A Study Evaluating the Efficacy and Safety of Oral Etrasimod in the Treatment of Adult Participants With Moderately to Severely Active Crohn's Disease

Clinical remission was considered as CDAI score <150. CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT: 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease.

SES-CD consisted of a composite score based on 4 components: size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed in 5 bowel segments: ileum; right; transverse; left colon and rectum. Size of ulcers score: 0= none, 1= aphthous ulcers, 2= large ulcers and 3= very large ulcers. Ulcerated surface score: 0= none, 1= <10%, 2= 10% - 30% and 3= >30%. Affected surface score: 0= unaffected segment, 1= <50%, 2= 50% - 75%, and 3= >75%. Presence of narrowing score: 0= none, 1= single, can be passed, 2= multiple, can be passed, 3= cannot be passed. Total SES-CD= sum of each component score for all 5 bowel segments and ranged from 0 (no disease) to 60 (severe disease), higher score indicated more severe disease.

CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT: 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease.

The plasma concentration of etrasimod at 4 hours post-dose has been reported in this outcome measure.

The average steady-state Ctrough for Week 2 through 14 was calculated based on individual Ctrough data from Week 2, Week 6 and Week 14.

Clinical remission was considered as CDAI score <150. CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT: 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease. MI method was used; percentage was calculated based on average response rate from MI datasets.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. MI method was used; percentage was calculated based on average response rate from MI datasets.

Clinical remission was CDAI score <150. CDAI was a composite index consisting of weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT: 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score: sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores= more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

Clinical remission was CDAI score <150. CDAI was a composite index consisting of weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT: 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score: sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores= more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from parent study (SS1) baseline in SES-CD. SES-CD= composite score based on 4 components: size of ulcers, ulcerated surface, affected surface, presence of narrowing in 5 segments: ileum; right; transverse; left colon; rectum. Size of ulcers score: 0=none,1= aphthous ulcers, 2= large ulcers, 3= very large ulcers. Ulcerated surface score: 0= none,1= <10%, 2= 10%-30%, 3= >30%. Affected surface score: 0= unaffected segment, 1= <50%, 2= 50%-75%,3= >75%. Presence of narrowing score: 0= none,1= single, can be passed, 2= multiple can be passed, 3= can't be passed. Total SES CD=sum of component scores for 5 bowel segments and ranged from 0 (no disease) - 60 (severe disease), higher score indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to FMD date.

Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from parent study (SS1) baseline in SES-CD. SES-CD= composite score based on 4 components: size of ulcers, ulcerated surface, affected surface, presence of narrowing in 5 segments: ileum; right; transverse; left colon; rectum. Size of ulcers score: 0=none,1= aphthous ulcers, 2= large ulcers, 3= very large ulcers. Ulcerated surface score: 0= none,1= <10%, 2= 10%-30%, 3= >30%. Affected surface score: 0= unaffected segment, 1= <50%, 2= 50%-75%,3= >75%. Presence of narrowing score: 0= none,1= single, can be passed, 2= multiple can be passed, 3= can't be passed. Total SES CD=sum of component scores for 5 bowel segments and ranged from 0 (no disease) - 60 (severe disease), higher score indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to FMD date.

Corticosteroid-free remission: CDAI score <150 without receiving corticosteroids for >=8 weeks prior to Week 52 (for participants receiving corticosteroids at baseline). CDAI: composite index consisting of weighted scoring of 8 disease activity variables: number of liquid stools; extent of abdominal pain from 0 (none)-3 (severe); general well-being from 0 (generally well)-4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of abdominal mass (0=none, 2=questionable, 5=definite); HCT 47 in men and 42 in women; percentage deviation from standard weight, lower bound -10. Total CDAI score=sum of variable scores*weighting factor and was from 0 (no disease)-600 (severe disease), higher score indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

Corticosteroid-free remission: CDAI score <150 without receiving corticosteroids for >=8 weeks prior to Week 52 (for participants receiving corticosteroids at baseline). CDAI: composite index consisting of weighted scoring of 8 disease activity variables: number of liquid stools; extent of abdominal pain from 0 (none)-3 (severe); general well-being from 0 (generally well)-4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of abdominal mass (0=none, 2=questionable, 5=definite); HCT 47 in men and 42 in women; percentage deviation from standard weight, lower bound -10. Total CDAI score=sum of variable scores*weighting factor and was from 0 (no disease)-600 (severe disease), higher score indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

