Orta@BMS.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 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the efficacy of RPC1063 vs placebo for induction of clinical remission at Week 8 in patients with moderately to severely active ulcerative colitis (UC)
    Protection of trial subjects
    Patient Confidentiality, Informed Consent and Archiving of Essential Documents
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Russian Federation: 44
    Worldwide total number of subjects
    197
    EEA total number of subjects
    78
    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)
    195
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at 57 sites from 13 countries located in Europe, North America, and the Asia-Pacific region.

    Pre-assignment
    Screening details
    Participants who received placebo, ozanimod 0.5 mg or ozanimod 1 mg capsules and completed the induction period and were non-responders at week 8 and those who completed the maintenance period or experienced a disease relapse, were given the option to enter the open label treatment period and received 1 mg ozanimod daily up to 6 years.

    Period 1
    Period 1 title
    Induction Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Investigational medicinal product and placebo capsules were identical in physical appearance. The treatment each participant received was not disclosed to the Investigator, study center personnel, participant, sponsor and their representatives. The treatment codes were held according to an Interactive Voice Response System (IVRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received identically matching placebo capsules daily for 9 weeks during the induction period (weeks 0-9).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo capsules daily during the induction period (Weeks 0-9). Nine weeks total treatment.

    Arm title
    Ozanimod Hydrochloride 0.5mg
    Arm description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Zeposia
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Arm title
    Ozanimod Hydrochloride 1 mg
    Arm description
    Participants received 1 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Zeposia
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Number of subjects in period 1
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Started
    65
    65
    67
    Received study drug
    65
    65
    67
    Completed
    60
    63
    63
    Not completed
    5
    2
    4
         Participant elected to stop dosing
    -
    -
    1
         Physician decision
    2
    -
    -
         Lack of efficacy
    1
    -
    -
         Adverse event, non-fatal
    1
    2
    -
         Consent withdrawn by subject
    1
    -
    3
    Period 2
    Period 2 title
    Maintenance Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Investigational medicinal product and placebo capsules were identical in physical appearance. The treatment each participant received was not disclosed to the Investigator, study center personnel, participant, sponsor and their representatives. The treatment codes were held according to an Interactive Voice Response System (IVRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received identically matching placebo capsules daily for 24 weeks during the maintenance period (weeks 9-32).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo capsules daily during the maintenance period (Weeks 9-32). Twenty-four weeks total treatment.

    Arm title
    Ozanimod Hydrochloride 0.5mg
    Arm description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily for 24 weeks during the maintenance period (weeks 9-32).
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Zeposia
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod hydrochloride 0.5mg capsules daily during the maintenance period (Weeks 9-32). Twenty-four weeks total treatment.

    Arm title
    Ozanimod Hydrochloride 1 mg
    Arm description
    Participants received 1 mg capsules of ozanimod hydrochloride daily for 24 weeks during the maintenance period (weeks 9-32).
    Arm type
    Experimental

    Investigational medicinal product name
    RPC1063
    Investigational medicinal product code
    Other name
    Zeposia
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ozanimod Hydrochloride 1 mg capsules daily during the maintenance period (Weeks 9-32). Twenty-four weeks total treatment.

    Number of subjects in period 2 [1]
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Started
    25
    36
    42
    Received Study Drug
    25
    36
    41
    Completed
    21
    30
    40
    Not completed
    4
    6
    2
         Noncompliance
    1
    -
    -
         Lack of efficacy
    1
    4
    1
         Adverse event, non-fatal
    2
    1
    -
         Consent withdrawn by subject
    -
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants were considered responders in the maintenance period, which is a lower number than those completed in the induction period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo capsules daily for 9 weeks during the induction period (weeks 0-9).

    Reporting group title
    Ozanimod Hydrochloride 0.5mg
    Reporting group description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Reporting group title
    Ozanimod Hydrochloride 1 mg
    Reporting group description
    Participants received 1 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Reporting group values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg Total
    Number of subjects
    65 65 67 197
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    64 64 67 195
        From 65-84 years
    1 1 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.9 ± 12.30 38.8 ± 12.06 41.8 ± 11.01 -
    Gender Categorical
    Units: Subjects
        Female
    30 33 19 82
        Male
    35 32 48 115
    Race
    Units: Subjects
        White
    61 59 62 182
        Black
    2 1 1 4
        Asian
    2 3 3 8
        American Indian or Alaska Native
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Other
    0 1 1 2
        Missing
    0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 1 0 3
        Not Hispanic or Latino
    63 64 67 194
    Mayo Score
    The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    8.6 ± 1.51 8.3 ± 1.45 8.5 ± 1.61 -
    Years Since Ulcerative Colitis Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    6.1 ± 5.46 5.9 ± 5.44 6.7 ± 6.76 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo capsules daily for 9 weeks during the induction period (weeks 0-9).

