Addition of Inclusion Criteria for Patient-reported Outcomes-2. The primary purpose of this protocol amendment was to add inclusion criteria for the PROs of abdominal pain and stool frequency. The rationale for this amendment was to align with the current critical endpoints for abdominal pain and stool frequency. Update of Exclusion Criterion Number 12 Exclusion criterion number 12 was updated to allow stable doses of antibiotics for the treatment of CD, provided that the dose had been stable for at least 2 weeks prior to the Screening Visit. In earlier GED-0301 studies, the use of antibiotics for the treatment of CD was prohibited. Following discussions with clinical investigators, the use of antibiotics could be commonly used as background therapy in subjects with CD and there was no reason to suspect a diminished effect of GED-0301 with its different mechanism of action. This change supported a broader subject population to be studied in this Phase 3 study. Revision of Exclusion Criterion Number 13 Exclusion criterion number 13 was revised to exclude subjects with prior treatment with 3 biologics as opposed to 2 biologics. The rationale was based on the expectation of responsiveness to GED-0301 (with a different mechanism of action than biologic therapy) in terms of clinical and endoscopic benefit, which was expected to be substantively similar in subjects having been exposed to either 2 or 3 biologics. The intention, therefore, was to study a broader group of subjects with prior biologic exposure. The target of 65% of the subjects in this study to be naive to prior biologic therapy was unchanged.

The purpose of the amendment was to prioritize the evaluation of clinical remission and endoscopic outcomes as primary and secondary endpoints. Endpoints were listed by 2 regions (US and rest of world). The primary efficacy measure was clinical remission at Week 12. The secondary efficacy measures include the evaluation of endoscopic remission at Week 52; clinical remission based on CDAI score at Week 12 (US only); clinical remission (based on stool frequency/abdominal pain and CDAI score for US, and CDAI score for ROW) at Week (Wk) 52; clinical response at Wk 12; ER-50 sustained clinical remission at Wk 12 and Wk 52; steroid-free clinical remission at Week 52; ER-25 at Wk 12; clinical remission at Wk 4; clinical response at Wk 4; and clinical remission (based on CDAI score) at Week 4. Inclusion/Exclusion Changes: Aminosalicylates were removed as one of the therapies that subjects may have failed to grant eligibility. Failed treatment with biologics was further specified to include infliximab, adalimumab, certolizumab, or vedolizumab. Clarification: the presence of active CD was to be determined by ileocolonoscopy at screening and Pan-colonic screening surveillance was removed. Those with increased risk of colorectal cancer should have had a colonoscopy with pan-colonic surveillance biopsies. The inclusion criterion requiring male subjects to use barrier contraception was removed and those taking an oral contraceptive as an alternative method of birth control based on physician judgment. The exclusion criteria were revised to clarify the requirements with respect to strictures. Prior use of biologics was updated to specify infliximab, adalimumab, certolizumab, or vedolizumab. Exclusion criteria considered the duration of 5 elimination half-lives for biologics, in addition to the 8-week and 1-month washout periods for biologics and investigational drug. Those with a diagnosis of colorectal dysplasia were excluded. Those with serious infections were also excluded.

The primary purpose of the amendment was to harmonize and reprioritize the order of endpoints based on regulatory agency feedback. There was now one set of endpoints for all regions. The primary efficacy measure was clinical remission (defined as a CDAI score < 150) at Week 12. Key secondary efficacy measures included: clinical remission at Week 52, ER-50 (defined as a reduction of at least 50% compared with baseline in the SES-CD) at Week 52, clinical response (defined as a decrease from baseline in CDAI ≥ 100 points) at Week 12, clinical response at Week 4, clinical remission at Week 4, steroid-free clinical remission at Week 52, sustained clinical remission at both Week 12 and Week 52, ER-25 (defined as a reduction of at least 25% compared with baseline in SES-CD) at Week 12, and the evaluation of endoscopic remission (defined as SES-CD ≤ 2) at Week 52. New exploratory endpoints included the proportion of subjects who achieved clinical remission for at least 80% of visits (for all subjects through Week 52, and from Weeks 12 to 52 for subjects with clinical remission at Week 12). Exploratory endpoints regarding corticosteroid-free clinical remission were revised for clarity. Monitoring of Liver Function Tests (LFTs) Additional guidance was added for those who developed changes in LFTs including, but not limited to, repeat testing, evaluation for cause, and close observation. Criteria were also provided to consider IP interruption or study discontinuation. This additional guidance was added at the request of the US FDA and was not specific to any signals observed with GED-0301. Discontinuation Criteria Text was updated to specify potential reasons for discontinuation including but not limited to subject safety (eg, LFT abnormalities), CD-related surgeries, initiation of biologics, and initiation of specific CD-related medications. The reasons for treatment and study discontinuation were updated to include lack of efficacy.