Endoscopic remission: SES-CD score <=4 and at least 2-point reduction from baseline with no sub-score >1. SES-CD consisted of a composite score based on 4 components: size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed in 5 segments: ileum; right; transverse; left colon and rectum. Size of ulcers score: 0=none, 1=aphthous ulcers, 2=large ulcers and 3=very large ulcers. Ulcerated surface score: 0= none, 1= <10%, 2= 10% - 30% and 3= >30%. Affected surface score: 0= unaffected segment, 1= <50%, 2= 50% - 75%, and 3= >75%. Presence of narrowing score: 0=none, 1= single, can be passed, 2=multiple, can be passed, 3= cannot be passed. Total SES CD=sum of each component score for all 5 bowel segments and ranged from 0 (no disease)-60 (severe disease), higher score indicated more severe disease.

Endoscopic remission: SES-CD score <=4 and at least 2-point reduction from baseline with no sub-score >1. SES-CD consisted of a composite score based on 4 components: size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed in 5 segments: ileum; right; transverse; left colon and rectum. Size of ulcers score: 0=none, 1=aphthous ulcers, 2=large ulcers and 3=very large ulcers. Ulcerated surface score: 0= none, 1= <10%, 2= 10% - 30% and 3= >30%. Affected surface score: 0= unaffected segment, 1= <50%, 2= 50% - 75%, and 3= >75%. Presence of narrowing score: 0=none, 1= single, can be passed, 2=multiple, can be passed, 3= cannot be passed. Total SES CD=sum of each component score for all 5 bowel segments and ranged from 0 (no disease)-60 (severe disease), higher score indicated more severe disease.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain.

Clinical response: clinical remission CDAI or >=100-point decrease from baseline in CDAI score where, clinical remission CDAI=CDAI <150. CDAI: composite index consisting of weighted scoring of 8 disease activity variables. Total CDAI: sum of variable scores*weighting factor and ranged from 0 (no disease) - 600 (severe disease), higher scores indicated more severe disease. Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from baseline in SES-CD. SES-CD comprised of 4 components assessed for 5 bowel segments. Each component score ranged from 0-3, higher scores indicated more severe condition. Total SES CD: sum of each component score of 5 bowel segments and ranged from 0 (no D) - 60 (severe disease), higher score indicated more severe disease. Percentage of participants with clinical response or endoscopic response at Week 52 is reported.

Clinical response: clinical remission CDAI or >=100-point decrease from baseline in CDAI score where, clinical remission CDAI=CDAI <150. CDAI: composite index consisting of weighted scoring of 8 disease activity variables. Total CDAI: sum of variable scores*weighting factor and ranged from 0 (no disease) - 600 (severe disease), higher scores indicated more severe disease. Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from baseline in SES-CD. SES-CD comprised of 4 components assessed for 5 bowel segments. Each component score ranged from 0-3, higher scores indicated more severe condition. Total SES CD: sum of each component score of 5 bowel segments and ranged from 0 (no D) - 60 (severe disease), higher score indicated more severe disease. Percentage of participants with clinical response or endoscopic response at Week 52 is reported.

CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease. SS3 Baseline was last non-missing measurement taken prior to date of FMD of SS3.

Clinical Response was clinical remission by CDAI or >=100-point decrease from baseline in CDAI score where, clinical remission CDAI= CDAI <150. CDAI: composite index consisting of weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none)-3 (severe); general well-being rating assessed from 0 (generally well) - 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide/opiates for diarrhea; presence of an abdominal mass (0=none, 2=questionable, 5=definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score= sum of variable scores*weighting factor and ranged from 0 (no disease) - 600 (severe disease), where higher scores indicated more severe disease. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

Clinical Response was clinical remission by CDAI or >=100-point decrease from baseline in CDAI score where, clinical remission CDAI= CDAI <150. CDAI: composite index consisting of weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none)-3 (severe); general well-being rating assessed from 0 (generally well) - 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide/opiates for diarrhea; presence of an abdominal mass (0=none, 2=questionable, 5=definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score= sum of variable scores*weighting factor and ranged from 0 (no disease) - 600 (severe disease), where higher scores indicated more severe disease. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