    Reporting group title
    Ozanimod Hydrochloride 0.5mg
    Reporting group description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Reporting group title
    Ozanimod Hydrochloride 1 mg
    Reporting group description
    Participants received 1 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.
    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo capsules daily for 24 weeks during the maintenance period (weeks 9-32).

    Reporting group title
    Ozanimod Hydrochloride 0.5mg
    Reporting group description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily for 24 weeks during the maintenance period (weeks 9-32).

    Reporting group title
    Ozanimod Hydrochloride 1 mg
    Reporting group description
    Participants received 1 mg capsules of ozanimod hydrochloride daily for 24 weeks during the maintenance period (weeks 9-32).

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received identically matching placebo capsules during the maintenance period.

    Subject analysis set title
    Ozanimod 0.5 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received 0.5 mg capsules daily during the maintenance period.

    Subject analysis set title
    Ozanimod 1 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received 1 mg capsules daily during the maintenance period.

    Subject analysis set title
    Open Label Treatment Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received placebo capsules, ozanimod 0.5 mg or ozanimod 1 mg capsules and completed the induction period and were non-responders at Week 8 and those who completed the maintenance period or experienced a disease relapse, were given the option to enter the open label treatment period (OLP) and received 1 mg ozanimod daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study.

    Primary: Percentage of Participants Who Achieved Clinical Remission Based on the Central Read of the Mayo Score (MS), at Week 8

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    End point title
    Percentage of Participants Who Achieved Clinical Remission Based on the Central Read of the Mayo Score (MS), at Week 8
    End point description
    Clinical Remission was defined as: Mayo score of <2 points and with no individual subscore of > 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. • Stool Frequency Subscore (SFS) • Rectal bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA) Clinical Remission was based on the 4-component Mayo definition. The intent to treat (ITT) population consisted of all randomized participants who received at least one dose of study treatment, with treatment. Participants with missing Mayo scores were classified as non-responders.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Percentage of Participants
        number (not applicable)
    6.2
    13.8
    16.4
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0482 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.262
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.969
         upper limit
    10.984
    Notes
    [1] - Stratified by prior anti-tumor necrosing factor (anti-TNF) therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1422 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    8.661
    Notes
    [2] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Percentage of Participants Who Achieved a Clinical Response in the Mayo Score (MS) at Week 8

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    End point title
    Percentage of Participants Who Achieved a Clinical Response in the Mayo Score (MS) at Week 8
    End point description
    Clinical response was defined as a reduction from baseline in Mayo score ≥3 points and ≥30%, and a decrease from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. Clinical Respone was based on the 4-component Mayo definition. The ITT population consisted of all randomized participants who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Participants with missing Mayo score were considered non-responders. Non responder imputa
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Units on a Scale
        number (not applicable)
    36.9
    53.8
    56.7
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0207 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.158
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.093
         upper limit
    4.263
    Notes
    [3] - Stratified by prior anti-TNF therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.0648
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.947
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.961
         upper limit
    3.946
    Notes
    [4] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Change from Baseline in Mayo Score at Week 8

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    End point title
    Change from Baseline in Mayo Score at Week 8
    End point description
    The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. • Stool Frequency Subscore (SFS) • Rectal bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA) The ITT population consisted of all randomized participants who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Includes participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    62
    64
    65
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    2.0 ± 2.52
    -2.6 ± 2.92
    -3.4 ± 2.79
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0042 [5]
    Method
    ANCOVA
    Confidence interval
    Notes
    [5] - The analysis of covariance model, adjusting for baseline Mayo score and prior anti-TNF (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1415 [6]
    Method
    ANCOVA
    Confidence interval
    Notes
    [6] - The analysis of covariance model, adjusting for baseline Mayo score and prior anti-TNF (yes or no)

