Etrasimod Versus Placebo for the Treatment of Moderately Active Ulcerative Colitis

MMS is used to assess disease activity in participants with UC and has following components: endoscopic score(ES),rectal bleeding(RB),stool frequency(SF).Each component score ranges from 0 to 3(0=normal,1=mild,2=moderate,3=severe); higher scores indicating more severe disease.ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy,scores ranged from 0(normal or inactive disease) to 3(severe disease \[spontaneous bleeding, ulceration\]).RB reported most severe amount of blood passed per rectum in 24-hour period,scores ranged from 0(no blood seen) to 3(blood alone passes).SF reported number of stools in 24-hour period relative to normal number of stools for that participant in same period,scores ranged from 0(normal number of stools) to 3(5 or more stools than normal).CR per FDA draft guidance defined as:SF=0 or 1 and no greater than baseline, RB=0,ES less than or equal to (\<=)1(excluding friability).Percentage of participants achieving CR at Week 52 was evaluated.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

MMS has following components: ES, RB and SF; each ranged as 0=normal,1=mild,2=moderate,3=severe; total MMS score 0-9; higher scores=more severe disease. ES:worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0(normal or inactive disease)to 3(severe disease). RB:most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0(no blood seen) to 3(blood alone passes). SF:number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0(normal number of stools)to 3(5 or more stools than normal). CR per FDA draft guidance as: SF =0 or =1 and no greater than baseline, RB=0, and ES \<=1(excluding friability). 4-week corticosteroid-free CR was defined as CR at Week 52 and corticosteroid-free for \>=4 weeks immediately prior to Week 52. The baseline was balanced between treatment groups and representative of participants with mildly to moderately active UC.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure who received oral corticosteroids for UC at baseline.

ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, scores ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]), higher scores = more severity. RB: reported the most severe amount of blood passed per rectum in a 24-hour period, scores ranged from 0 (no blood seen) to 3 (blood alone passes), higher scores = more severity. SF reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0 (normal number of stools) to 3 (5 or more stools than normal), higher scores = more severity. Percentage of participants with reduction from baseline in both ES and RB or in both ES and SF at Week 12 was evaluated in this endpoint. The baseline primary analysis set was balanced between treatment groups and representative of participants with mildly to moderately active UC.

Time frame: Baseline to Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

MMS is used to assess disease activity in participants with UC and has following components: ES, RB and SF. Each component score ranges from 0 to 3 (0= normal, 1= mild, 2= moderate, 3= severe); higher scores = more severe disease. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0 (normal or inactive disease) to 3 (severe disease). RB: reported the most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0 (no blood seen) to 3 (blood alone passes). SF reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0 (normal number of stools) to 3 (5 or more stools than normal). Clinical remission per FDA draft guidance: SF =0 or =1 and no greater than baseline, RB =0, and ES \<=1 (excluding friability). Percentage of participants who achieved clinical remission at both the time points Week 12 and Week 52 \[Combined\] are reported.

Time frame: Weeks 12 and 52 [Combined]

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

MMS is used to assess disease activity in participants with UC and has following components: ES, RB and SF. Each component score ranges from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe); higher scores indicating more severe disease. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, scores ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]). RB reported the most severe amount of blood passed per rectum in a 24-hour period, scores ranged from 0 (no blood seen) to 3 (blood alone passes). SF reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0 (normal number of stools) to 3 (5 or more stools than normal). CR per FDA draft guidance was defined as: SF=0 or =1 and no greater than baseline, RB=0, and ES \<=1 (excluding friability). Percentage of participants achieving CR at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Clinical response was defined as a \>=2-point and \>=30 percentage (%) decrease from baseline in MMS, and a \>=1-point decrease from baseline in RB subscore or an absolute RB subscore \<=1 and is as per FDA draft guidance. MMS was used to assess disease activity in participants with UC and has following components: ES, RB and SF. Each component score ranges from 0 to 3 (0= normal, 1= mild, 2= moderate, 3= severe); where total score is sum of three components giving total MMS score as 0 to 9; higher scores indicating more severe disease. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]). Percentage of participants achieving clinical response at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS 4-6, baseline ES \>=2 and baseline RB score \>=1.

