Crohn's Disease
Conditions
Keywords
Etrasimod, Crohn's disease, APD334, Inflammatory bowel disease
Brief summary
This is a Phase 2/3 study that comprises 5 substudies designed to evaluate the efficacy, safety, and tolerability of oral etrasimod as therapy in adult participants with moderately to severely active Crohn's disease (CD) who are refractory or intolerant to at least 1 of the current therapies for CD (ie, corticosteroids, immunosuppressants, or biologics). The overall duration of this study is up to 282 weeks, inclusive of the Screening Period, Treatment Period of up to 274 weeks (Induction, Extension or Maintenance, and Long-term Extension Periods), and the 4-Week Follow-Up Period for safety assessment.
Detailed description
This study includes 5 substudies: Substudy A - Phase 2: A Phase 2, randomized, double-blind, substudy to assess the safety, tolerability, and efficacy of oral etrasimod therapy in participants with moderate to severe CD that supports the selection of an induction and maintenance dose(s) for Phase 3. Substudy 1 - Phase 2: A Phase 2b randomized, double-blind, placebo-controlled, dose-ranging induction substudy to evaluate etrasimod as induction therapy and select an induction and maintenance dose(s) for continued evaluation in Phase 3. Substudy 2 - Induction: A Phase 3 randomized, double-blind, placebo-controlled substudy to evaluate etrasimod as induction therapy. Substudy 3 - Maintenance: A Phase 3 randomized, double-blind, placebo-controlled substudy to evaluate etrasimod as maintenance therapy. Participants from Substudy 1 and Substudy 2 will be enrolled in Substudy 3. Substudy 4 - Long-Term Extension: A long-term extension substudy for participants who complete at least 52 weeks of treatment. Participants from Substudy 3 and Substudy A are planned to be enrolled in Substudy 4.
Interventions
DRUGEtrasimod
Dose A taken by mouth, once daily.
DRUGPlacebo
Etrasimod matching placebo tablet taken by mouth, once daily.
Sponsors
Pfizer
Arena is a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Eligibility criteria applicable to all substudies: Inclusion Criteria: * Men or women 18 to 80 years of age, * Ability to provide written informed consent or assent and to be compliant with the schedule of protocol assessments * Diagnosed with Crohn's disease (CD) ≥ 3 months * Have moderately to severely active CD at Screening * Demonstrated inadequate response (ie, primary non-response), loss of response to, or intolerance to ≥ 1 of the following therapies for the treatment of CD: 1. Oral corticosteroids (eg, prednisone or its equivalent, budesonide) 2. Immunosuppressants (eg, azathioprine \[AZA\], 6 mercaptopurine \[6-MP\], or methotrexate \[MTX\]) 3. Tumor necrosis factor alpha (TNFα) antagonists (eg, infliximab, adalimumab, certolizumab pegol, or biosimilars) 4. Integrin receptor antagonist (eg, vedolizumab) 5. Interleukin -12/-23 antagonist (eg, ustekinumab) * Females of childbearing potential must be nonpregnant * Females of childbearing potential and males must use contraception
Exclusion criteria
* History of inadequate response (ie, primary non-response) to agents from ≥ 2 classes of biologics marketed for the treatment of CD (ie, TNFα antagonists, interleukin 12/ 23 antagonist, and integrin receptor antagonist). * Have ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, diverticular disease associated colitis, toxic megacolon, or active infectious colitis or test positive for Clostridioides difficile toxin at Screening. * Have functional or post-operative short-bowel syndrome or any associated complications that may require surgery or interfere with efficacy assessments * Had surgical treatment for intra abdominal abscesses ≤ 8 weeks prior to randomization or surgical treatment for perianal abscesses ≤ 4 weeks prior to randomization. * Had intestinal resection ≤ 24 weeks prior to randomization or other intra abdominal surgeries ≤ 12 weeks prior to randomization. * Have an ileostomy or a colostomy. Inclusion Criteria for Substudy 3: \- Participants who entered the Extended Induction Period of Substudy 1 and Substudy 2 must have completed the Extended Induction -Week 6 Visit Inclusion Criteria for Substudy 4: \- Participant must have completed the Week 52 Visit of Substudy 3 or the Week 66 Visit of Substudy A
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Endoscopic Response by SES-CD at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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 consisted of composite score based on size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed 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=cannot be passed. Total SES CD=sum of each domain score for all 5 bowel segments and ranged from 0 (no disease) to 60 (severe disease), higher score= more severe disease. |