    Secondary: Percentage of Participants with Mucosal Healing at Week 8

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    End point title
    Percentage of Participants with Mucosal Healing at Week 8
    End point description
    Mucosal healing is defined as an endoscopy subscore ≤ 1 point. Endoscopy subscores were calculated based on central endoscopy reading. The endoscopy scale: 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) The ITT population consisted of all randomized participants who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Units on a Scale
        number (not applicable)
    12.3
    27.7
    34.3
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.861
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.572
         upper limit
    9.484
    Notes
    [7] - Stratified by prior anti-TNF therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0348 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.647
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.058
         upper limit
    6.621
    Notes
    [8] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Percentage of Participants Who Achieved Clinical Remission in the Mayo Score at Week 32

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    End point title
    Percentage of Participants Who Achieved Clinical Remission in the Mayo Score at Week 32
    End point description
    Clinical Remission was defined as: Mayo score of <2 points and with no individual subscore of > 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. • Stool Frequency Subscore (SFS) • Rectal bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA) The ITT population consisted of all randomized participants who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Participants with missing Mayo score were considered non-responders. NRI.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Percentage of Participants
        number (not applicable)
    6.2
    26.2
    20.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0108 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.332
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.323
         upper limit
    14.186
    Notes
    [9] - Stratified by prior anti-TNF therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.443
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.706
         upper limit
    17.365
    Notes
    [10] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Percentage of Participants Who Achieved a Clinical Response at Week 32

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    End point title
    Percentage of Participants Who Achieved a Clinical Response at Week 32
    End point description
    Clinical response was defined as a reduction from baseline in Mayo score ≥3 points and 30%, and a decrease from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician’s global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. The ITT population = all randomized subjects who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Subjects with missing Mayo score were considered non-responders. NRI.
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Percentage of Participants
        number (not applicable)
    20.0
    35.4
    50.7
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.871
         upper limit
    8.678
    Notes
    [11] - Stratified by prior anti-TNF therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0571 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.154
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.974
         upper limit
    4.763
    Notes
    [12] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Percentage of Participants with Mucosal Healing at Week 32

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    End point title
    Percentage of Participants with Mucosal Healing at Week 32
    End point description
    Mucosal healing is defined as an endoscopy subscore ≤ 1 point. Endoscopy subscores were calculated based on central endoscopy reading. The endoscopy scale: 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) The ITT population consisted of all randomized participants who received at least one dose of study treatment, with treatment assignment designated according to randomized treatment. Non-responder imputation (NRI).
    End point type
    Secondary
    End point timeframe
    Week 32
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Percentage of Participants
        number (not applicable)
    12.3
    32.3
    32.8
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Ozanimod Hydrochloride 1 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0046 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.557
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.444
         upper limit
    8.762
    Notes
    [13] - Stratified by prior anti-TNF therapy experience, (yes or no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Ozanimod Hydrochloride 0.5mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0064 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.428
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.384
         upper limit
    8.494
    Notes
    [14] - Stratified by prior anti-TNF therapy experience, (yes or no).

    Secondary: Number of Participants with Treatment Emergent Adverse Events During the Induction Period

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    End point title
    Number of Participants with Treatment Emergent Adverse Events During the Induction Period
    End point description
    A TEAE was defined as any event with an onset date on or after first dose date or any ongoing event on the first dose date that worsens in severity after first dose date and until 30 days following the last dose of treatment with the study drug. earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = an AE usually transient in nature and generally not interfering with normal activities; Moderate = an AE that is sufficiently discomforting to interfere with normal activities; Severe = an AE that is incapacitating and prevents normal activities. Safety population = all participants who were enrolled and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of investigational product (IP) up to 90 days after the last dose of IP or at follow-up visit; the mean total duration of IP exposure was 52.8 days, 56.1 days and 50.8 days respectively for 0.5 mg, 1 mg ozanimod and placebo.
    End point values
    Placebo Ozanimod Hydrochloride 0.5mg Ozanimod Hydrochloride 1 mg
    Number of subjects analysed
    65
    65
    67
    Units: Participants
    number (not applicable)
        ≥ 1 TEAE
    21
    24
    17
        ≥ 1 Moderate or Severe TEAE
    7
    12
    6
        ≥ 1 Severe TEAE
    2
    1
    1
        ≥ 1 Possibly, Probably or Definitely Related TEAE
    2
    5
    5
        ≥ 1 Serious SAE
    4
    1
    2
        ≥ 1 Possibly, Probably or Related Serious TEAE
    0
    0
    0
        ≥ 1 TEAE Leading to Withdrawal From Study
    1
    2
    1
        Death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events During the Maintenance Period

