The first amendment to the protocol, dated 01 May 2015, included the following important changes: • The term partial MCS was changed to 3-component MCS throughout the protocol. • Use of Inflammatory Bowel Disease Questionnaire and corresponding exploratory objective, endpoint, and analysis were added. • Definition of an intolerable AE was added. • A clarification was made to specify that the stool sample collected during the study was used for the analysis of both the fecal calprotectin assay and for culture, ova, and parasite evaluation and C difficile assay. • Requirement for a chest X-ray to be taken at the Week 12 visit was removed for subjects not continuing into the extension study. • Clarified that study medication should be taken after an overnight fast (~8 hours) and food should be avoided for ~1 hour after dosing. • Inclusion criterion pertaining to corticosteroid usage was updated to remove the references pertaining to the allowance of corticosteroid tapering in the study, with the requirement of stable dosage regimen throughout the study duration for corticosteroid usage. • The requirement of capping the number of subjects with prior exposure to TNFα antagonists for randomization into the study was added. • Information about blinding requirements for analysis of total lymphocyte and white blood cell (WBC) counts to be followed during the study was added. • The ECG assessment information was updated to clarify that the ECGs were to be read and interpreted by both the study physician and centrally. • Reference to “continuous telemetry” in the protocol was corrected to “Holter monitoring.” • The laboratory parameters were updated to add and remove certain evaluation parameters from the assessments. • “Pharmacodynamic” assessments in the study were replaced with “hematologic” assessments. • Subgroup analyses parameters for fecal calprotectin and CRP were defined.

The second amendment to the protocol, dated 17 Jun 2015, included the following important changes: • Analysis time points to the efficacy parameters of rectal bleeding, stool frequency, fecal calprotectin, CRP reduction, and 2-component Mayo Score were added. • The following exploratory endpoints were added: (1) change from baseline in Mayo endoscopic subscore at Week 12; (2) change from baseline in Mayo PGA at Week 12; (3) change from baseline in 2-component Mayo score at Weeks 1, 2, 4, 8, and 12; and (4) change from baseline in lymphocyte counts at Weeks 1, 2, 4, 8, 12, and 14. • A secondary method for the primary efficacy analysis was added, which included a logistic regression analysis with terms of treatment, presence or absence of current oral corticosteroid therapy at baseline, previous exposure to TNFα antagonists, and the interaction between 2 stratification factors (if appropriate). • Requirement of clinical laboratory tests to be performed at screening and Week 12 under fasting conditions was removed. • Inclusion criterion related to colonoscopy for subjects with history of extensive pancolitis or left-sided colitis was clarified. • Exclusion criterion pertaining to the serology requirements was updated to exclude subjects without documented varicella zoster virus (VZV) IgG antibody status. • Addition of 3 exclusion criteria: (1) use of moderate to strong inhibitors of CYP2C9; (2) history of severe renal impairment; and (3) history of severe hepatic impairment. • Dosage instructions for study drug administration were clarified to instruct subjects not to take their study drug dose at home on days with scheduled study visits in order to complete predose study procedures and to remain fasted as instructed on the days of scheduled visits prior to dosing. • Moderate to strong inhibitors of CYP2C9 were added to the excluded (i.e., prohibited) medications list.

The third amendment to the protocol, dated 30 Jun 2015, included the following important changes: • An exclusion criterion of “previous treatment with 2 or more biologic agents” was added. • Vedolizumab was added to the list of medications that were to be excluded within 60 days prior to randomization. • Consideration for a repeat flexible proctosigmoidoscopy was added.

The fourth amendment to the protocol, dated 21 Sep 2015, included the following important changes: • Information on retinal photos to be taken at each ophthalmoscopy was added. Requirement of Week 12 ophthalmoscopy applicable only to subjects who did not enter the extension study was removed. • Inclusion criterion about the permitted use of corticosteroids prior to study entry was updated. • Exclusion criteria related to history or evidence of adenomatous colonic polyps and colonic mucosal dysplasia were updated.

The fifth amendment to the protocol, dated 10 Oct 2016, included the following important changes: • Subject entry requirement for participation in the extension Study APD334-005 was updated to include only responders and not both responders and nonresponders. • Blood sample collection at 8 hours postdose for PK assessments was removed. • Added possibility to prolong time window for screening to 35 days. Extended window for specified procedures (proctosigmoidoscopy) to 10 days. Removed all other visit and procedure windows. • The duration within which certain screening procedures were to be completed prior to randomization was updated from 7 to 10 days. • Assessment timings and requirements for heart rate, blood pressure, and ECG measurements were updated. • Exclusion criterion related to use of biologic agents prior to study entry was updated, with subjects who received previous treatment with more than 3 biologics were not to be enrolled. • Additional monitoring considerations for changes in heart rate and ECG parameters were added. • Recipient of notification of SAE was changed from the Sponsor to PPD (contract research organization [CRO]). • Information on extending the screening period window to 35 days and clarification on rescreening procedures was added. • Information about the 2-component May score to be calculated at Weeks 1, 2, 4, and 8 was added. • Added specification that APD334-003 study will remain blinded until completion of the APD334-005 study. • Clarified that clinical laboratory tests and CBC tests should be performed prior to dosing.

The sixth amendment to the protocol, dated 27 Mar 2017, included the following important changes: • The primary objective was updated to determine the effect of treatment with etrasimod in improving 3-component MCS (score ranging from 0 to 9, including stool frequency, rectal bleeding, and findings on endoscopy) at Week 12. • The following secondary objectives were added: (1) to determine the effect of treatment with etrasimod on a combination of clinical remission and clinical response reflected by a composite endpoint at 12 weeks; and (2) to determine the effect of treatment with etrasimod in inducing clinical remission at 12 weeks. • The following exploratory objectives were added: (1) to determine the effect of etrasimod treatment on total MCS at 12 weeks; and (2) to determine dose response effect of etrasimod on 3-component MCS, combination of clinical remission and clinical response reflected by a composite endpoint, clinical remission, clinical response, and endoscopic improvement, at 12 weeks. • The primary, secondary, and exploratory efficacy endpoints were updated based on the changes made to the study objectives. • The study design information was updated to designate this study as a proof of concept study. • Subject entry requirement for participation in the extension Study APD334-005 was updated to include both responders and nonresponders. • Inclusion criterion about integrin antagonists was updated to include subjects in the study who had discontinued prior treatment with vedolizumab despite clinical benefit. • The exclusion criterion of “a history of primary nonresponse to a treatment regimen of vedolizumab per the current labeling and/or institutional standard of care. • Sample size language was changed to up to 240, with the added statement that the Sponsor can stop enrollment for any reason prior to that. • Sponsor considerations for conducting interim analysis were added. • Added section that outlined reasons to terminate the study.