| Percentage of Participants With Endoscopic Response by Simple Endoscopic Score in Crohn's Disease (SES-CD) at Week 14: SSA | Week 14 of SSA | Endoscopic response: SES-CD score \<=4 and at least 2-point reduction from baseline with no subscore \>1 or \>=50% decrease from study baseline in SES-CD. 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. |
| Percentage of Participants With Endoscopic Response by SES-CD at Week 14: SS1 | Week 14 of SS1 | Endoscopic response: SES-CD score \<=4 and at least 2-point reduction from baseline with no subscore \>1 or \>=50% decrease from study baseline in SES-CD. SES-CD consisted of 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)-60 (severe disease), higher score indicated more severe disease. Multiple imputation (MI) method used; percentage calculated based on average response rate from MI datasets. |
| Percentage of Participants With Clinical Remission by CDAI at Week 52: SS3 Responder Cohort | Week 52 of study | 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); hematocrit (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. |
| Percentage of Participants With Clinical Remission by CDAI at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Response by SES-CD at Week 52: SS3 Responder Cohort | Week 52 of study | 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 consisted of composite score based on size of ulcers, ulcerated surface, affected surface and presence of narrowing assessed 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=cannot be passed. Total SES CD=sum of each domain score for all 5 bowel segments and ranged from 0 (no disease) to 60 (severe disease), higher score= more severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of Etrasimod at 4 Hours Post-dose: SSA | 4 hours post-dose on Day 1 | The plasma concentration of etrasimod at 4 hours post-dose has been reported in this outcome measure. |
| Steady State Trough Concentration (Ctrough,ss) of Etrasimod From Week 2 to Week 14: SSA | From Week 2 to Week 14 | 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. |
| Change From Baseline in Absolute Lymphocyte Count (ALC) at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Percent Change From Baseline in ALC at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Change From Baseline in ALC at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Percent Change From Baseline in ALC at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Change From Baseline in Fecal Calprotectin (FCP) Concentration at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Percent Change From Baseline in FCP Concentration at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Change From Baseline in FCP Concentration at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Percent Change From Baseline in FCP Concentration at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Change From Baseline in C-Reactive Protein (CRP) at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Percent Change From Baseline in CRP at Week 14 in Induction Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | — |
| Change From Baseline in CRP at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Percent Change From Baseline in CRP at Week 66 in Extension Period: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 66 of SSA | — |
| Percentage of Participants With Clinical Remission by CDAI at Week 14: SS1 | Week 14 of SS1 | 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. |
| Percentage of Participants With Clinical Remission by Patient Reported Outcomes 2 (PRO2) at Week 14: SS1 | Week 14 of SS1 | 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. |
| Percentage of Participants With Clinical Remission by CDAI at Week 52 Among Participants With Clinical Remission by CDAI at SS3 Baseline: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Remission by PRO2 at Week 52: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Remission by CDAI at Week 52 Among Participants With Clinical Remission by CDAI at SS3 Baseline: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Response at Week 52 Among Participants With Endoscopic Response at SS3 Baseline: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Response at Week 52 Among Participants With Endoscopic Response at SS3 Baseline: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Corticosteroid-Free Clinical Remission by CDAI at Week 52 Among Participants Receiving Corticosteroids at SS3 Baseline: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Corticosteroid-Free Clinical Remission by CDAI at Week 52 Among Participants Receiving Corticosteroids at SS3 Baseline: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Remission at Week 52: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Remission at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Remission by PRO2 at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Response or Endoscopic Response at Week 52: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Response or Endoscopic Response at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Change From Baseline in CDAI Score at Weeks 20, 28, 36, 44 and 52: SS3 Responder Cohort | Baseline, study Weeks 20, 28, 36, 44, 52 | 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. |
