Primary Outcomes

Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Remission

Time: Week 12

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Description: Endoscopic response defined as decrease from Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD).

Measure: Percentage of Participants With Endoscopic Response

Time: Week 12

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Secondary Outcomes

Description: Clinical remission per average daily SF and average daily AP score.

Measure: Percentage of Participants With Clinical Remission

Time: Up to Week 12

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Response

Time: Up to Week 12

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Description: The FACIT-Fatigue is a validated tool that measures an individual's level of fatigue during their usual daily activities.

Measure: Change From Baseline of Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue

Time: Week 12

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Remission

Time: Week 4

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease. Endoscopic response defined as decrease from Baseline in SES-CD.

Measure: Percentage of Participants With CDAI Clinical Response and Endoscopic Response

Time: Week 12

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Description: SF remission is defined using the average daily SF, and not worse than baseline.

Measure: Percentage of Participants With Stool Frequency (SF) Remission

Time: Week 12

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Description: AP remission is defined using the average daily AP score, and not worse than baseline.

Measure: Percentage of Participants With Abdominal Pain (AP) Remission

Time: Week 12

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Description: Endoscopic remission is defined as decrease in SES-CD as compared to baseline

Measure: Percentage of Participants With Endoscopic Remission

Time: Week 12

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Description: Enhanced clinical response defined as decrease in average daily SF and/or decrease in average daily AP score, and/or clinical remission per average daily SF and average daily AP score.

Measure: Percentage of Participants With Enhanced Clinical Response

Time: Up to Week 12

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Description: Endoscopic healing was assessed using SES-CD.

Measure: Percentage of Participants With Ulcer-Free Endoscopy

Time: Week 12

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Description: Manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver.

Measure: Percentage of Participants With Resolution of Extra-Intestinal Manifestations (EIMs), in Participants With EIMs at Baseline

Time: Week 12

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Description: Participants with an event that results in admission to the hospital.

Measure: Percentage of Participants With CD-Related Hospitalization

Time: Up to Week 12

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Description: Participants without draining fistulas at Week 12 in participants who had draining fistulas at baseline.

Measure: Percentage of Participants Without Draining Fistulas in Participants With Draining Fistulas at Baseline

Time: Week 12

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Primary Outcomes

Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease. The CDAI clinical remission is defined as a CDAI score of < 150.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Remission

Time: Week 52

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Description: Endoscopic response defined as decrease from Baseline of the induction study in Simple Endoscopic Score for Crohn's Disease (SES-CD).

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Endoscopic Response

Time: Week 52

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Description: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent AEs are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section.

Measure: Sub-Study 3: Number of Participants With Adverse Events

Time: Up to Week 220

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Secondary Outcomes

Description: Clinical remission per average daily stool frequency (SF) and average daily AP score.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Clinical Remission

Time: Week 52

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With CDAI Clinical Remission Among Participants With CDAI Clinical Remission in Week 0

Time: Week 52

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Description: Endoscopic healing was assessed using SES-CD.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Ulcer-Free Endoscopy

Time: Week 52

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Description: Endoscopic Remission is defined as SES-CD <= 4 and at least a 2 point reduction versus baseline and no subscore greater than 1 in any individual variable, as scored by a central reviewer

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Endoscopic Remission

Time: Week 52

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Description: The FACIT-Fatigue is a validated tool that measures an individual's level of fatigue during their usual daily activities over the past week.

Measure: Sub-Study 1 and Sub-Study 2: Change From Baseline of Induction in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)

Time: Week 52

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Description: Participants who discontinued corticosteroid use and achieved clinical remission per average daily SF and average daily AP score.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants Who Discontinued Corticosteroid Use for 90 Days and Achieved Clinical Remission in Participants Taking Steroids at Baseline

Time: Week 52

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Response

Time: Week 52

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Description: SF Remission is defined by an average daily SF <= 2.8 and not worse than baseline.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Stool Frequency (SF) Remission

Time: Week 52

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Description: AP Remission is defined by an average daily AP <= 1 and not worse than baseline.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Abdominal Pain (AP) Remission

Time: Week 52

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease. The CDAI clinical remission is defined as a CDAI score of < 150. Endoscopic response defined as decrease from Baseline of the induction study in Simple Endoscopic Score for Crohn's Disease (SES-CD).

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With CDAI Clinical Remission and Endoscopic Response

Time: Week 52

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Description: Enhanced clinical response defined as decrease in average daily SF and/or decrease in average daily AP score, and/or clinical remission per average daily SF and average daily AP score.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Enhanced Clinical Response

Time: Week 52

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Description: Deep remission defined as subjects with both clinical remission (per average daily SF and average daily AP score) and endoscopic healing (assessed using SES-CD).

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Deep Remission

Time: Week 52

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Description: Manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Resolution of Extra-Intestinal Manifestations (EIMs) in Participants With Any EIMs at Baseline of Induction

Time: Week 52

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Description: Participants with an event that results in admission to the hospital.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With CD-Related Hospitalizations

Time: Up to Week 52

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Description: Participants without draining fistulas at Week 52 in subjects with draining fistulas at baseline of the induction study.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants Without Draining Fistulas in Participants With Draining Fistulas at Baseline of Induction

Time: Week 52

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Description: Participants who underwent surgery related to CD.

Measure: Sub-Study 1 and Sub-Study 2: Percentage of Participants With Crohn's Disease (CD)-Related Surgeries

Time: Up to Week 52

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Primary Outcomes

Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Remission

Time: Week 12

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Description: Endoscopic response defined as decrease from Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD).

Measure: Percentage of Participants With Endoscopic Response

Time: Week 12

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Secondary Outcomes

Description: Clinical remission per average daily stool frequency (SF) and average daily abdominal pain (AP) score.

Measure: Percentage of Participants With Clinical Remission

Time: Week 12

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Response

Time: Up to Week 12

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Description: The FACIT-Fatigue is a validated tool that measures an individual's level of fatigue during their usual daily activities.

Measure: Change From Baseline of Induction in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue

Time: Week 12

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease.

Measure: Percentage of Participants With Crohn's Disease Activity Index (CDAI) Clinical Remission

Time: Week 4

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Description: The CDAI is used to evaluate disease activity in patients with Crohn's disease. Endoscopic response defined as decrease from Baseline in SES-CD.

Measure: Percentage of Participants With CDAI Clinical Response and Endoscopic Response

Time: Week 12

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Description: SF remission is defined using the average daily SF, and not worse than baseline.

