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    Clinical Trial Results:
    Induction Study #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active Crohn's Disease

    Summary
    EudraCT number
    		 2017-004293-33
    Trial protocol
    		 HU   SK   LT   DE   FR   SI   AT   BG   GR   ES   SE   NL   PL   PT   FI  
    Global end of trial date
    21 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2024
    First version publication date
    27 Nov 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RPC01-3202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03440385
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium,
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@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
    18 Mar 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study to explore the effect of oral ozanimod as an induction treatment for participants with moderately to severely active Crohn's Disease.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Georgia: 54
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Ukraine: 84
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    China: 64
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    South Africa: 2
    Worldwide total number of subjects
    606
    EEA total number of subjects
    184
    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)
    571
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled in 26 countries.

    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
    		 Ozanimod
    Arm description
    		 Participants with moderate to severe acute Crohn's disease were administered Ozanimod capsule orally. Participants were administered 0.23 milligram (mg) of Ozanimod capsule (daily) from Day 1 to Day 4 followed by 0.46 mg of Ozanimod (2 capsules of 0.23 mg daily) from Day 5 to Day 7 followed by 0.92 mg of Ozanimod capsule (daily) from Day 8 to Week 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ozanimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.92 mg capsule

    Arm title
    		 Placebo
    Arm description
    		 Participants with moderate to severely active Crohn's disease were orally administered Placebo (daily) from Day 1 to Week 12.
    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
    Administered as capsule

    Number of subjects in period 1
    		Ozanimod Placebo
    Started
    403
    203
    Completed
    360
    183
    Not completed
    43
    20
         Consent withdrawn by subject
    12
    6
         Site Closed
    1
    -
         Adverse event, non-fatal
    15
    11
         Other Reason
    4
    1
         Lost to follow-up
    2
    -
         Lack of efficacy
    9
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Ozanimod
    Reporting group description
    		 Participants with moderate to severe acute Crohn's disease were administered Ozanimod capsule orally. Participants were administered 0.23 milligram (mg) of Ozanimod capsule (daily) from Day 1 to Day 4 followed by 0.46 mg of Ozanimod (2 capsules of 0.23 mg daily) from Day 5 to Day 7 followed by 0.92 mg of Ozanimod capsule (daily) from Day 8 to Week 12.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants with moderate to severely active Crohn's disease were orally administered Placebo (daily) from Day 1 to Week 12.

    Reporting group values
    		 Ozanimod Placebo Total
    Number of subjects
    		 403 203 606
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 378 193 571
        From 65-84 years
    		 25 10 35
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.8 ( 13.69 ) 37.7 ( 13.79 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 182 90 272
        Male
    		 221 113 334
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 12 25
        Not Hispanic or Latino
    		 378 188 566
        Unknown or Not Reported
    		 12 3 15
    Race/Ethnicity, Customized
    Units: Subjects
        WHITE
    		 329 166 495
        BLACK OR AFRICAN AMERICAN
    		 7 1 8
        AMERICAN INDIAN OR ALASKA NATIVE
    		 1 0 1
        ASIAN
    		 47 29 76
        NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER
    		 1 0 1
        OTHER
    		 8 4 12
        NOT REPORTED
    		 10 3 13

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Ozanimod
    Reporting group description
    		 Participants with moderate to severe acute Crohn's disease were administered Ozanimod capsule orally. Participants were administered 0.23 milligram (mg) of Ozanimod capsule (daily) from Day 1 to Day 4 followed by 0.46 mg of Ozanimod (2 capsules of 0.23 mg daily) from Day 5 to Day 7 followed by 0.92 mg of Ozanimod capsule (daily) from Day 8 to Week 12.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants with moderate to severely active Crohn's disease were orally administered Placebo (daily) from Day 1 to Week 12.

    Primary: Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score < 150

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    End point title
    		 Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score < 150
    End point description
    The CDAI is a composite score that is used to measure the clinical activity of Crohn's disease (CD). The CDAI uses a questionnaire with 8 disease activity variables: number of soft/liquid stools, severity of abdominal pain, general well-being, presence of complications, need for antidiarrheal drugs, presence of an abdominal mass, hematocrit, and deviation in body weight. The sub scores of number of soft/liquid stool, severity of abdominal pain (0 [none] to 3 [Severe]), general well-being (0 [well] to 4 [terrible] were summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    29.8
    30.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8125
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.39

    Secondary: Percentage of Participants with Abdominal Pain and Stool Frequency Clinical Remission