| Change From Baseline in CDAI Score at Weeks 20, 28, 36, 44 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 20, 28, 36, 44, 52 | 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. |
| Percentage of Participants With Clinical Response by CDAI at Week 52 Among Participants With Clinical Response by CDAI at SS3 Baseline: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Response by CDAI at Week 52 Among Participants With Clinical Response by CDAI at SS3 Baseline: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Change From Baseline in Crohn's Disease Patient-Reported Outcomes (CD-PRO) Module Scores at Weeks 28 and 52: SS3 Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Change From Baseline in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) at Weeks 28 and 52: SS3 Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Change From Baseline in SF-36 at Weeks 28 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Weeks 28 and 52: SS3 Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Change From Baseline in FACIT-F at Weeks 28 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Percentage of Participants With Clinical Remission by PRO2 at Week 52 Among Participants With Clinical Remission by PRO2 at SS3 Baseline: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Clinical Remission by PRO2 at Week 52 Among Participants With Clinical Remission by PRO2 at Study Entry: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Change From Baseline in PRO2 Scores at Weeks 20, 28, 36, 44 and 52: SS3 Responder Cohort | Baseline, study Weeks 20, 28, 36, 44 and 52 | 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. |
| Change From Baseline in PRO2 Scores at Weeks 20, 28, 36, 44 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 20, 28, 36, 44 and 52 | 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: SS3 Responder Cohort | From first maintenance dose in SS3 until date of clinical remission and FCP normalization or censoring date (maximum up to 42 weeks) | 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: SS3 Non-Responder Cohort | From first maintenance dose in SS3 until date of clinical remission and FCP normalization or censoring date (maximum up to 42 weeks) | 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: SS3 Responder Cohort | From first maintenance dose in SS3 until date of clinical response and FCP normalization or censoring date (maximum up to 42 weeks) | 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: SS3 Non-Responder Cohort | From first maintenance dose in SS3 until date of clinical response and FCP normalization or censoring date (maximum up to 42 weeks) | 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. |
| Change From Baseline in SES-CD Score at Week 52: SS3 Responder Cohort | Baseline and Week 52 of study | 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. |
| Change From Baseline in SES-CD Score at Week 52: SS3 Non-Responder Cohort | Baseline and Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Response and Clinical Remission by PRO2 at Week 52: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Response and Clinical Remission by PRO2 at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Remission and Clinical Remission by PRO2 at Week 52: SS3 Responder Cohort | Week 52 of study | 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. |
| Percentage of Participants With Endoscopic Remission and Clinical Remission by PRO2 at Week 52: SS3 Non-Responder Cohort | Week 52 of study | 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. |
| Number of Participants According to Markedly Abnormal Criteria for Electrocardiogram (ECG) Parameters: SS4 | Baseline, Weeks 52, and 104 of SS4 | 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. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs by Severity and Treatment Related TEAEs: SS3 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 38 weeks; maximum follow-up: 42 weeks) | 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. |