Measure: Percentage of Participants With Stool Frequency (SF) Remission

Time: Week 12

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Description: AP remission is defined using the average daily AP, and not worse than baseline.

Measure: Percentage of Participants With Abdominal Pain (AP) Remission

Time: Week 12

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Description: Endoscopic remission is defined as decrease in SES-CD as compared to baseline

Measure: Percentage of Participants With Endoscopic Remission

Time: Week 12

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Description: Enhanced clinical response defined as decrease in average daily SF and/or decrease in average daily AP score, and/or clinical remission per average daily SF and average daily AP score.

Measure: Percentage of Participants With Enhanced Clinical Response

Time: Up to Week 12

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Description: Endoscopic healing was assessed using SES-CD.

Measure: Percentage of Participants With Ulcer-Free Endoscopy

Time: Week 12

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Description: Manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver.

Measure: Percentage of Participants With Resolution of Extra-Intestinal Manifestations (EIMs), in Participants With EIMs at Baseline

Time: Week 12

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Description: Participants with an event that results in admission to the hospital.

Measure: Percentage of Participants With CD-Related Hospitalization

Time: Up to Week 12

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Description: Participants without draining fistulas at Week 12 in participants who had draining fistulas at baseline.

Measure: Percentage of Participants Without Draining Fistulas in Participants With Draining Fistulas at Baseline

Time: Week 12

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Primary Outcomes

Description: CDAI is defined as CDAI <150.

Measure: Sub-Study 1: Percentage of Participants with Clinical Remission per Crohn's Disease Activity Index (CDAI)

Time: Week 52

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Description: Endoscopic response is defined as decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from Baseline.

Measure: Sub-Study 1: Percentage of Participants with Endoscopic Response

Time: Week 52

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Description: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. For more details on adverse events please see the Adverse Event section.

Measure: Sub-Study 2: Number of Participants with Adverse Events

Time: Through Week 240

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Secondary Outcomes

Description: Clinical remission is defined based on average daily stool frequency (SF) AND average daily abdominal pain (AP) score.

Measure: Sub-Study 1: Percentage of Participants with Clinical Remission per Patient-Reported Outcomes (PROs)

Time: Week 52

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Description: Decrease of at least 100 points in CDAI from Baseline.

Measure: Sub-Study 1: Percentage of Participants Achieving Clinical Response 100 (CR-100)

Time: Week 52

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Description: Endoscopic remission is defined per Simplified Endoscopic Score for Crohn's Disease (SES-CD).

Measure: Sub-Study 1: Percentage of Participants with Endoscopic Remission

Time: Week 52

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Description: This is assessed in participants taking corticosteroids at Baseline. Clinical remission is defined based on average daily stool frequency (SF) AND average daily abdominal pain (AP) score.

Measure: Sub-Study 1: Percentage of Participants who Discontinue Corticosteroid Use for Crohn's Disease at Least 90 Days Prior to Week 52 and Achieve Clinical Remission, in Participants Taking Corticosteroids at Baseline.

Time: Week 52

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Description: CDAI is defined as CDAI <150. Endoscopic remission is defined per SES-CD.

Measure: Sub-Study 1: Percentage of Participants with Clinical Remission per CDAI and Endoscopic Remission

Time: Week 52

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Description: CDAI remission is defined as CDAI < 150.

Measure: Sub-Study 1: Percentage of Participants with Clinical Remission per Crohn's Disease Activity Index (CDAI)

Time: Through Week 52

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Description: The IBDQ is used to assess the quality of life of patients with inflammatory bowel disease.

Measure: Sub-Study 1: Change in Inflammatory Bowel Disease Questionnaire (IBDQ)

Time: Baseline (Week 0) to Week 52

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Description: The FACIT-F questionnaire was developed to assess fatigue.

Measure: Sub-Study 1: Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)

Time: Baseline (Week 0) to Week 52

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Description: This is assessed by reviewing participant's hospitalization data.

Measure: Sub-Study 1: Percentage of Participants with Hospitalizations due to Crohn's Disease (CD)

Time: Week 52

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Description: EIMs are defined as manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver.

Measure: Sub-Study 1: Percentage of Participants with Resolution of Extra-Intestinal Manifestation (EIMs) , in Participants with EIMs at Baseline

Time: Week 52

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Primary Outcomes

Description: Multiplex assay will be used to measure TNFα and downstream chemokines including CCL2, CCL4, CCL7, CXCL10 in breast milk of two groups of participants (women with IBD and healthy controls). (The unit of measurement is the same for all these cytokines)

Measure: Levels of TNFα and its downstream chemokines (CCL2, CCL4, CCL7, and CXCL10) in breast milk of women with IBD and healthy controls by Multiplex assay

Time: 4 years

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Secondary Outcomes

Description: ELISA assay will be used to measure total and free drug levels (bound and unbound to TNFα) in breast milk of lactating women with IBD. (The unit of measurement is the same for infliximab and adalimumab).

Measure: Milk concentration of TNFα inhibitors (infliximab, adalimumab) at different time-points between two doses of medication, in lactating women with IBD by ELISA assay

Time: 4 years

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Description: The infants of women with IBD and healthy controls will be examined for cognitive development using Bayley-III

Measure: Scores on cognitive subset of Bayley Scales of Infant and Toddler development- Third Version (Bayley-III) in infants of healthy controls and women with IBD

Time: 4 years

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Description: Infants of healthy controls and women with IBD will be examined for communication and problem-solving development using the ASQ®-3. This supplementary measure is intended to provide additional data as an alternative to Bayley test under unprecedented circumstances which preclude participants to complete Bayley test at the Hospital for Sick Children

Measure: Scores on the "Problem-solving" and "Communication" subscales of The Ages and Stages Questionnaire (ASQ®-3) in infants of healthy controls and women with IBD

Time: 4 years

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Description: An estimation of the population distribution of anti-TNFα antibodies (infliximab and adalimumab) in breast milk of women with IBD will be made, using population pharmacokinetic modelling

Measure: Simulated/predicted profiles of TNFα inhibitors (infliximab, adalimumab) in breast milk in a large population of lactating women with IBD by population pharmacokinetic modelling

Time: 4 years

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Primary Outcomes

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score < 150

Time: Week 12

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Secondary Outcomes

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary.

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline

Time: Week 12

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Description: The SES-CD assesses the degree of inflammation. The SES-CD assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing.