Clinical response was defined as a \>=2-point and \>=30 % decrease from baseline in MMS, and a \>=1-point decrease from baseline in RB subscore or an absolute RB subscore \<=1 and is as per FDA draft guidance. MMS is used to assess disease activity in participants with UC and has following components: ES, RB and SF. Each component scores ranges from 0 to 3 (0= normal, 1= mild, 2= moderate, 3= severe); where total score is sum of three components giving total MMS score as 0 to 9; higher scores indicating more severe disease. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, scores ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]). Percentage of participants achieving clinical response at Week 52 was evaluated in this endpoint.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS 4-6, baseline ES \>=2 and baseline RB score \>=1.

Complete symptomatic remission was defined as participants with RB = 0 and SF = 0. SF subscore: reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, scores ranged from 0 (normal number of stools) to 3 (5 or more stools than normal), higher scores = more severity. RB subscore: reported the most severe amount of blood passed per rectum in a 24-hour period, scores ranged from 0 (no blood seen) to 3 (blood alone passes), higher scores = more severity. Percentage of participants achieving complete symptomatic remission at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Complete symptomatic remission was defined as participants with RB = 0 and SF = 0. SF subscore: reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, scores ranged from 0 (normal number of stools) to 3 (5 or more stools than normal), higher scores = more severity. RB subscore: reported the most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0 (no blood seen) to 3 (blood alone passes), higher scores = more severity. Percentage of participants achieving complete symptomatic remission at Week 52 was evaluated in this endpoint.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Endoscopic improvement was defined as ES \<=1 (excluding friability). ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, scores ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]), higher scores = more severity. Percentage of participants achieving endoscopic improvement at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Endoscopic improvement was defined as ES \<=1 (excluding friability). ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]), higher scores = more severity. Percentage of participants achieving endoscopic improvement at Week 52 was evaluated in this endpoint.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Histologic-endoscopic mucosal improvement was defined as ES \<=1 (excluding friability) with Geboes score \<2.0. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, scores ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]), higher scores = more severity. The Geboes score grading system was a validated score for evaluating histologic disease activity in UC as follows: grade 0 = structural and architectural changes; grade 1 = chronic inflammatory infiltrate; grade 2 = lamina propria neutrophils and eosinophils; grade 3 = neutrophils in the epithelium; grade 4 = crypt destruction; grade 5 = erosions or ulceration. A higher Geboes score indicated more severe disease. Percentage of participants achieving mucosal improvement at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Histologic-endoscopic mucosal improvement was defined as ES \<=1 (excluding friability) with Geboes score \<2.0. ES reported worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0 (normal or inactive disease) to 3 (severe disease \[spontaneous bleeding, ulceration\]), higher scores = more severity. The Geboes score grading system was a validated score for evaluating histologic disease activity in UC as follows: grade 0 = structural and architectural changes; grade 1 = chronic inflammatory infiltrate; grade 2 = lamina propria neutrophils and eosinophils; grade 3 = neutrophils in the epithelium; grade 4 = crypt destruction; grade 5 = erosions or ulceration. A higher Geboes score indicated more severe disease. Percentage of participants achieving mucosal improvement at Week 52 was evaluated in this endpoint.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

RHI is an evaluative index, derived from the Geboes score, that is designed to be reproducible and responsive to clinically meaningful change in disease activity over time. Histologic response based on RHI was defined as decrease in RHI of \>=7 points from baseline. Total RHI score ranges from 0 (no disease activity) to 33 (severe disease activity), higher score = more severity. Percentage of participants achieving histologic response based on RHI at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Histologic response based on the Geboes grading system was defined as Geboes score \<=3.1. The Geboes score grading system is a validated score for evaluating histologic disease activity in UC as follows: grade 0 = structural and architectural changes; grade 1 = chronic inflammatory infiltrate; grade 2 = lamina propria neutrophils and eosinophils; grade 3 = neutrophils in the epithelium; grade 4 = crypt destruction; grade 5 = erosions or ulceration. A higher Geboes score indicated more severe disease. Percentage of participants achieving histologic response based on the Geboes grading system at week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Symptomatic remission was defined as SF =0 (or = 1 with a \>= 1 point decrease from baseline) and RB =0. SF subscore: reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, scores ranged from 0 (normal number of stools) to 3 (5 or more stools than normal), higher scores = more severity. RB subscore: reported the most severe amount of blood passed per rectum in a 24-hour period, scores ranged from 0 (no blood seen) to 3 (blood alone passes), higher scores = more severity. Percentage of participants achieving symptomatic remission at Week 12 was evaluated in this endpoint.

