Safety and Efficacy of Andecaliximab (GS-5745) in Adults With Moderately to Severely Active Ulcerative Colitis

Study Overview
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Brief Summary
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The primary objectives of this study are as follows: 1) To evaluate the efficacy of andecaliximab to induce endoscopy, rectal bleeding, and stool frequency (EBS) clinical remission at Week 8 (Cohort 1); 2) To evaluate the efficacy of andecaliximab to maintain EBS clinical remission at Week 52 (Cohort 2); and 3) To evaluate the safety and tolerability of andecaliximab. The study will consist of 3 parts: Induction Phase (Cohort 1), Maintenance Phase (Cohort 2), and an optional Extended Treatment Phase.

Official Title
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A Combined Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Induction and Maintenance Study Evaluating the Safety and Efficacy of GS-5745 in Subjects With Moderately to Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Biological: Andecaliximab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Ulcerative Colitis (UC) confirmed on endoscopy Moderately to severely active UC (Mayo Score 6-12) May be receiving oral 5-aminosalicylate (ASA), oral corticosteroid, azathioprine, 6-mercaptopurine (MP), or methotrexate Treatment failure with at least one of the following agents received: corticosteroids, immunomodulators, tumor necrosis factor-alpha (TNFα) antagonists, vedolizumab Key Exclusion Criteria: Diagnose of Crohn's disease or indeterminate colitis Pregnant or lactating females Any chronic medical condition (including, but not limited to cardiac or pulmonary disease, alcohol or drug abuse) Exhibit severe UC / clinically significant active infection History of malignancy in the last 5 years Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Andecaliximab Every 2 Weeks<br>Participants will receive andecaliximab 150 mg administered via subcutaneous (SC) injection alternating with matching placebo weekly for a total of 4 doses of andecaliximab. Based on Week 8 assessment results, participants will either continue in Blinded Maintenance Treatment phase or will be offered Open-Label andecaliximab 150 mg administered via SC injection weekly for up to Week 51. | Biological: Andecaliximab<br>* Andecaliximab 150 mg administered via SC injection<br>* Other names: GS-5745;Biological: Placebo<br>* Placebo matched to andecaliximab administered via SC injection<br>|
| Experimental: Andecaliximab Weekly<br>Participants will receive andecaliximab 150 mg administered via SC injection once weekly for a total of 8 doses. Based on Week 8 assessment results, participants will either continue in Blinded Maintenance Treatment phase or will be offered Open-Label andecaliximab 150 mg administered via SC injection weekly for up to Week 51. | Biological: Andecaliximab<br>* Andecaliximab 150 mg administered via SC injection<br>* Other names: GS-5745;|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to andecaliximab administered via SC injection once weekly for a total of 8 doses. Based on Week 8 assessment results, participants will either continue in Blinded Maintenance Treatment phase or will be offered Open-Label andecaliximab 150 mg administered via SC injection weekly for up to Week 51. | Biological: Andecaliximab<br>* Andecaliximab 150 mg administered via SC injection<br>* Other names: GS-5745;Biological: Placebo<br>* Placebo matched to andecaliximab administered via SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Cohort 1, Percentage of Participants With EBS Clinical Remission at Week 8 | EBS clinical remission was defined as an endoscopic subscore of 0 or 1 (endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]); rectal bleeding subscore of 0 (rectal bleeding subscore range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes); and at least a 1-point decrease in stool frequency from baseline to achieve a subscore of 0 or 1 (stool frequency subscore range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal). | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Cohort 1, Percentage of Participants With MCS Remission at Week 8 | The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and physician's global assessment (PGA). The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. The MCS remission was defined as a MCS of ≤ 2 points and no individual subscore > 1 point. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening. | Week 8 | 
| For Cohort 1, Percentage of Participants With MCS Response at Week 8 | The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and PGA. The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening. The MCS response was defined as a MCS reduction of ≥ 3 points and at least 30% from baseline, with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. | Week 8 | 
| For Cohort 1, Percentage of Participants With Endoscopic Remission at Week 8 | Endoscopic remission was defined as endoscopic subscore of 0. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration). | Week 8 | 
| For Cohort 1, Percentage of Participants With Endoscopic Response at Week 8 | Endoscopic response was defined as endoscopic subscore of 0 or 1. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration). | Week 8 | 
| For Cohort 1, Percentage of Participants With Mucosal Healing as Determined by the Geboes Histologic Scoring System at Week 8 | Mucosal healing was defined as elimination of ulcers/erosion, elimination of crypt destruction, elimination of intraepithelial neutrophils, elimination of lamina propria neutrophils, and reduction in lamina propria chronic inflammatory cells to at most a mild increase. When measured by the Geboes histologic scoring system, it was the selection of the following combined scores of ≤ 3 for Grade 0 (Structural Architectural Change), ≤ 1 for Grade 1 (Chronic Inflammatory Infiltrate), ≤ 3 for Grade 2A (Lamina Propria Eosinophils), and 0 for Grade 2B (Lamina Propria Neutrophils), Grade 3 (Neutrophils in Epithelium), Grade 4 (Crypt Destruction), and Grade 5 (Erosion or Ulceration). Total Geboes histologic score ranged from 0 to 22, with higher scores indicating greater disease severity. | Week 8 | 
| For Cohort 1, Percentage of Participants With MCS Remission (Alternative Definition) at Week 8 | The MCS remission (alternative definition) was defined as a rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and PGA subscore (range: 0 to 3 with higher score indicating the severe disease) of 0, and an endoscopic subscore (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]) of 0 or 1 for an overall MCS of ≤ 1. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating disease worsening. | Week 8 |