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    End point title
    Number of Participants with Treatment Emergent Adverse Events During the Maintenance Period
    End point description
    A TEAE was defined as any event with an onset date on or after first dose date or any ongoing event on the first dose date that worsens in severity after first dose date and until 30 days following the last dose of treatment with the study drug. earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = an AE usually transient in nature and generally not interfering with normal activities; Moderate = an AE that is sufficiently discomforting to interfere with normal activities; Severe = an AE that is incapacitating and prevents normal activities. Safety population included all participants who were enrolled and received at least 1 dose of investigational product
    End point type
    Secondary
    End point timeframe
    From the first dose of IP up to 90 days after the last dose of IP or at follow-up visit; the mean total duration of IP exposure was 156.3 days, 171.1 days and 154.5 days respectively for 0.5 mg, 1 mg ozanimod and placebo.
    End point values
    Placebo Ozanimod 0.5 mg Ozanimod 1 mg
    Number of subjects analysed
    25
    36
    42
    Units: Participants
        ≥ 1 TEAE
    8
    4
    11
        ≥ 1 Moderate or Severe TEAE
    4
    1
    5
        ≥ 1 Severe TEAE
    1
    0
    1
        ≥ 1 Possibly, Probably or Definitely Related TEAE
    0
    0
    2
        ≥ 1 Serious TEAE
    2
    0
    1
        ≥ 1 Possibly, Probably or Related Serious TEAE
    0
    0
    0
        ≥ 1 TEAE Leading to Withdrawal From Study
    3
    0
    0
        Death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events During the Open-Label Treatment Period (OLP)

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    End point title
    Number of Participants with Treatment Emergent Adverse Events During the Open-Label Treatment Period (OLP)
    End point description
    A TEAE was defined as any event with an onset date on or after first dose date or any ongoing event on the first dose date that worsens in severity after first dose date and until 30 days following the last dose of treatment with the study drug. earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = an AE usually transient in nature and generally not interfering with normal activities; Moderate = an AE that is sufficiently discomforting to interfere with normal activities; Severe = an AE that is incapacitating and prevents normal activities. Safety population included all participants who were enrolled and received at least 1 dose of investigational product
    End point type
    Secondary
    End point timeframe
    From the first dose of IP until 90 days after the last dose of IP or at follow-up visit; the mean total duration of study drug exposure in the OLP was 2.42 years.
    End point values
    Open Label Treatment Period
    Number of subjects analysed
    170
    Units: Participants
        ≥ 1 TEAE
    101
        ≥ 1 Moderate or Severe TEAE
    63
        ≥ 1 Severe TEAE
    17
        ≥ 1 Possible, Probable or Related TEAE
    27
        ≥ 1 Related TEAE
    2
        ≥ 1 Serious TEAE
    27
        ≥ 1 Related Serious TEAE
    0
        ≥ 1 Possible, Probable or Related Serious TEAE
    4
        ≥ 1 TEAE Leading to Discontinuation of IP
    14
        ≥ 1 TEAE Leading to Withdrawal from Study
    13
        Death
    1
        Death Possible, Probable or Related to IP
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of IP up to 90 days after the last dose of IP or at follow-up visit; the mean total duration of IP exposure was 52.8 days, 56.1 days and 50.8 days respectively for 0.5 mg, 1 mg ozanimod and placebo during the induction period.
    Adverse event reporting additional description
    The mean total duration of study drug exposure was 156.3 days, 171.1 days and 154.5 days respectively for 0.5 mg, 1 mg ozanimod and placebo during the maintenance period and 2.42 years during the open label treatment period,
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Induction Period: Placebo
    Reporting group description
    Participants received identically matching placebo capsules daily for 9 weeks during the induction period (weeks 0 to 9)

    Reporting group title
    Induction Period: Ozanimod HCL 0.5 mg
    Reporting group description
    Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Reporting group title
    Induction Period: Ozanimod HCL 1 mg
    Reporting group description
    Participants received 1mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks.