The CD-PRO was a validated instrument designed to assess the signs, symptoms, and impact of CD through 6 modules: Systemic Symptoms, Coping Strategies, Daily Life Impact, Emotional Impact, Bowel Signs and Symptoms and Functional Symptoms. Each module ranged from 0 to 16, where higher scores indicated more severe disease. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The CD-PRO was a validated instrument designed to assess the signs, symptoms, and impact of CD through 6 modules: Systemic Symptoms, Coping Strategies, Daily Life Impact, Emotional Impact, Bowel Signs and Symptoms and Functional Symptoms. Each module ranged from 0 to 16, where higher scores indicated more severe disease. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The IBDQ was a validated 32 item questionnaire used to assess health related quality of life in participants with IBD. Response to each of the questions ranged from 1 to 7 where higher scores indicated better quality of life. The total IBDQ scores were calculated as sum of individual item scores and ranged from 32 (very poor health-related quality of life) to 224 (perfect health-related quality of life) where higher scores indicated better quality of life. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The IBDQ was a validated 32 item questionnaire used to assess health related quality of life in participants with IBD. Response to each of the questions ranged from 1 to 7 where higher scores indicated better quality of life. The total IBDQ scores were calculated as sum of individual item scores and ranged from 32 (very poor health-related quality of life) to 224 (perfect health-related quality of life) where higher scores indicated better quality of life. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The SF-36 was a health-related survey that assessed participant's health status and consisted of 36 questions measuring 8 health domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social function and vitality. The 8 domains are combined to form 2 component scores mental (MCS) and physical (PCS). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain was scored by summing the individual items and transforming the total SF-36 scores into a 0 to 100 scale with higher scores indicating better health status. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

The SF-36 was a health-related survey that assessed participant's health status and consisted of 36 questions measuring 8 health domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social function and vitality. The 8 domains are combined to form 2 component scores MCS and PCS. MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain was scored by summing the individual items and transforming the total SF-36 scores into a 0 to 100 scale with higher scores indicating better health status. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

The FACIT-F was a participant completed questionnaire consisting of 13 items that assess fatigue. Participants responded to each item on a 5-point scale based on their experience of fatigue during the past 7 days (0 = not at all; 1 = a little bit; 2 =somewhat; 3 = quite a bit; 4 = very much). Instrument scoring yielded a total FACIT-F score range from 0 to 52 (negatively worded items were reversed during analysis), with higher scores representing better participant status (less fatigue). SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

The FACIT-F was a participant completed questionnaire consisting of 13 items that assess fatigue. Participants responded to each item on a 5-point scale based on their experience of fatigue during the past 7 days (0 = not at all; 1 = a little bit; 2 =somewhat; 3 = quite a bit; 4 = very much). Instrument scoring yielded a total FACIT-F score range from 0 to 52 (negatively worded items were reversed during analysis), with higher scores representing better participant status (less fatigue). SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. SS3 Baseline was defined as last non-missing measurement taken prior to date of FMD of SS3.

Time to remission by PRO2 and FCP concentrations was defined as time to onset of clinical remission by PRO2 and FCP normalization. Clinical remission by PRO2 was defined as PRO2 score <8. Normalization of FCP was defined as FCP <=150 milligrams per kilogram. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Participants who did not achieve remission or discontinued from study were censored at 7 days after last dose of study drug.

Time to remission by PRO2 and FCP concentrations was defined as time to onset of clinical remission by PRO2 and FCP normalization. Clinical remission by PRO2 was defined as PRO2 score <8. Normalization of FCP was defined as FCP <=150 milligrams per kilogram. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Participants who did not achieve remission or discontinued from study were censored at 7 days after last dose of study drug.

Time to response by PRO2 and FCP concentrations: time to onset of PRO2 response and FCP normalization. Clinical response by PRO2: clinical remission by PRO2 or >= 8-point decrease from baseline in PRO2 score. Clinical remission by PRO2: PRO2 score <8. Normalization of FCP: FCP <=150 milligrams per kilogram. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Participants who did not achieve response or discontinued from study were censored at 7 days after last dose of study drug.