| Number of Participants With TEAEs of Special Interest: SS3 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 38 weeks; maximum follow-up: 42 weeks) | 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. |
| Number of Participants With Clinically Meaningful Changes in Laboratory Parameters: SS3 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 38 weeks; maximum follow-up: 42 weeks) | 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. |
| Number of Participants With TEAEs, SAEs, TEAEs by Severity and Treatment Related TEAEs: SS4 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 166.3 weeks; maximum follow-up: 170.3 weeks) | 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. |
| Number of Participants With TEAEs of Special Interest: SS4 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 166.3 weeks; maximum follow-up: 170.3 weeks) | 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. |
| Number of Participants With Clinically Meaningful Changes in Laboratory Parameters: SS4 | From first dose of study treatment (Day 1) up to 4 weeks post last dose of study treatment (maximum treatment exposure: 166.3 weeks; maximum follow-up: 170.3 weeks) | 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. |
| Number of Participants According to Markedly Abnormal Criteria for Vital Signs: SS4 | Baseline, Weeks 1, 12, 24, 36, 52, 64, 76, 88 and 104 of SS4 | 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. |
| Percentage of Participants With Clinical Remission by CDAI at Weeks 12, 24, 36, 52, 64, 76, 88 and 104: SS4 | Weeks 12, 24, 36, 52, 64, 76, 88 and 104 of 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. |
| Percentage of Participants With Clinical Response by CDAI at Weeks 12, 24, 36, 52, 64, 76, 88 and 104: SS4 | Weeks 12, 24, 36, 52, 64, 76, 88 and 104 of SS4 | 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. |
| Change From Baseline in Crohn's Disease Patient-Reported Outcomes (CD-PRO) Module Scores at Weeks 28 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Percentage of Participants With Clinical Remission by PRO2 at Weeks 12, 24, 36, 52, 64, 76, 88 and 104: SS4 | Weeks 12, 24, 36, 52, 64, 76, 88 and 104 of SS4 | 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. |
| Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) at Weeks 28 and 52: SS3 Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Change From Baseline in IBDQ at Weeks 28 and 52: SS3 Non-Responder Cohort | Baseline, study Weeks 28 and 52 | 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. |
| Percentage of Participants With Clinical Remission by CDAI at Week 14: SSA | Week 14 of SSA | 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. |
| Change From Baseline in SES-CD Score at Week 14: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | 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. |
| Change From Baseline in CDAI Score at Week 14: SSA | Baseline (last measurement taken prior to the first dose of study treatment) and Week 14 of SSA | 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. |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, Egypt, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Japan, Lebanon, Lithuania, Malaysia, Mexico, Moldova, Netherlands, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
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Participant flow
Recruitment details
379 participants (84 in sub-study A \[SSA\]; 295 in SS1) enrolled. Participants who completed treatment and met study specific criteria in SS1 eligible for SS3. Participants from SS3 and SSA who completed at least 52 and 66 weeks of treatment, respectively eligible for SS4. Sub-studies planned: SSA, SS1, SS2, SS3 and SS4. The study (including SS3 and SS4) terminated early due to insufficient induction treatment benefit of etrasimod as observed in SS1. SS2 not initiated; its results not reported.
Pre-assignment details
SS3 had responder cohort (RC) and non-responder cohort (NRC). Participants at and after Week 6 of SS3 in RC were assessed for loss of response (LOR) defined as Crohn's Disease Activity Index (CDAI) score \>=220 and \>=100-point increase from maintenance first dose (MFD) visit. As pre-planned participants from RC who had LOR were summarized in RC till the confirmed LOR visit and data after LOR was summarized under NRC along with participants in NRC from start of SS3 for safety analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized SS1 <=18 years | 0 Participants |
| Age, Customized SS1 >=65 years | 4 Participants |
| Age, Customized SS1 Between 18 and 65 years | 95 Participants |
| Age, Customized SS1 Not Disclosed | 0 Participants |
| Age, Customized SS3 <=18 years | 0 Participants |
| Age, Customized SS3 >=65 years | 6 Participants |
| Age, Customized SS3 Between 18 and 65 years | 202 Participants |
| Age, Customized SS3 Not Disclosed | 0 Participants |
| Age, Customized SS4 <=18 years | 0 Participants |
| Age, Customized SS4 >=65 years | 4 Participants |
| Age, Customized SS4 Between 18 and 65 years | 67 Participants |
| Age, Customized SS4 Not Disclosed | 0 Participants |
| Age, Customized SSA <=18 years | 0 Participants |
| Age, Customized SSA >=65 years | 0 Participants |
| Age, Customized SSA Between 18 and 65 years | 81 Participants |
| Age, Customized SSA Not Disclosed | 1 Participants |
| Race/Ethnicity, Customized SS1 American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized SS1 Asian | 4 Participants |
| Race/Ethnicity, Customized SS1 Black or African American | 1 Participants |
| Race/Ethnicity, Customized SS1 Hispanic or Latino | 10 Participants |
| Race/Ethnicity, Customized SS1 More than one race | 0 Participants |
| Race/Ethnicity, Customized SS1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized SS1 Not Disclosed | 0 Participants |
| Race/Ethnicity, Customized SS1 Not Hispanic or Latino | 263 Participants |
| Race/Ethnicity, Customized SS1 Unknown or Not Reported | 13 Participants |
| Race/Ethnicity, Customized SS1 White | 87 Participants |
| Race/Ethnicity, Customized SS3 American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized SS3 Asian | 5 Participants |
| Race/Ethnicity, Customized SS3 Black or African American | 1 Participants |
| Race/Ethnicity, Customized SS3 Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized SS3 More than one race | 0 Participants |
| Race/Ethnicity, Customized SS3 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized SS3 Not Disclosed | 0 Participants |
| Race/Ethnicity, Customized SS3 Not Hispanic or Latino | 32 Participants |
| Race/Ethnicity, Customized SS3 Unknown or Not Reported | 3 Participants |
| Race/Ethnicity, Customized SS3 White | 39 Participants |
| Race/Ethnicity, Customized SS4 American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized SS4 Asian | 4 Participants |
| Race/Ethnicity, Customized SS4 Black or African American | 1 Participants |
| Race/Ethnicity, Customized SS4 Hispanic or Latino | 6 Participants |
| Race/Ethnicity, Customized SS4 More than one race | 0 Participants |
| Race/Ethnicity, Customized SS4 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized SS4 Not Disclosed | 0 Participants |
| Race/Ethnicity, Customized SS4 Not Hispanic or Latino | 128 Participants |
| Race/Ethnicity, Customized SS4 Unknown or Not Reported | 4 Participants |
| Race/Ethnicity, Customized SS4 White | 65 Participants |
| Race/Ethnicity, Customized SSA American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized SSA Asian | 1 Participants |
| Race/Ethnicity, Customized SSA Black or African American | 0 Participants |
| Race/Ethnicity, Customized SSA Hispanic or Latino | 5 Participants |
| Race/Ethnicity, Customized SSA More than one race | 0 Participants |
| Race/Ethnicity, Customized SSA Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized SSA Not Disclosed | 0 Participants |
| Race/Ethnicity, Customized SSA Not Hispanic or Latino | 74 Participants |
| Race/Ethnicity, Customized SSA Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized SSA White | 0 Participants |
| Sex/Gender, Customized SS1 Female | 143 Participants |
| Sex/Gender, Customized SS1 Male | 51 Participants |
| Sex/Gender, Customized SS1 Not Disclosed | 0 Participants |
| Sex/Gender, Customized SS3 Female | 22 Participants |
| Sex/Gender, Customized SS3 Male | 25 Participants |
| Sex/Gender, Customized SS3 Not Disclosed | 0 Participants |
| Sex/Gender, Customized SS4 Female | 71 Participants |
| Sex/Gender, Customized SS4 Male | 72 Participants |
| Sex/Gender, Customized SS4 Not Disclosed | 0 Participants |
| Sex/Gender, Customized SSA Female | 0 Participants |
| Sex/Gender, Customized SSA Male | 0 Participants |
| Sex/Gender, Customized SSA Not Disclosed | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk | EG022 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 42 | 0 / 41 | 0 / 1 | 0 / 28 | 0 / 2 | 0 / 34 | 0 / 100 | 0 / 98 | 0 / 97 | 0 / 17 | 0 / 18 | 0 / 37 | 0 / 36 | 0 / 47 | 0 / 38 | 0 / 33 | 0 / 28 | 0 / 35 | 0 / 38 | 0 / 23 | 1 / 72 | 0 / 71 |
| other Total, other adverse events | 0 / 1 | 19 / 42 | 21 / 41 | 0 / 1 | 19 / 28 | 2 / 2 | 23 / 34 | 45 / 100 | 40 / 98 | 34 / 97 | 6 / 17 | 9 / 18 | 11 / 37 | 6 / 36 | 31 / 47 | 24 / 38 | 20 / 33 | 17 / 28 | 15 / 35 | 17 / 38 | 11 / 23 | 43 / 72 | 36 / 71 |
| serious Total, serious adverse events | 0 / 1 | 2 / 42 | 1 / 41 | 1 / 1 | 4 / 28 | 1 / 2 | 5 / 34 | 6 / 100 | 11 / 98 | 9 / 97 | 0 / 17 | 2 / 18 | 3 / 37 | 3 / 36 | 2 / 47 | 4 / 38 | 3 / 33 | 6 / 28 | 4 / 35 | 5 / 38 | 4 / 23 | 10 / 72 | 8 / 71 |
Outcome results
None listed