Time frame: Week 12

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

Symptomatic remission was defined as SF =0 (or = 1 with a \>= 1 point decrease from baseline) and RB =0. SF subscore: reported number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, scores ranged from 0 (normal number of stools) to 3 (5 or more stools than normal), higher scores = more severity. RB subscore: reported the most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0 (no blood seen) to 3 (blood alone passes), higher scores = more severity. Percentage of participants achieving symptomatic remission at Week 52 was evaluated in this endpoint.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

MMS has following components:ES, RB and SF. Each component score ranges from 0 to 3(0=normal,1=mild,2=moderate,3=severe); higher scores indicating more severe disease. ES:worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0(normal or inactive disease)to 3(severe disease). RB:most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0(no blood seen)to 3(blood alone passes). SF:number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0(normal number of stools)to 3(5 or more stools than normal). CR per FDA draft guidance as: SF =0 or =1 and no greater than baseline, RB=0, and ES \<=1(excluding friability). 12-week corticosteroid-free CR was defined as CR at Week 52 and corticosteroid-free for \>=12 weeks immediately prior to Week 52. The baseline was balanced between treatment groups and representative of participants with mildly to moderately active UC.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure who received oral corticosteroids for UC at baseline.

MMS has following components: ES, RB and SF. Each component score ranges from 0 to 3 (0=normal,1=mild,2=moderate,3=severe); higher scores indicating more severe disease. ES: worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0(normal or inactive disease) to 3 (severe disease). RB: most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0(no blood seen) to 3 (blood alone passes). SF: number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0(normal number of stools) to 3 (5 or more stools than normal). CR per FDA draft guidance as: SF =0 or =1 and no greater than baseline, RB=0, and ES \<=1(excluding friability). 12-week corticosteroid-free CR was defined as CR at Week 52 and corticosteroid-free for \>=12 weeks immediately prior to Week 52.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

MMS has following components: ES, RB and SF. Each component score ranges from 0 to 3 (0=normal,1=mild,2=moderate,3=severe); where total score is sum of three components giving total MMS score as 0 to 9; higher scores indicating more severe disease. ES: worst appearance of mucosa on flexible sigmoidoscopy or colonoscopy, score ranged from 0(normal or inactive disease) to 3 (severe disease). RB: most severe amount of blood passed per rectum in a 24-hour period, score ranged from 0(no blood seen) to 3 (blood alone passes). SF: number of stools in a 24-hour period relative to normal number of stools for that participant in the same period, score ranged from 0 (normal number of stools) to 3 (5 or more stools than normal). CR per FDA draft guidance as: SF =0 or =1 and no greater than baseline, RB=0, and ES \<=1(excluding friability). 4-week corticosteroid-free CR was defined as CR at Week 52 and corticosteroid-free for \>=4 weeks immediately prior to Week 52.

Time frame: Week 52

Population: Primary analysis set included all randomized participants who received at least 1 dose of study treatment with baseline MMS \[total score range: 0 to 9, higher score = more severity\] 4-6, baseline ES greater than or equal to (\>=2) and baseline RB score \>=1.

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and all non-SAEs.

Time frame: From first dose of study treatment up to 4 weeks post last dose of study treatment (up to 56 Weeks)

Population: Safety set included all randomized participants who received at least 1 dose of study treatment.

An AE was any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Severity was classified using common terminology criteria for adverse events (CTCAE), version 5.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death related to AE. Only those categories in which at least 1 participant had data for any reporting group were reported.

Time frame: From first dose of study treatment up to 4 weeks post last dose of study treatment (up to 56 Weeks)

Population: Safety set included all randomized participants who received at least 1 dose of study treatment.