Time to response by PRO2 and FCP concentrations: time to onset of PRO2 response and FCP normalization. Clinical response by PRO2: clinical remission by PRO2 or >= 8-point decrease from baseline in PRO2 score. Clinical remission by PRO2: PRO2 score <8. Normalization of FCP: FCP <=150 milligrams per kilogram. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Participants who did not achieve response or discontinued from study were censored at 7 days after last dose of study drug.

SES-CD was an endoscopic grading system which consisted of composite score based on 4 components: size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed in 5 segments: ileum; right; transverse; left colon and rectum. Size of ulcers score: 0= none, 1= aphthous ulcers, 2=large ulcers and 3=very large ulcers. Ulcerated surface score: 0=none, 1= <10%, 2= 10% - 30% and 3= >30%. Affected surface score: 0=unaffected segment, 1= <50%, 2= 50% - 75%, and 3= >75%. Presence of narrowing score: 0=none, 1=single, can be passed, 2=multiple can be passed, 3=cannot be passed. Total SES CD= sum of each component score for all 5 bowel segments and ranged from 0 (no disease)-60 (severe disease), higher score indicated more severe disease. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

SES-CD was an endoscopic grading system which consisted of composite score based on 4 components: size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed in 5 segments: ileum; right; transverse; left colon and rectum. Size of ulcers score: 0= none, 1= aphthous ulcers, 2=large ulcers and 3=very large ulcers. Ulcerated surface score: 0=none, 1= <10%, 2= 10% - 30% and 3= >30%. Affected surface score: 0=unaffected segment, 1= <50%, 2= 50% - 75%, and 3= >75%. Presence of narrowing score: 0=none, 1=single, can be passed, 2=multiple can be passed, 3=cannot be passed. Total SES CD= sum of each component score for all 5 bowel segments and ranged from 0 (no disease)-60 (severe disease), higher score indicated more severe disease. SS3 Baseline= last non-missing measurement taken prior to date of FMD of SS3.

Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from parent study (SS1) baseline in SES-CD. SES-CD had 4 components assessed for 5 bowel segments where, each component score ranged from 0 to 3, higher scores=more severe condition. Total SES CD score was determined by sum of each component score for all 5 bowel segments and ranged from 0-60, higher score=more severe disease. Clinical remission by PRO2: PRO2 score <8. PRO2 was patient-reported outcome measure based on abdominal pain and stool frequency components of CDAI. Abdominal pain graded from 0 (none)-3 (severe) each day for 7 days. Stool frequency was number of liquid or soft stools each day for 7 days. Total PRO2 score calculated as sum of averaged abdominal pain/stool frequency variable scores*weighting factor. PRO2 score had minimum score of 0 and had no upper bound, with higher score indicating more frequent stools and more severe abdominal pain.

Endoscopic response: SES-CD score <=4 and at least 2-point reduction from baseline with no subscore >1 or >=50% decrease from parent study (SS1) baseline in SES-CD. SES-CD had 4 components assessed for 5 bowel segments where, each component score ranged from 0 to 3, higher scores=more severe condition. Total SES CD score was determined by sum of each component score for all 5 bowel segments and ranged from 0-60, higher score=more severe disease. Clinical remission by PRO2: PRO2 score <8. PRO2 was patient-reported outcome measure based on abdominal pain and stool frequency components of CDAI. Abdominal pain graded from 0 (none)-3 (severe) each day for 7 days. Stool frequency was number of liquid or soft stools each day for 7 days. Total PRO2 score calculated as sum of averaged abdominal pain/stool frequency variable scores*weighting factor. PRO2 score had minimum score of 0 and had no upper bound, with higher score indicating more frequent stools and more severe abdominal pain.

Endoscopic remission: SES-CD <=4 and at least 2-point reduction from baseline with no sub-score >1. SES-CD comprised of 4 components assessed for 5 bowel segments where, each component score ranged from 0 to 3, higher scores indicated more severe condition. Total SES CD score was determined by sum of each component score for all 5 bowel segments and ranged from 0 to 60, higher score indicated more severe disease. Clinical remission by PRO2 was defined as PRO2 score <8. PRO2 was patient-reported outcome measure based on abdominal pain and stool frequency components of CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. Stool frequency was number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as sum of averaged abdominal pain/stool frequency variable scores*weighting factor. PRO2 score had a minimum score of 0 and had no upper bound, with higher score indicating more frequent stools and more severe abdominal pain.