Measure: Proportion of subjects with a Simple Endoscopic Score for Crohn's Disease (SES-CD) score decrease from baseline of ≥ 50%

Time: Week 12

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Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150

Time: Week 12

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Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

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Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

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Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD ≤ 4 points and decrease ≥2 points at week 12

Time: Up to approximately week 12

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Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD decrease from baseline of ≥ 50% at week 12.

Time: Up to approximately week 12

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Description: Global Histologic Disease Activity score is a measure of histologic inflammation.

Measure: Histologic Improvement based on differences between ozanimod and placebo in histologic disease activity scores (ie, Global Histologic Disease Activity Score changes (Geboes, 2000)

Time: Week 12

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Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 70 points

Time: Week 12

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Description: Ulcer size will be measured during endoscopy, and assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with absence of ulcers ≥ 0.5 cm with no segment with any ulcerated surface ≥ 10%

Time: Week 12

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Description: The CDEIS assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with a Crohn's Disease Endoscopic Index of Severity (CDEIS) decrease from baseline of ≥ 50%

Time: Week 12

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Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical remission, defined as Pediatric Crohn's Disease Activity Index (PCDAI) ≤ 10 points at week 12

Time: Up to approximately week 12

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Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical response, defined as a decrease in PCDAI ≥ 15 points from baseline

Time: Up to approximately week 12

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Description: T and B cell panels consisting of Treg cells, naïve T and B cells, memory cells and plasmablasts are evaluated for assessment of immune status.

Measure: Assessment of circulating lymphocyte concentration

Time: Up to approximately week 12

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Description: Interferon signature are assessed in the blood and in colon biopsies to evaluate differences based on disease activity.

Measure: Assessment of gene expression

Time: Up to approximately week 12

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Description: Protein biomarkers such as high-density lipoprotein, C-reactive protein, fecal calprotectin, Immunoglobulin A (IgA) are measured in addition to assessing clinical endpoints to help evaluate disease activity.

Measure: Assessment of protein biomarker concentration

Time: Up to approximately week 12

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Description: Markers such as Interferon Regulatory Factor 5 are evaluated to better understand genetic variations that could lead to differences in response to Ozanimod.

Measure: Assessment of pharmacogenetics

Time: Up to approximately week 12

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Description: SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG) from serum samples are measured to support advancing the understanding of the impact of SARS-CoV-2 on ozanimod and Crohn's disease. It may also be used to support health authority requests for analysis and advancement of pharmacodiagnostic development to better target drugs to the right patients

Measure: Assessment of impact of SARS-CoV-2 serologic status on subjects receiving ozanimod and CD

Time: Up to approximately week 12

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Primary Outcomes

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score < 150

Time: Week 12

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Secondary Outcomes

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary.

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline

Time: Week 12

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Description: The SES-CD assesses the degree of inflammation. The SES-CD assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing.

Measure: Proportion of subjects with a Simple Endoscopic Score for Crohn's Disease (SES-CD) score decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

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Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD ≤ 4 points and decrease ≥2 points

Time: Up to approximately week 12

---

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 12

---

Description: Global Histologic Disease Activity score is a measure of histologic inflammation.

Measure: Histologic Improvement based on differences between ozanimod and placebo in histologic disease activity scores (ie, Global Histologic Disease Activity Score changes (Geboes, 2000)

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 70 points

Time: Week 12

---

Description: Ulcer size will be measured during endoscopy, and assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with absence of ulcers ≥ 0.5 cm with no segment with any ulcerated surface ≥ 10%

Time: Week 12

---

Description: The CDEIS assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with a Crohn's Disease Endoscopic Index of Severity (CDEIS) decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical remission, defined as Pediatric Crohn's Disease Activity Index (PCDAI) ≤ 10 points

Time: Up to approximately week 12

---

Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical response, defined as a decrease in PCDAI ≥ 15 points from baseline

Time: Up to approximately week 12

---

Description: T and B cell panels consisting of Treg cells, naïve T and B cells, memory cells and plasmablasts are evaluated for assessment of immune status.

Measure: Assessment of circulating lymphocyte concentration

Time: Up to approximately week 12

---

Description: Interferon signature are assessed in the blood and in colon biopsies to evaluate differences based on disease activity.

Measure: Assessment of gene expression

Time: Up to approximately week 12

---

Description: Protein biomarkers such as high-density lipoprotein, C-reactive protein, fecal calprotectin, Immunoglobulin A (IgA) are measured in addition to assessing clinical endpoints to help evaluate disease activity.

Measure: Assessment of protein biomarker concentration

Time: Up to approximately week 12

---

Description: Markers such as Interferon Regulatory Factor 5 are evaluated to better understand genetic variations that could lead to differences in response to Ozanimod.

Measure: Assessment of pharmacogenetics

Time: Up to approximately week 12

---

Description: SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG) from serum samples are measured to support advancing the understanding of the impact of SARS-CoV-2 on ozanimod and Crohn's disease. It may also be used to support health authority requests for analysis and advancement of pharmacodiagnostic development to better target drugs to the right patients

Measure: Assessment of impact of SARS-CoV-2 serologic status on subjects receiving ozanimod and CD

Time: Up to approximately week 12

---

Primary Outcomes

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score < 150

Time: Week 12

---

Secondary Outcomes

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary.

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline

Time: Week 12

---

Description: The SES-CD assesses the degree of inflammation. The SES-CD assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing.

Measure: Proportion of subjects with a Simple Endoscopic Score for Crohn's Disease (SES-CD) score decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease from baseline of ≥ 50%

Time: Week 12

---

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD ≤ 4 points and decrease ≥2 points

Time: Up to approximately week 12

---

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of inflammation.

Measure: Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points and both no worse than baseline AND an SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 12

---

Description: Global Histologic Disease Activity score is a measure of histologic inflammation.

Measure: Histologic Improvement based on differences between ozanimod and placebo in histologic disease activity scores (ie, Global Histologic Disease Activity Score changes (Geboes, 2000)

Time: Week 12

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 70 points

Time: Week 12

---

Description: Ulcer size will be measured during endoscopy, and assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with absence of ulcers ≥ 0.5 cm with no segment with any ulcerated surface ≥ 10%

Time: Week 12

---

Description: The CDEIS assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with a Crohn's Disease Endoscopic Index of Severity (CDEIS) decrease from baseline of ≥ 50%

Time: Week 12

---

Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical remission, defined as Pediatric Crohn's Disease Activity Index (PCDAI) ≤ 10 points

Time: Up to approximately week 12

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Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with clinical response, defined as a decrease in PCDAI ≥ 15 points from baseline

Time: Up to approximately week 12

---

Description: T and B cell panels consisting of Treg cells, naïve T and B cells, memory cells and plasmablasts are evaluated for assessment of immune status.

Measure: Assessment of circulating lymphocyte concentration

Time: Up to approximately week 12

---

Description: Interferon signature are assessed in the blood and in colon biopsies to evaluate differences based on disease activity.

Measure: Assessment of gene expression

Time: Up to approximately week 12

---

Description: Protein biomarkers such as high-density lipoprotein, C-reactive protein, fecal calprotectin, Immunoglobulin A (IgA) are measured in addition to assessing clinical endpoints to help evaluate disease activity.

Measure: Assessment of protein biomarker concentration

Time: Up to approximately week 12

---

Description: Markers such as Interferon Regulatory Factor 5 are evaluated to better understand genetic variations that could lead to differences in response to Ozanimod.

Measure: Assessment of pharmacogenetics

Time: Up to approximately week 12

---

Description: SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG) from serum samples are measured to support advancing the understanding of the impact of SARS-CoV-2 on ozanimod and Crohn's disease. It may also be used to support health authority requests for analysis and advancement of pharmacodiagnostic development to better target drugs to the right patients

Measure: Assessment of impact of SARS-CoV-2 serologic status on subjects receiving ozanimod and CD

Time: Up to approximately week 12

---

Primary Outcomes

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score of < 150

Time: Up to approximately week 52

---

Description: The SES-CD assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with a Simple Endoscopic Score for Crohn's Disease (SESCD) score decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Secondary Outcomes

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point and average daily stool frequency ≤ 3 points with abdominal pain and stool frequency no worse than baseline

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score of < 150

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score < 150 at Week 52, while remaining corticosteroid-free in the prior 12 weeks

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score of < 150 in subjects with a CDAI score < 150 at pre-randomization

Time: Up to approximately week 52

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Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD.

Measure: Proportion of subjects with a CDAI score of < 150 at Week 52 and at ≥ 80% of visits between Week 8 and Week 52, inclusive, in subjects with a CDAI score <150 at pre-randomization

Time: Up to approximately week 52

---

Description: Ulcer size will be measured during endoscopy, and assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with absence of ulcers ≥ 0.5 cm with no segment with any ulcerated surface ≥10%

Time: Up to approximately week 52

---

Description: Global Histologic Disease Activity score is a measure of histologic inflammation.

Measure: Histologic improvement based on differences between ozanimod and placebo in histologic disease activity scores (ie, Global Histologic Disease Activity Score [GHAS] changes (Geboes, 2000))

Time: Up to approximately week 52

---

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of endoscopic inflammation

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline and an SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with CDAI score of < 150 and SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Description: Abdominal pain scores and stool frequency scores are patient reported outcomes collected from the patient diary. The SES-CD assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline and an SES-CD ≤ 4 points and a SES-CD decrease ≥2 points

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Description: The Crohn's Disease Activity Index (CDAI) is a composite score that is used to measure the clinical activity of CD and the SES-CD assesses the degree of endoscopic inflammation

Measure: Proportion of subjects with CDAI reduction from baseline of ≥ 70 points

Time: Up to approximately week 52

---

Description: Global Histologic Disease Activity score is a measure of histologic inflammation

Measure: Proportion of subjects with mucosal healing (SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points) and histologic improvement by GHAS or Robarts Histologic Index (RHI)

Time: Up to approximately week 52

---

Description: Time to relapse is defined as an increase in the CDAI score from Maintenance Day 1 of ≥ 100 points and a CDAI score > 220, SES-CD score ≥ 6 [or ≥ 4 if isolated ileal disease.

Measure: Time to relapse and exclusion of other causes of an increase in disease activity unrelated to underlying CD (eg, infections, change in medication)

Time: Up to approximately week 52

---

Description: The CDEIS assesses the degree of endoscopic inflammation.

Measure: Proportion of subjects with a Crohn's Disease Endoscopic Index of Severity (CDEIS) decrease from baseline of ≥ 50%

Time: Up to approximately week 52

---

Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with Pediatric Crohn's Disease Activity Index (PCDAI) ≤ 10 points

Time: Up to approximately week 52

---

Description: The PCDAI is an instrument that was developed and validated for numerical assessment of disease activity in children and adolescents with CD (Hyams, 1991). The PCDAI includes subjective patient historical information, physical examination findings, objective laboratory parameters, data on weight gain/loss, and height velocity.

Measure: Proportion of adolescent subjects with decrease from baseline in PCDAI score ≥15 points

Time: Up to approximately week 52

---

Description: The IBDQ is a self-administered, 32-item questionnaire concerning 4 dimensions of quality of life (Hlavaty, 2006).

Measure: Change from baseline (Induction) in Inflammatory Bowel Disease Questionnaire (IBDQ) scores (adult subjects only)

Time: Up to approximately week 52

---

Description: The medical outcomes SF-36 questionnaire provides a measure of the subject's health status. The SF-36 consists of either scaled scores, which are the weighted sums of the questions in their section.

Measure: Change from baseline (Induction) in 36-Item Short Form-36 Survey (SF-36) scores (adult subjects only)

Time: Up to approximately week 52

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Description: The WPAI-CD (Reilly, 1993) is a validated, reliable and responsive instrument that assesses the impact of CD on work and activity during the past 7 days (Reilly, 2008).

Measure: Change from baseline (Induction) in Work Productivity and Activity Impairment questionnaire for Crohn's disease (WPAI-CD) scores (adult subjects only)

Time: Up to approximately week 52

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Description: The EQ-5D (The EuroQol Group, 1990) is a validated, 6-item, self-administered instrument designed to measure generic health status.

Measure: Change from baseline (Induction) in EuroQol 5 dimensions questionnaire (EQ-5D) scores

Time: Up to approximately week 52

---

Description: The PGIC scale evaluates all aspects of patient's health and assesses if there has been an improvement or decline in clinical status. The self-report measure PGIC reflects a patient's belief about the efficacy of treatment.

Measure: Patient Global Impression of Change (PGIC) scores (adult subjects only)

Time: Up to approximately week 52

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Description: Healthcare resource utilization will be evaluated in this study to assess the impact of CD and health-related outcomes (hospitalizations, emergency department or urgent care clinic visits, procedures, and physician visits).

Measure: Differences in CD-related hospitalizations, procedures, and surgery

Time: Up to approximately week 52

---

Description: T and B cell panels consisting of Treg cells, naïve T and B cells, memory cells and plasmablasts are evaluated for assessment of immune status.

Measure: Assessment of circulating lymphocyte concentration

Time: Up to approximately week 52

---

Description: Interferon signature are assessed in the blood and in colon biopsies to evaluate differences based on disease activity.

Measure: Assessment of gene expression

Time: Up to approximately week 52

---

Description: Protein biomarkers such as high-density lipoprotein, C-reactive protein, fecal calprotectin, Immunoglobulin A (IgA) are measured in addition to assessing clinical endpoints to help evaluate disease activity.

Measure: Assessment of protein biomarker concentration

Time: Up to approximately week 52

---

Description: Markers such as Interferon Regulatory Factor 5 are evaluated to better understand genetic variations that could lead to differences in response to Ozanimod.

Measure: Assessment of pharmacogenetics

Time: Up to approximately week 52

---

Description: SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG) from serum samples are measured to support advancing the understanding of the impact of SARS-CoV-2 on ozanimod and Crohn's disease. It may also be used to support health authority requests for analysis and advancement of pharmacodiagnostic development to better target drugs to the right patients

Measure: Assessment of impact of SARS-CoV-2 serologic status on subjects receiving ozanimod and CD

Time: Up to approximately week 52

---

Primary Outcomes

Description: Clinical remission is determined by meeting the criteria for remission using the 2-item patient reported outcome (PRO) subscores of average worst daily abdominal pain (based on 11 point numeric rating scale [NRS] ranging from 0 [No pain] to 10 [Worst imaginable pain]) and average daily stool frequency of type 6/7 as per the Bristol Stool Form Scale (BSFS) (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission at Week 16

Time: Week 16

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Description: Endoscopic response is measured by a decrease from baseline in simple endoscopic score for Crohn's disease (SES-CD) (ranging from 0 to 56, with higher values indicating more severe disease). Number of participants with endoscopic response will be reported.

Measure: Number of Participants With Endoscopic Response at Week 16

Time: Week 16

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Secondary Outcomes

Description: Clinical remission is defined by Crohn's Disease Activity Index CDAI score. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical remission as measured by CDAI will be reported.

Measure: Number of Participants With Clinical Remission as Measured by Crohn's Disease Activity Index (CDAI) at Week 16

Time: Week 16

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Description: Enhanced endoscopic response is measured by a decrease from baseline in SES-CD (range from 0 to 56, with higher values indicating more severe disease). Number of participants with enhanced endoscopic response will be reported.

Measure: Number of Participants With Enhanced Endoscopic Response at Week 16

Time: Week 16

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Description: Clinical remission is determined by meeting the criteria for clinical remission using the 2-item PRO subscores of average worst daily abdominal pain (based on the 4-point scale ranging from 0 = none to 3 = severe) and average daily stool frequency of type 6/7 (very soft stools/liquid stools) as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission by 2-item Patient Reported Outcome (PRO) at Week 16

Time: Week 16

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Description: Clinical response as per 2-item PRO score is to meet at least 1 of the 2 criteria over the 7 most recent days: 1. A decrease in the average daily abdominal pain based on 11-point NRS ranging 0 (No pain) to 10 (Worst imaginable pain), with stool frequency of type 6/7 (very soft/liquid stools) either: a) not worsening from baseline and/or b) meeting the criteria for clinical remission, that is based on the average daily stool frequency of type 6/7 as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]). 2. A decrease from baseline in the average daily stool frequency of type 6/7 as per the BSFS, with the average daily worst abdominal pain either: a) not worsening from baseline and/or b) meeting the criteria for clinical remission (based on average daily abdominal pain using a 11-point NRS). Number of participants with clinical response will be reported.

Measure: Number of Participants With Clinical Response at Week 16

Time: Week 16

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Description: Number of participants with both clinical remission by 2-item PRO as determined by meeting the criteria for clinical remission using the 2-item PRO subscores of average worst daily abdominal pain (based on the 4-point scale ranging from 0 = none to 3 = severe) and average daily stool frequency of type 6/7 (very soft stools/liquid stools) as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days and endoscopic response, as measured by a decrease in SES-CD (range from 0 to 56, with higher values indicating more severe disease).

Measure: Number of Participants With Clinical Remission and Endoscopic Response at Week 16

Time: Week 16

---

Description: Complete endoscopic healing at Week 16 as measured by SES-CD (ranging from 0 to 56, with higher values indicating more severe disease) will be assessed. Number of participants with complete endoscopic healing will be reported.

Measure: Number of Participants With Complete Endoscopic Healing at Week 16

Time: Week 16

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Description: Clinical response as measured by at least a 100-point reduction in the CDAI from baseline (CDAI-100 response) will be assessed. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical response CDAI -100 at Week 16 will be reported.

Measure: Number of Participants With Clinical Response as Measured by Crohn's Disease Activity Index (CDAI) -100 at Week 16

Time: Week 16

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Description: Clinical response as measured by at least a 70-point reduction in the CDAI from baseline (CDAI-70 response) will be assessed. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical response CDAI -70 at Week 16 will be reported.

Measure: Number of Participants With Clinical Response as Measured by Crohn's Disease Activity Index (CDAI) -70 at Week 16

Time: Week 16

---

Description: Clinical remission is determined by meeting the criteria for remission using the 2-item patient reported outcome (PRO) subscores of average worst daily abdominal pain (based on 11-point numeric rating scale [NRS] ranging from 0 [No pain] to 10 [Worst imaginable pain]) and average daily stool frequency of type 6/7 as per the Bristol Stool Form Scale (BSFS) (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission Over Time

Time: Baseline up to Week 16

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Description: Patient-reported CD clinical signs and symptom data will be collected using a daily e-diary. Participants record abdominal pain severity (numeric rating scale [NRS]), very soft stool/liquid stool frequency (as shown by BSFS [ranging from type 1 {separate hard lumps-like stools} to type 7 {entirely liquid stools}] type 6/7), total stool frequency, rectal bleeding frequency, rectal urgency frequency, nausea severity (none to severe), vomiting frequency, incontinence frequency, abdominal pain used in CDAI and general wellbeing (generally well to terrible).

Measure: Change From Baseline in Individual and Total Sign/Symptom Score Based on Participant Daily e-Diary Entries at Week 16

Time: Baseline, Week 16

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Description: Endoscopic healing at Week 16 measured as SES-CD (ranging from 0 to 56, with higher values indicating more severe disease) individual variables (Size of Ulcers, Ulcerated surface, Affected surface and Presence of Narrowing) will be assessed as well. Number of participants with endoscopic healing will be reported.

Measure: Number of Participants With Endoscopic Healing at Week 16

Time: Week 16

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Description: The IBDQ consists of 32 items grouped into 4 domains scored as bowel (10 to 70), systemic (5 to 35), emotional (12 to 84), and social function (5 to 35). The total score ranges from 32 to 224. For each domain and the total score, a higher score indicates better health-related quality of life

Measure: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total (Absolute) Score

Time: Baseline, Week 8, Week 12, up to Week 16, or early termination

---

Description: The Short form-36 health survey is used to assess HRQL. It consists of 36 items that are aggregated into 8 multi-item scales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role- emotional, and mental health), with scores ranging from 0 to 100. Higher scores indicate better HRQL.

Measure: Change From Baseline in Short Form (SF)-36 at Week 16

Time: Baseline, Week 16

---

Description: Incidence of all cause hospitalizations will be assessed.

Measure: Incidence of Hospitalizations

Time: Baseline up to Week 32

---

Description: Incidence of total inpatient days will be assessed.

Measure: Incidence of Total Inpatient Days

Time: Baseline up to Week 32

---

Description: Incidence of Crohn's disease-related surgeries and other surgical procedures.

Measure: Incidence of Crohn's Disease (CD)-related and Other Surgeries

Time: Baseline up to Week 32

---

Primary Outcomes

Description: Clinical remission is determined by meeting the criteria for remission using the 2-item patient reported outcome (PRO) subscores of average worst daily abdominal pain (based on 11 point numeric rating scale [NRS] ranging from 0 [No pain] to 10 [Worst imaginable pain]) and average daily stool frequency of type 6/7 as per the Bristol Stool Form Scale (BSFS) (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission at Week 16

Time: Week 16

---

Description: Endoscopic response is measured by a decrease from baseline in simple endoscopic score for Crohn's disease (SES-CD) (ranging from 0 to 56, with higher values indicating more severe disease). Number of participants with endoscopic response will be reported.

Measure: Number of Participants With Endoscopic Response at Week 16

Time: Week 16

---

Secondary Outcomes

Description: Clinical remission is defined by Crohn's Disease Activity Index CDAI score. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical remission as measured by CDAI will be reported.

Measure: Number of Participants With Clinical Remission as Measured by Crohn's Disease Activity Index (CDAI) at Week 16

Time: Week 16

---

Description: Enhanced endoscopic response is measured by a decrease from baseline in SES-CD (range from 0 to 56, with higher values indicating more severe disease). Number of participants with enhanced endoscopic response will be reported.

Measure: Number of Participants With Enhanced Endoscopic Response at Week 16

Time: Week 16

---

Description: Clinical remission is determined by meeting the criteria for clinical remission using the 2-item PRO subscores of average worst daily abdominal pain (based on the 4-point scale ranging from 0 = none to 3 = severe) and average daily stool frequency of type 6/7 (very soft stools/liquid stools) as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission by 2-item Patient Reported Outcome (PRO) at Week 16

Time: Week 16

---

Description: Clinical response as per 2-item PRO score is to meet at least 1 of the 2 criteria over the 7 most recent days: 1. A decrease in the average daily abdominal pain based on 11-point NRS ranging 0 (No pain) to 10 (Worst imaginable pain), with stool frequency of type 6/7 (very soft/liquid stools) either: a) not worsening from baseline and/or b) meeting the criteria for clinical remission, that is based on the average daily stool frequency of type 6/7 as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]). 2. A decrease from baseline in the average daily stool frequency of type 6/7 as per the BSFS, with the average daily worst abdominal pain either: a) not worsening from baseline and/or b) meeting the criteria for clinical remission (based on average daily abdominal pain using a 11-point NRS). Number of participants with clinical response will be reported.

Measure: Number of Participants With Clinical Response at Week 16

Time: Week 16

---

Description: Number of participants with both clinical remission by 2-item PRO as determined by meeting the criteria for clinical remission using the 2-item PRO subscores of average worst daily abdominal pain (based on the 4-point scale ranging from 0 = none to 3 = severe) and average daily stool frequency of type 6/7 (very soft stools/liquid stools) as per the BSFS (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days and endoscopic response, as measured by a decrease in SES-CD (range from 0 to 56, with higher values indicating more severe disease).

Measure: Number of Participants With Clinical Remission and Endoscopic Response at Week 16

Time: Week 16

---

Description: Complete endoscopic healing at Week 16 as measured by SES-CD (ranging from 0 to 56, with higher values indicating more severe disease) will be assessed. Number of participants with complete endoscopic healing will be reported.

Measure: Number of Participants With Complete Endoscopic Healing at Week 16

Time: Week 16

---

Description: Clinical response as measured by at least a 100-point reduction in the CDAI from baseline (CDAI-100 response) will be assessed. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical response CDAI -100 at Week 16 will be reported.

Measure: Number of Participants With Clinical Response as Measured by Crohn's Disease Activity Index (CDAI) -100 at Week 16

Time: Week 16

---

Description: Clinical response as measured by at least a 70-point reduction in the CDAI from baseline (CDAI-70 response) will be assessed. CDAI is used to assess CD which range from 0-149 points: Asymptomatic remission, 150-220 points: Mild to moderate active CD, 221-450 points: Moderate to severe active CD, >451 points: Severely active to fulminant disease. Number of participants with clinical response CDAI -70 at Week 16 will be reported.

Measure: Number of Participants With Clinical Response as Measured by Crohn's Disease Activity Index (CDAI) -70 at Week 16

Time: Week 16

---

Description: Clinical remission is determined by meeting the criteria for remission using the 2-item patient reported outcome (PRO) subscores of average worst daily abdominal pain (based on 11-point numeric rating scale [NRS] ranging from 0 [No pain] to 10 [Worst imaginable pain]) and average daily stool frequency of type 6/7 as per the Bristol Stool Form Scale (BSFS) (ranging from type 1 [separate hard lumps-like stools] to type 7 [entirely liquid stools]) over the 7 most recent days. Number of participants with clinical remission will be reported.

Measure: Number of Participants With Clinical Remission Over Time

Time: Baseline up to Week 16

---

Description: Patient-reported CD clinical signs and symptom data will be collected using a daily e-diary. Participants record abdominal pain severity (numeric rating scale [NRS]), very soft stool/liquid stool frequency (as shown by BSFS [ranging from type 1 {separate hard lumps-like stools} to type 7 {entirely liquid stools}] type 6/7), total stool frequency, rectal bleeding frequency, rectal urgency frequency, nausea severity (none to severe), vomiting frequency, incontinence frequency, abdominal pain used in CDAI and general wellbeing (generally well to terrible).

Measure: Change From Baseline in Individual and Total Sign/Symptom Score Based on Participant Daily e-Diary Entries at Week 16

Time: Baseline, Week 16

---

Description: Endoscopic healing at Week 16 measured as SES-CD (ranging from 0 to 56, with higher values indicating more severe disease) individual variables (Size of Ulcers, Ulcerated surface, Affected surface and Presence of Narrowing) will be assessed as well. Number of participants with endoscopic healing will be reported.

Measure: Number of Participants With Endoscopic Healing at Week 16

Time: Week 16

---

Description: The IBDQ consists of 32 items grouped into 4 domains scored as bowel (10 to 70), systemic (5 to 35), emotional (12 to 84), and social function (5 to 35). The total score ranges from 32 to 224. For each domain and the total score, a higher score indicates better health-related quality of life

Measure: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total (Absolute) Score

Time: Baseline, Week 8, Week 12, up to Week 16, or early termination

---

Description: The Short form-36 health survey is used to assess HRQL. It consists of 36 items that are aggregated into 8 multi-item scales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role- emotional, and mental health), with scores ranging from 0 to 100. Higher scores indicate better HRQL.

Measure: Change From Baseline in Short Form (SF)-36 at Week 16

Time: Baseline, Week 16

---

Description: Incidence of all cause hospitalizations will be assessed.

Measure: Incidence of Hospitalizations

Time: Baseline up to Week 32

---

Description: Incidence of total inpatient days will be assessed.

Measure: Incidence of Total Inpatient Days

Time: Baseline up to Week 32

---

Description: Incidence of Crohn's disease-related surgeries and other surgical procedures.

Measure: Incidence of Crohn's Disease (CD)-related and Other Surgeries

Time: Baseline up to Week 32

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Primary Outcomes

Description: Endoscopic recurrence is defined as a Rutgeerts' score greater than or equal to (>=) i2. The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The scale ranges from i0 to i4; where i0 equal to (=) no lesions, i1= less than or equal to (<=) 5 aphthous ulcers, i2= greater than (>) 5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis, i3= diffuse aphthous ileitis with diffusely inflamed mucosa and i4= diffuse inflammation with larger ulcers, nodules, and/or narrowing.

Measure: Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26

Time: Week 26

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Secondary Outcomes

Description: Stool samples will be collected for analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity.

Measure: Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30

Time: Weeks 3, 6, 12, 18, 26 and 30

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Measure: Ctrough: Observed Plasma Trough Concentrations of TAK-018

Time: Week 3 pre-dose and at multiple time points (up to 12 hours) post-dose

---

Primary Outcomes

Description: Covid-19 infection rates in cannabis users will be compared to rates in the general population. Our online questionnaire responses will compare infection rates of cannabis users in this study against the Johns Hopkins University Coronavirus Research Center data (https://coronavirus.jhu.edu).

Measure: Prevention of COVID-19

Time: Five years

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Description: Severity of persistent symptoms in cannabis users testing positive for active infection and/or antibodies will also be compared to the general population. Patients will answer the widely used FLU-PRO questionnaire, which asks about flu symptoms and severity, to capture diagnoses, symptoms, and medical interventions related to COVID-19. The data from cannabis user patients will be compared with national and international data surveys, such as the Covid Symptom Study (https://covid.joinzoe.com/us-2).

Measure: Treatment of COVID-19

Time: Five years

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Description: The primary objective is to assess the efficacy and safety of medical cannabis as medicine for treatment of chronic pain and other chronic debilitating diseases. Pain will be measured by Brief Pain Inventory (BPI) numeric scale. Change from baseline in BPI will be assessed at 3-month intervals. For prospective associations between cannabis use and outcomes, use of a lagged mixed-effects models will examine temporal associations between cannabis use and pain severity, opioid sparing, and patient satisfaction. Data will be analyzed from baseline and the annual follow-up waves.

Measure: Treatment of Symptoms

Time: Five years

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Secondary Outcomes

Description: Secondary objectives include evaluating increases or decreases in quality of life, and increases or decreases in concomitant opioid use. Satisfaction with treatment will be measured by a Visual Analog Score (VAS). Change From baseline in Satisfaction with treatment measured by (VAS) be assessed at 3-month intervals.

Measure: Cannabis Impact on Quality of Life

Time: Five years

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Description: Tertiary objectives will examine preferences for routes of administration, and preferences for THC / CBD ratios. Categorical factors will be summarized using frequencies and percentages, while continuous measure distributions will be described using means, standard deviations, and quartiles of interest.

Measure: Cannabis Route and Dosing

Time: Five years

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Description: Incidence of Treatment-Related Adverse Events will be measured by Physician Global Assessment (PGA) numeric scale. Number of participants with Treatment-Related Adverse Events will be assessed by CTCAE v4.0.

Measure: Monitoring Adverse Events

Time: Five years

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Primary Outcomes

Description: An AE is any untoward medical occurrence in a participant administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an AE with an onset that occurs after receiving study drug.

Measure: Percentage of Participants with at Least 1 Treatment-Emergent Adverse Event (TEAE)

Time: From administration of repeat dose up to 156 weeks post-repeat administration

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Description: An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Measure: Percentage of Participants with at Least 1 Treatment Emergent Serious Adverse Event (TESAE)

Time: From administration of repeat dose up to 156 weeks post-repeat administration

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Description: An SSR includes pregnancy, any case in which a pregnant participant is exposed to a study product or in which a female participant or female partner of a male participant becomes pregnant following treatment with a study product. Exposure is considered either through maternal exposure or via semen following paternal exposure or infant exposure from breast milk.

Measure: Percentage of Participants with Special Situation Reports (SSRs)

Time: From administration of repeat dose up to 156 weeks post-repeat administration

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Description: AESI includes immunogenicity/alloimmune reactions, hypersensitivity, transmission of infectious agents, tumorgenicity, ectopic tissue formation, medication errors.

Measure: Percentage of Participants with Adverse Event of Special Interest (AESI)

Time: From administration of repeat dose up to 156 weeks post-repeat administration

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Secondary Outcomes

Description: Combined remission is defined as the closure of all treated external openings that were draining at baseline (i.e., baseline visit), despite gentle finger compression and absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central magnetic resonance imaging (MRI) assessment.

Measure: Percentage of Participants who Achieve Combined Remission of Perianal Fistula(s)

Time: At Week 24 and at Week 156 post-repeat administration

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Description: Clinical remission is defined as closure of all treated external fistula openings that were draining at baseline despite gentle finger compression.

Measure: Percentage of Participants who Achieve Clinical Remission

Time: At Weeks 6, 24, 52, 104, and 156 post-repeat administration

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Description: Clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression.

Measure: Percentage of Participants who Achieve Clinical Response

Time: At Weeks 6, 24, 52, 104, and 156 post-repeat administration

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Description: Relapse is defined as reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed that were in the combined remission at Week 24 or the development of a collection >2 cm (in at least 2 dimensions) confirmed by centrally read MRI assessment.

Measure: Percentage of Participants with Relapse From Week 24 Combined Remission

Time: From Week 24 to Week 156 post-repeat administration

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Description: Time to Relapse is defined as the time in days to reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed, relative to Week 24.

Measure: Time to Relapse

Time: From Week 24 to the Day of relapse post-repeat administration

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Measure: Percentage of Participants with New Perianal Abscess in Treated Fistula

Time: Up to Week 156 post-repeat administration

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Description: The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) discharge; (b) pain; (c) restriction of sexual activity; (d) type of perianal disease; and (e) degree of induration. Each item is graded on a 5-point scale ranging from no symptoms (score of 0) to severe symptoms (score of 4) and total range of score is from 0 to 20. Higher score means more severe disease.

Measure: Change From Baseline in Score of Discharge and Pain Items of Perianal Disease Activity Index (PDAI) Score

Time: Baseline to Weeks 6, 24, 52, 104, and 156 post-repeat administration

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Primary Outcomes

Description: Maximum observed plasma concentration (Cmax) of Midazolam

Measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam

Time: Up to 71 Days

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Description: Time to maximum plasma concentration (Tmax) of Midazolam

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to time of the last measurable concentration

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Measurable Concentration (AUCt) of Midazolam

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to infinity

Measure: AUC From Time 0 to Infinity (AUCinf) of Midazolam

Time: Up to 71 Days

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Description: Terminal phase elimination rate constant (β) for Midazolam

Measure: Terminal Phase Elimination Rate Constant (β) of Midazolam

Time: Up to 71 Days

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Description: Terminal phase elimination half-life (t1/2) of Midazolam

Measure: Terminal Phase Elimination Half-Life (t1/2) of Midazolam

Time: Up to 71 Days

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Description: Maximum observed plasma concentration (Cmax) of Caffeine

Measure: Maximum Observed Plasma Concentration (Cmax) of Caffeine

Time: Up to 71 Days

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Description: Time to maximum plasma concentration (Tmax) of Caffeine

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of Caffeine

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to time of the last measurable concentration

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Measurable Concentration (AUCt) of Caffeine

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to infinity

Measure: AUC From Time 0 to Infinity (AUCinf) of Caffeine

Time: Up to 71 Days

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Description: Terminal phase elimination rate constant (β) for Caffeine

Measure: Terminal Phase Elimination Rate Constant (β) of Caffeine

Time: Up to 71 Days

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Description: Terminal phase elimination half-life (t1/2) of Caffeine

Measure: Terminal Phase Elimination Half-Life (t1/2) of Caffeine

Time: Up to 71 Days

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Description: Maximum observed plasma concentration (Cmax) of Warfarin

Measure: Maximum Observed Plasma Concentration (Cmax) of Warfarin

Time: Up to 71 Days

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Description: Time to maximum plasma concentration (Tmax) of Warfarin

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of Warfarin

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to time of the last measurable concentration

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Measurable Concentration (AUCt) of Warfarin

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to infinity

Measure: AUC From Time 0 to Infinity (AUCinf) of Warfarin

Time: Up to 71 Days

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Description: Terminal phase elimination rate constant (β) for Warfarin

Measure: Terminal Phase Elimination Rate Constant (β) of Warfarin

Time: Up to 71 Days

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Description: Terminal phase elimination half-life (t1/2) of Warfarin

Measure: Terminal Phase Elimination Half-Life (t1/2) of Warfarin

Time: Up to 71 Days

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Description: Maximum observed plasma concentration (Cmax) of Omeprazole

Measure: Maximum Observed Plasma Concentration (Cmax) of Omeprazole

Time: Up to 71 Days

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Description: Time to maximum plasma concentration (Tmax) of Omeprazole

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of Omeprazole

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to time of the last measurable concentration

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Measurable Concentration (AUCt) of Omeprazole

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to infinity

Measure: AUC From Time 0 to Infinity (AUCinf) of Omeprazole

Time: Up to 71 Days

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Description: Terminal phase elimination rate constant (β) for Omeprazole

Measure: Terminal Phase Elimination Rate Constant (β) of Omeprazole

Time: Up to 71 Days

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Description: Terminal phase elimination half-life (t1/2) of Omeprazole

Measure: Terminal Phase Elimination Half-Life (t1/2) of Omeprazole

Time: Up to 71 Days

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Description: Maximum observed plasma concentration (Cmax) of Metoprolol

Measure: Maximum Observed Plasma Concentration (Cmax) of Metoprolol

Time: Up to 71 Days

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Description: Time to maximum plasma concentration (Tmax) of Metoprolol

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of Metoprolol

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to time of the last measurable concentration

Measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Measurable Concentration (AUCt) of Metoprolol

Time: Up to 71 Days

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Description: Area Under the Plasma Concentration-time Curve (AUC) from time 0 to infinity

Measure: AUC From Time 0 to Infinity (AUCinf) of Metoprolol

Time: Up to 71 Days

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Description: Terminal phase elimination rate constant (β) for Metoprolol

Measure: Terminal Phase Elimination Rate Constant (β) of Metoprolol

Time: Up to 71 Days

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Description: Terminal phase elimination half-life (t1/2) of Metoprolol

Measure: Terminal Phase Elimination Half-Life (t1/2) of Metoprolol

Time: Up to 71 Days

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