    Reporting group title
    Maintenance Period: Placebo
    Reporting group description
    Participants originally assigned to placebo who completed the induction period and were responders at week 8 continued to receive placebo in the maintenance period. Participants received identically matching placebo capsules daily during the maintenance period (weeks 9-32).

    Reporting group title
    Maintenance Period: Ozanimod HCL 0.5 mg
    Reporting group description
    Participants originally assigned to ozanimod 0.5 mg who completed the induction period and were responders at week 8 continued to receive ozanimod 0.5 mg daily in the maintenance period. Participants received 0.5 mg ozanimod capsules daily during the maintenance period (weeks 9 to 32).

    Reporting group title
    Maintenance Period: Ozanimod HCL 1 mg
    Reporting group description
    Participants originally assigned to ozanimod 1 mg who completed the induction period and were responders at week 8 continued to receive ozanimod 0.5 mg daily in the maintenance period. Participants received 1 mg ozanimod capsules daily during the maintenance period (weeks 9 to 32).

    Reporting group title
    Open-Label Treatment Period (OLP): Placebo/Ozanimod
    Reporting group description
    Participants who received placebo capsules and completed the induction period and were non-responders at Week 8 and those who completed the maintenance period or experienced a disease relapse, were given the option to enter the open label treatment period (OLP) and receive 1 mg ozanimod daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study.

    Reporting group title
    OLP: Ozanimod 0.5 mg/Ozanimod 1 mg
    Reporting group description
    Participants who received ozanimod 0.5 mg capsules and completed the induction period and were non-responders at Week 8 and who completed the maintenance period or experienced a disease relapse, were given the option to enter the OLP and receive 1 mg ozaninod capsules daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study.

    Reporting group title
    OLP: Ozanimod 1mg/Ozanimod 1 mg
    Reporting group description
    Participants who received 1 mg ozanimod capsules and completed the induction period and were non-responders at Week 8 and those who completed the maintenance period or experienced a disease relapse, were given the option to enter the open label treatment period (OLP) and continue to receive 1 mg ozaninod daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study.

    Serious adverse events
    Induction Period: Placebo Induction Period: Ozanimod HCL 0.5 mg Induction Period: Ozanimod HCL 1 mg Maintenance Period: Placebo Maintenance Period: Ozanimod HCL 0.5 mg Maintenance Period: Ozanimod HCL 1 mg Open-Label Treatment Period (OLP): Placebo/Ozanimod OLP: Ozanimod 0.5 mg/Ozanimod 1 mg OLP: Ozanimod 1mg/Ozanimod 1 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 65 (1.54%)
    2 / 67 (2.99%)
    2 / 25 (8.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
    5 / 55 (9.09%)
    14 / 56 (25.00%)
    11 / 59 (18.64%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hyperpyrexia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pulmonary bulla
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary microemboli
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 65 (0.00%)
    2 / 67 (2.99%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    1 / 56 (1.79%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    Induction Period: Placebo Induction Period: Ozanimod HCL 0.5 mg Induction Period: Ozanimod HCL 1 mg Maintenance Period: Placebo Maintenance Period: Ozanimod HCL 0.5 mg Maintenance Period: Ozanimod HCL 1 mg Open-Label Treatment Period (OLP): Placebo/Ozanimod OLP: Ozanimod 0.5 mg/Ozanimod 1 mg OLP: Ozanimod 1mg/Ozanimod 1 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 65 (13.85%)
    8 / 65 (12.31%)
    8 / 67 (11.94%)
    3 / 25 (12.00%)
    2 / 36 (5.56%)
    2 / 42 (4.76%)
    19 / 55 (34.55%)
    17 / 56 (30.36%)
    22 / 59 (37.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    1 / 56 (1.79%)
    7 / 59 (11.86%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    1
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    2 / 67 (2.99%)
    0 / 25 (0.00%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
    1 / 55 (1.82%)
    2 / 56 (3.57%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    3
    2
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    3 / 56 (5.36%)
    5 / 59 (8.47%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    3
    7
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    3 / 56 (5.36%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 65 (6.15%)
    4 / 65 (6.15%)
    1 / 67 (1.49%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    4 / 55 (7.27%)
    3 / 56 (5.36%)
    0 / 59 (0.00%)
         occurrences all number
    4
    4
    1
    0
    0
    0
    9
    5
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 65 (0.00%)
    2 / 67 (2.99%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    1 / 56 (1.79%)
    3 / 59 (5.08%)
         occurrences all number
    3
    0
    2
    0
    0
    0
    3
    1
    3
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 65 (3.08%)
    0 / 67 (0.00%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
    4 / 55 (7.27%)
    0 / 56 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    1
    5
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 65 (1.54%)
    1 / 67 (1.49%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    1 / 56 (1.79%)
    4 / 59 (6.78%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    2
    1
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    4
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    3 / 56 (5.36%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    1
    3
    4
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 25 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    1 / 56 (1.79%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    1 / 25 (4.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    2 / 56 (3.57%)
    5 / 59 (8.47%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    4
    2
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2012
    • The limit on the proportion of patients that have previously received anti-TNF therapy anticipated to participate in the study has been increased from 35% to 50%. • The examination of the patient’s skin for lesions has been incorporated into the PE by the Investigator. If a skin lesion is identified the subject will be referred to a Dermatologist. • PFT are no longer required at screening, Week 8 and 20 and will not be performed unless new pulmonary/respiratory signs and symptoms are noted. PFT will be done at End of Study/ET on all patients. • All patients with clinically relevant pulmonary signs and symptom will be excluded from the study, unless it is found that the subject’s FEV1 and FVC were both > 70% of predicted value on pulmonary function testing during screening. • DLCO (diffusing capacity of the lung for carbon monoxide) has been removed from the PFT requirements. • OCT (Optical coherence tomography) will be required at Screening and at the End of Study/ET but an OCT at Week 8 has been removed. • Vedolizumab has been added to the list of medications that require a 4 month wash out. • Patients that were unresponsive to vedolizumab have been excluded from the study. • The protocol has been modified to more clarify windows allowed during dose titration. • The protocol has been modified to clarify the cardiac monitoring requirements and to clarify how the cardiac monitoring requirements will be modified once review of HR and Holter monitoring data from ongoing studies is complete and that review shows no notable HR or conduction abnormalities.
    08 Nov 2012
    • Increased the limit on the proportion of patients who had previously received anti-TNF therapy from 35% to 50% • Incorporated skin examinations into the physical examination by the Investigator with referrals to dermatologists as needed • Reduced the frequency of PFT and allowed for exceptions to DLCO testing • Excluded patients with clinically relevant pulmonary signs and symptoms unless the patient’s FEV1 and FVC were both > 70% of predicted values at Screening • Reduced frequency of OCT assessment • Added vedolizumab to the list of medications requiring a 4-month washout and excluded patients who were unresponsive to vedolizumab • Added WBC alert criteria and the corresponding actions that should be taken regarding stopping and restarting study drug
    05 Aug 2013
    • Divided the Induction Period into a dose titration period lasting from 8 to 15 days and an assigned dose treatment period of 8 weeks. Changed the length of the induction period from 8 weeks to 9-10 weeks depending on the length of the titration period. • Allowed patients who complete the Maintenance Period or who relapse during the Maintenance Period to participate in the Open-Label Period • Extended the Open-Label Period until the last patient who enters the Open-Label Period completed 20 weeks in the Open-Label Period • Allowed patients to participate who had past history of stable cardiac conditions, chronic hepatitis A or hepatitis E infection, or current well-controlled type 2 diabetes • Excluded patients who had failed to respond to anti- integrin therapies • Added an interim analysis to be completed after 50% of patients completed Week 8
    03 Feb 2014
    • Increased the upper limit of the eligible age range from ≤ 65 years to ≤ 75 years • Increased the allowed concomitant daily dose of prednisone from ≤ 20 mg to ≤ 30 mg • Allowed patients who failed to respond to anti-integrin agents to participate in the trial • Allow patients receiving azathioprine, 6-MP, or methotrexate at Screening to continue these medications until randomization • Removed the interim analysis and defined the levels of significance for the final analyses • Removed substrates and weak inhibitors of CYP3A4 from the list of prohibited concomitant medications • Removed cardiac monitoring during dose escalation on Days 5 and 8 unless a patient had experienced cardiac safety issues on Day 1
    23 Dec 2014
    • Increased the duration of the Open-Label Period to up to 6 years, or approximately December 2019, or until marketing approval • Added endoscopies and Mayo score calculation at 48- week intervals for patients who continue in the Open- Label Period past Week 8

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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