Endoscopic remission: SES-CD <=4 and at least 2-point reduction from baseline with no sub-score >1. SES-CD comprised of 4 components assessed for 5 bowel segments where, each component score ranged from 0 to 3, higher scores indicated more severe condition. Total SES CD score was determined by sum of each component score for all 5 bowel segments and ranged from 0 to 60, higher score indicated more severe disease. Clinical remission by PRO2 was defined as PRO2 score <8. PRO2 was patient-reported outcome measure based on abdominal pain and stool frequency components of CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. Stool frequency was number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as sum of averaged abdominal pain/stool frequency variable scores*weighting factor. PRO2 score had a minimum score of 0 and had no upper bound, with higher score indicating more frequent stools and more severe abdominal pain.

Pre-defined markedly abnormal criteria for ECG parameters included: QT interval: >500 (milliseconds [msec]); change from SS4 baseline >30 msec and change from SS4 baseline >60 msec. QT interval corrected using Fridericia's formula (QTcF) (msec): >=450 (male) or >=470 (female) msec; change from SS4 baseline >30 msec; change from SS4 baseline >60 msec. PR interval (msec): >230 msec. Only those ECG parameters in which at least 1 participant in any of the reporting arm had markedly abnormal criteria are reported in this outcome measure. SS4 Baseline was defined as the last non-missing measurement taken up to the date of first dose in the SS4.

AE: any untoward medical occurrence that did not necessarily have a causal relationship with treatment. SAE: an AE that met one of the following criteria: resulted in death; was life-threatening; required inpatient or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect or medically significant. AEs were graded by the National Cancer Institute Common Terminology Criteria for AE version 5 where, Grade(G) 1: mild AE; G2: moderate; G3: severe; G4: life-threatening consequences, urgent intervention indicated; G5: death related to AE. AE was considered TEAE if it started or worsened in severity on or after the first dose of study treatment. Treatment related AEs were AEs that were related to the study treatment and relatedness was judged by investigator.

The TEAEs of special interest included: cardiovascular events (bradycardia, atrioventricular [AV] conduction delay, and hypertension); macular edema; pulmonary disorders (airflow obstruction [forced expiratory volume in 1 second, and forced vital capacity], decreased gas exchange [diffusing capacity of the lung for carbon monoxide]); infections (severe infections, opportunistic infections, and herpes simplex and herpes zoster); liver injury (liver transaminases elevation, and bilirubin elevation); posterior reversible encephalopathy syndrome; and malignancies. Number of participants with any TEAEs of special interest were reported in this outcome measure.

Clinically meaningful laboratory abnormalities:Hemoglobin, Hematocrit, Erythrocytes (<0.8*LLN); Ery. Volume, Hemoglobin,Mean Corpuscular HGB Concentration <0.8*LLN or >1.5*LLN;Reticulocytes, Leukocytes, Lymphocytes, Neutrophils, Neutrophils, Basophils, Eosinophils, Monocytes (>1.2*ULN), Prothrombin Time(>1.1*ULN).Clinical Chemistry: Bilirubin, Direct Bilirubin, Indirect Bilirubin (1.5*ULN), Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase (>3.0*ULN); Albumin, Urate (<0.8*LLN and >1.2*ULN; Urea Nitrogen,Creatinine Cholesterol >1.3*ULN; Cholesterol <0.8*LLN or >1.2*LLN, Triglycerides,Potassium,Calcium < 0.9x LLN \& >1.1x ULN; Bicarbonate, Glucose, Creatine Kinase. Urinalysis: Glucose, Ketones, Protein, Hemoglobin, Urobilinogen, Bilirubin, Nitrite >=1; Leukocyte Erythrocytes, Leukocytes >=20; Epithelial Cells>=6, Hyaline Cast>1; Bacteria>20. Number of participants with any laboratory abnormality meeting specified criteria is included.