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    End point title
    		 Percentage of Participants with Abdominal Pain and Stool Frequency Clinical Remission
    End point description
    Abdominal pain and stool frequency clinical remission was defined as average daily abdominal pain score ≤ 1 point, and average daily stool frequency ≤ 3 times with abdominal pain and stool frequency no worse than baseline at Week 12. Participants entered the responses in diaries daily. The 7 days entries prior to Week 12 visit were considered for calculating average abdominal pain score and stool frequency. The abdominal pain was graded on severity of 0 (none) to 3 (severe) scale and stool frequency was defined number of liquid or soft stools per day. Baseline was defined as the last assessment prior to the start time of the first drug administration if time of measurement is available else the last assessment prior to or on the date of the first drug administration.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    29.0
    26.6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.54
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.66

    Secondary: Percentage of Participants with a Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score Decrease from Baseline of ≥ 50%

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    End point title
    		 Percentage of Participants with a Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score Decrease from Baseline of ≥ 50%
    End point description
    The SES-CD assessed the degree of inflammation. The SES-CD assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing. Each of these components was scored on a scale of 0 (none/unaffected) to 3 (worst). In the SES-CD, each of these 4 components are assessed in the five segments: ileum, right colon, transverse colon, left colon, and rectum. The SES-CD was the sum of the individual scores of each of the components across the five segments. The range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for the overall SES-CD score, with larger scores indicating greater degree of inflammation. Baseline was defined as the last assessment prior to the start time of the first drug administration if time of measurement is available else the last assessment prior to or on the date of the first drug administration.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    25.6
    21.2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2411
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.95

    Secondary: Percentage of Participants with Reduction from Baseline in the Crohn's Disease Activity Index (CDAI) score of >= 100 points or a total CDAI score < 150

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    End point title
    		 Percentage of Participants with Reduction from Baseline in the Crohn's Disease Activity Index (CDAI) score of >= 100 points or a total CDAI score < 150
    End point description
    The CDAI is a composite score that is used to measure the clinical activity of Crohn's disease (CD). The CDAI uses a questionnaire with 8 disease activity variables: number of soft/liquid stools, severity of abdominal pain, general well-being, presence of complications, need for antidiarrheal drugs, presence of an abdominal mass, hematocrit, and deviation in body weight. The sub scores of number of soft/liquid stool, severity of abdominal pain (0 [none] to 3 [Severe]), general well-being (0 [well] to 4 [terrible] were summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Baseline was defined as the last assessment prior to the start time of the first drug administration if time of measurement is available else the last assessment prior to or on the date of the first drug administration.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    46.2
    47.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7469
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.34

    Secondary: Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score Reduction from Baseline of ≥ 100 points or CDAI score < 150 and SES-CD Decrease from Baseline of ≥ 50%

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    End point title
    		 Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score Reduction from Baseline of ≥ 100 points or CDAI score < 150 and SES-CD Decrease from Baseline of ≥ 50%
    End point description
    CDAI include 8 components number of soft/liquid stools, severity of abdominal pain, wellbeing, complications, need antidiarrheal drugs, abdominal mass, hematocrit, deviation in body wt. Subscores of numbers of soft/liquid stool, severity of abdominal pain (0 [none] to 3 [Severe]), general well-being (0 [well] to 4 [terrible] were summed over the 7 days prior to visit. The others weighted to create the total CDAI score ranging 0-600 with higher score indicating worse outcome. The SES-CD has 4 components size of ulcers, ulcerated surface, affected surface, presence of narrowing. Each component was scored on scale of 0 (none) to 3 (worst). In SES-CD, each of 4 components are assessed in the five segments: ileum, right, transverse, left colon, and rectum. The SES-CD was the sum of the individual scores of each of the components across the five segments. The range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for overall, with larger scores show greater degree of inflammation.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    16.9
    14.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4255
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.97

    Secondary: Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score < 150 and Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score Decrease from Baseline of ≥ 50%

    		 Close Top of page
    End point title
    		 Percentage of Participants with Crohn's Disease Activity Index (CDAI) Score < 150 and Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score Decrease from Baseline of ≥ 50%
    End point description
    CDAI include 8 components number of soft/liquid stools, severity of abdominal pain, wellbeing, complications, need antidiarrheal drugs, abdominal mass, hematocrit, deviation in body wt. Subscores of numbers of soft/liquid stool, severity of abdominal pain (0 [none] to 3 [Severe]), general well-being (0 [well] to 4 [terrible] were summed over the 7 days prior to visit. The others weighted to create the total CDAI score ranging 0-600 with higher score indicating worse outcome. The SES-CD has 4 components size of ulcers, ulcerated surface, affected surface, presence of narrowing. Each component was scored on scale of 0 (none) to 3 (worst). In SES-CD, each of 4 components are assessed in the five segments: ileum, right, transverse, left colon, and rectum. The SES-CD was the sum of the individual scores of each of the components across the five segments. The range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for overall, with larger scores show greater degree of inflammation.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    11.7
    11.3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9313
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.76

    Secondary: Percentage of Participants with Abdominal Pain and Stool Frequency Clinical Remission and a Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score <= 4 Points and Decrease >= 2 Points

    		 Close Top of page
    End point title
    		 Percentage of Participants with Abdominal Pain and Stool Frequency Clinical Remission and a Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score <= 4 Points and Decrease >= 2 Points
    End point description
    Abdominal pain (AP) and stool frequency (SF) clinical remission was defined as average daily abdominal pain score ≤ 1 point, and average daily stool frequency ≤ 3 times with AP and SF no worse than baseline at Week 12. Participants entered responses in diaries daily. The 7 days entries prior to visit were considered for calculating average AP score and SF. The AP was graded on severity of 0 (none) to 3 (severe) scale and SF was defined number of liquid or soft stools per day. The SES-CD has 4 components size of ulcers, ulcerated surface, affected surface, presence of narrowing. Each component was scored on scale of 0 (none) to 3 (worst). In SES-CD, each of 4 components are assessed in the five segments: ileum, right, transverse, left colon, and rectum. The SES-CD was the sum of the individual scores of each of the components across the five segments. The range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for overall, with larger scores show greater degree of inflammation.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    10.4
    8.4
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4339
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.31

    Secondary: Percentage of Participants with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) Decrease from Baseline of ≥ 50%

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    End point title
    		 Percentage of Participants with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) Decrease from Baseline of ≥ 50%
    End point description
    CDEIS is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon. The CDEIS divides the intestine into 5 segments: rectum, sigmoid and left colon, transverse colon, right colon, and ileum. Four variables are assessed in each segment: the presence of deep ulceration, the presence of superficial ulceration, the percentage of ulcerated surface, and the percentage of surface affected by CD, indicated on 10-cm visual analogue scales. In addition, the presence of ulcerated stenosis and the presence of nonulcerated stenosis are also assessed over the entire intestine. These factors are weighted and summed to calculate the total score ranging from 0- 44, with higher scores indicating more severe disease.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    27.5
    21.7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1187
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.11

    Secondary: Percentage of Participants with CDAI Reduction from Baseline of >=70 points

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    End point title
    		 Percentage of Participants with CDAI Reduction from Baseline of >=70 points
    End point description
    The CDAI is a composite score that is used to measure the clinical activity of Crohn's disease (CD). The CDAI uses a questionnaire with 8 disease activity variables: number of soft/liquid stools, severity of abdominal pain, general well-being, presence of complications, need for antidiarrheal drugs, presence of an abdominal mass, hematocrit, and deviation in body weight. The sub scores of number of soft/liquid stool, severity of abdominal pain (0 [none] to 3 [Severe]), general well-being (0 [well] to 4 [terrible] were summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Baseline was defined as the last assessment prior to the start time of the first drug administration if time of measurement is available else the last assessment prior to or on the date of the first drug administration.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    52.9
    51.7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.82
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.47

    Secondary: Percentage of Participants with Absence of Ulcers ≥ 0.5 cm with no Segment with any Ulcerated Surface ≥10%

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    End point title
    		 Percentage of Participants with Absence of Ulcers ≥ 0.5 cm with no Segment with any Ulcerated Surface ≥10%
    End point description
    The ulcerated surface were assessed via endoscopy.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of partiicpants
        number (not applicable)
    25.3
    24.1
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6906
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.59

    Secondary: Percentage of Participants with Abdominal Pain (AP) and Stool Frequency (SF) Clinical Remission and an Endoscopic (50%) Response

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    End point title
    		 Percentage of Participants with Abdominal Pain (AP) and Stool Frequency (SF) Clinical Remission and an Endoscopic (50%) Response
    End point description
    AP and SF clinical remission is average daily abdominal pain score ≤ 1 point, and average daily stool frequency ≤ 3 times with AP and SF no worse than baseline at Week 12. Participants entered responses in diaries daily. The 7 days entries prior to visit were considered for calculating average AP score and SF. AP was graded on severity of 0 (none) to 3 (severe) scale and SF was defined number of liquid or soft stools per day. SES-CD has 4 components size of ulcers, ulcerated surface, affected surface, presence of narrowing. Each component was scored on scale of 0 (none) to 3 (worst). Endoscopic Response is defined as >= 50% decrease from baseline in SES-CD. In SES-CD, each of 4 components are assessed in five segments: ileum, right, transverse, left colon, and rectum. The SES-CD was sum of individual scores of each of components across five segments. Range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for overall, with larger scores show greater degree of inflammation.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of particpants
        number (not applicable)
    11.7
    9.4
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.403
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.26

    Secondary: Percentage of Participants with Global Histologic Activity Score (GHAS) Remission

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    End point title
    		 Percentage of Participants with Global Histologic Activity Score (GHAS) Remission
    End point description
    GHAS assesses the inflammation and mucosal damage. GHAS has 8 components Epithelial damage, Architectural changes, Infiltration of mononuclear cells in the lamina propria, Infiltration of polymorphonuclear cells in the lamina propria, Polymorphonuclear cells in epithelium, Presence of erosion and/or ulcers, Presence of granuloma and number of biopsy specimens affected. Each of these components was scored on a scale of 0 (none/unaffected) to 2 (worst). Each of these 8 components are assessed in the five segments: ileum, right colon, transverse colon, left colon, and rectum. Within each segment, the GHAS score has a range of 0 – 16, and the total GHAS score has a range of 0 – 80. Higher numbers correspond to more inflammation and more mucosal damage. Baseline was defined as the last assessment prior to the start time of the first drug administration if time of measurement is available else the last assessment prior to or on the date of the first drug administration.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    13.6
    10.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.333
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.2

    Secondary: Percentage of Participants with Robarts Histologic Index (RHI) Mucosal Healing at Week 12

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    End point title
    		 Percentage of Participants with Robarts Histologic Index (RHI) Mucosal Healing at Week 12
    End point description
    RHI mucosal healing was defined as RHI remission combined with SES-CD <= 4 points and a SES-CD decrease from baseline >= 2 points with no SES-CD sub-score >1 point. RHI Remission is defined as no active inflammation in any measured segment. The SES-CD assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing. Each of these components was scored on a scale of 0 (none/unaffected) to 3 (worst). In the SES-CD, each of these 4 components are assessed in the five segments: ileum, right colon, transverse colon, left colon, and rectum. The SES-CD was the sum of the individual scores of each of the components across the five segments. The range of SES-CD scores was 0 - 12 for each segment, and 0 - 60 for the overall SES-CD score, with larger scores indicating greater degree of inflammation.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Ozanimod Placebo
    Number of subjects analysed
    403
    203
    Units: percentage of participants
        number (not applicable)
    4.0
    4.9
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ozanimod v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.563 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.78
    Notes
    [1] - Odds ratio, and p-value are obtained using the CMH test stratified by corticosteroid use at baseline (yes or no), and prior biologic use (yes or no).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality, non serious adverse events and serious adverse events were collected from the first dose and up to approximately 31 weeks.
    Adverse event reporting additional description
    Treated population include all the participants who were treated with at least one dose of study drug. 1 participant earlier randomized or pre-assigned to Placebo arm in error received Ozanimod
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants with moderate to severely active Crohn's disease were orally administered Placebo (daily) from Day 1 to Week 12.

    Reporting group title
    Ozanimod 0.92 mg
    Reporting group description
    		 Participants with moderate to severe acute Crohn's disease were administered Ozanimod capsule orally. Participants were administered 0.23 milligram (mg) of Ozanimod capsule (daily) from Day 1 to Day 4 followed by 0.46 mg of Ozanimod (2 capsules of 0.23 mg daily) from Day 5 to Day 7 followed by 0.92 mg of Ozanimod capsule (daily) from Day 8 to Week 12.

    Serious adverse events
    		 Placebo Ozanimod 0.92 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 202 (5.45%)
    24 / 404 (5.94%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    6 / 202 (2.97%)
    10 / 404 (2.48%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 202 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 202 (0.00%)
    4 / 404 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis enteropathic
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ozanimod 0.92 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 202 (5.45%)
    15 / 404 (3.71%)
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    11 / 202 (5.45%)
    15 / 404 (3.71%)
         occurrences all number
    13
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2017
    The CDEIS is being introduced as an additional secondary endpoint because it is an established endoscopic measure. A change has been made to provide further guidance to investigators on the management of subjects with symptomatic bradycardia, including a reference to local guidelines.
    18 Jun 2018
    Exploratory endpoints updated
    10 Jun 2019
    Revisions to reflect the addition of adolescent subjects. Change to safety follow up from 75 days to 90-day (±10 days) Safety Follow-up Visit to ensure adequate collection of adverse events that could be associated with investigational drug.
    03 Sep 2020
    Adjustment of Sample Size, Refinement of Per-Protocol Population, Update Summary of Clinical Studies in Inflammatory Bowel Disease (IBD), Exploratory, Endoscopic Remission Endpoint, and Exclusion criteria was updated
    14 Jan 2021
    Removal of Adolescent Subjects

    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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