AE: any untoward medical occurrence that did not necessarily have a causal relationship with treatment. SAE: an AE that met one of the following criteria: resulted in death; was life-threatening; required inpatient or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect or medically significant. AEs were graded by the National Cancer Institute Common Terminology Criteria for AE version 5 where, G1: mild AE; G2: moderate; G3: severe; G4: life-threatening consequences, urgent intervention indicated; G5: death related to AE. AE was considered TEAE if it started or worsened in severity on or after the first dose of study treatment. Treatment related AEs were AEs that were related to the study treatment and relatedness was judged by investigator.

The TEAEs of special interest included: cardiovascular events (bradycardia, AV conduction delay, and hypertension); macular edema; pulmonary disorders (airflow obstruction [forced expiratory volume in 1 second, and forced vital capacity], decreased gas exchange [diffusing capacity of the lung for carbon monoxide]); infections (severe infections, opportunistic infections, and herpes simplex and herpes zoster); liver injury (liver transaminases elevation, and bilirubin elevation); posterior reversible encephalopathy syndrome; and malignancies. Number of participants with any TEAEs of special interest were reported in this outcome measure.

Clinically meaningful laboratory abnormalities:Hemoglobin, Hematocrit, Erythrocytes (<0.8*LLN); Ery. Volume, Hemoglobin,Mean Corpuscular HGB Concentration <0.8*LLN or >1.5*LLN;Reticulocytes, Leukocytes, Lymphocytes, Neutrophils, Neutrophils, Basophils, Eosinophils, Monocytes (>1.2*ULN), Prothrombin Time(>1.1*ULN).Clinical Chemistry: Bilirubin, Direct Bilirubin, Indirect Bilirubin (1.5*ULN), Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase (>3.0*ULN); Albumin, Urate (<0.8*LLN and >1.2*ULN; Urea Nitrogen,Creatinine Cholesterol >1.3*ULN; Cholesterol <0.8*LLN or >1.2*LLN, Triglycerides,Potassium,Calcium < 0.9x LLN \& >1.1x ULN; Bicarbonate, Glucose, Creatine Kinase. Urinalysis: Glucose, Ketones, Protein, Hemoglobin, Urobilinogen, Bilirubin, Nitrite >=1; Leukocyte Erythrocytes, Leukocytes >=20; Epithelial Cells>=6, Hyaline Cast>1; Bacteria>20. Number of participants with any laboratory abnormality meeting specified criteria is included.

Pre-defined markedly abnormal criteria for vital signs included: Systolic blood pressure (millimeters of mercury [mmHg]): low: <=90 mmHg and high: >150 mmHg. Diastolic blood pressure (mmHg): low: <=50 mmHg and high: >90 mmHg. Heart rate (beats per minute [bpm]): low: <40 bpm, <50 bpm and high: >100 bpm. Only those vital signs parameters in which at least 1 participant in any of the reporting arm had markedly abnormal criteria are reported in this outcome measure. SS4 baseline=the last non-missing measurement taken up to the date of first dose in the SS4.

Clinical remission was considered as CDAI score <150. CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease.

Clinical Response was defined as having clinical remission CDAI or >=100-point decrease from baseline in CDAI score where, clinical remission was considered as CDAI <150. CDAI was a composite index consisting of a weighted scoring of 8 disease activity variables: number of liquid or soft stools; extent of abdominal pain graded from 0 (none) to 3 (severe); general well-being rating assessed from 0 (generally well) to 4 (terrible); presence of complications; taking diphenoxylate/atropine, loperamide or opiates for diarrhea; presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); HCT 47 in men and 42 in women and percentage deviation from standard weight, lower bound -10. Total CDAI score was calculated as the sum of variable scores*weighting factor and ranged from 0 (no disease) to 600 (severe disease), where higher scores indicated more severe disease.

Clinical remission was defined as PRO2 score <8. The PRO2 was a patient-reported outcome measure based on abdominal pain and stool frequency components of the CDAI. The abdominal pain rating was graded from 0 (none) to 3 (severe) each day for 7 days. The stool frequency was defined as number of liquid or soft stools each day for 7 days. Total PRO2 score was calculated as the sum of averaged abdominal pain/stool frequency variable scores*weighting factor. The PRO2 score had a minimum score of 0 and had no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain.