Safety and Efficacy of Andecaliximab in Participants With Moderately to Severely Active Crohn's Disease

Study Overview
=================
Brief Summary
-----------------
This study will primarily evaluate the safety and efficacy of andecaliximab in adults with active Crohn's disease. The study will consist of a Double-Blind Phase of 8 weeks followed by an Open-Label Extension. Participants who complete the Double-Blind Phase will be eligible to enroll in the optional Open-Label Extension for an additional 44 weeks. Participants who complete Week 52 assessments will be eligible to enter the Extended Treatment Phase to continue treatment with andecaliximab for an additional 156 weeks.

Official Title
-----------------
A Phase 2, Double-blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of GS-5745 in Subjects With Moderately to Severely Active Crohn's Disease

Conditions
-----------------
Crohn's Disease

Intervention / Treatment
-----------------
* Drug: Andecaliximab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Ability to provide a written informed consent Females of childbearing potential must have a negative pregnancy test at screening and baseline Documented diagnosis of Crohn's disease with a minimum disease duration of 6 months with involvement of the ileum and/or colon at a minimum Moderately to severely active Crohn's disease as defined by a Crohn's Disease Activity Index (CDAI) total score between 220-450 (inclusive) AND with evidence of active disease as measured by ileocolonoscopy Within the previous 5 years, demonstrated an inadequate clinical response or intolerance of at least one of the following agents: Corticosteroids Immunomodulators Tumor necrosis factor-alpha (TNFα) antagonists Vedolizumab May be receiving the following drugs: Oral 5-aminosalicylate (5-ASA) Oral corticosteroid therapy Antidiarrheals for chronic diarrhea Azathioprine or 6-mercaptopurine (6-MP) or methotrexate Antibiotics for the treatment of Crohn's disease Able to comply with the dosing instructions for study drug and able to comply with the study visits and requirements Key Exclusion Criteria: Evidence of abscess at screening Extensive colonic resection (subtotal or total colectomy) or history of > 2 small bowel resections Ileostomy, colostomy, or symptomatic stenosis of the intestine Current use of oral corticosteroids at a dose equivalent to > 30 mg/day of prednisone Ulcerative colitis or indeterminate colitis Short bowel syndrome Stool sample positive for Clostridium difficile (C. difficile) toxin, E. coli, Salmonella, Shigella, Campylobacter or Yersinia Treatment with any monoclonal antibody within 4 weeks of screening History or evidence of colonic mucosal dysplasia HIV, hepatitis B, hepatitis C, or tuberculosis (TB) infection Participated in a clinical study with an investigational drug or biologic within the last 30 days Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) that, in the opinion of the investigator, would make the individual unsuitable for the study or would prevent compliance with the study protocol Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Andecaliximab 150 mg Every 2 Weeks<br>Double-Blind Phase: Participants will receive 1 single-use prefilled syringe (PFS) of andecaliximab 150 mg and matching placebo coadministered at Weeks 0, 2, 4, and 6 and 2 single-use PFS of placebo coadministered at Weeks 1, 3, 5, and 7. Open-Label Phase: Participants will be eligible to enroll in the Open-Label Phase to receive andecaliximab 150 mg weekly for an additional 44 weeks. Extended Treatment Phase: Participants who complete Week 52 assessments will be eligible to enter into the Extended Treatment Phase to continue treatment with andecaliximab 150 mg for an additional 156 weeks. | Drug: Andecaliximab<br>* Andecaliximab administered via subcutaneous (SC) injection<br>* Other names: GS-5745;Drug: Placebo<br>* Placebo to match andecaliximab administered via SC injection<br>|
| Experimental: Andecaliximab 150 mg Weekly<br>Double-Blind Phase: Participants will receive 1 single-use PFS of andecaliximab 150 mg and matching placebo coadministered weekly for 8 weeks. Open-Label Phase: Participants will be eligible to enroll in the Open-Label Phase to receive andecaliximab 150 mg weekly for an additional 44 weeks. Extended Treatment Phase: Participants who complete Week 52 assessments will be eligible to enter into the Extended Treatment Phase to continue treatment with andecaliximab 150 mg for an additional 156 weeks. | Drug: Andecaliximab<br>* Andecaliximab administered via subcutaneous (SC) injection<br>* Other names: GS-5745;Drug: Placebo<br>* Placebo to match andecaliximab administered via SC injection<br>|
| Experimental: Andecaliximab 300 mg Weekly<br>Double-Blind Phase: Participants will receive 2 single-use PFS of andecaliximab 150 mg coadministered weekly for 8 weeks. Open-Label Phase: Participants will be eligible to enroll in the Open-Label Phase to receive andecaliximab 150 mg weekly for an additional 44 weeks. Extended Treatment Phase: Participants who complete Week 52 assessments will be eligible to enter into the Extended Treatment Phase to continue treatment with andecaliximab 150 mg for an additional 156 weeks. | Drug: Andecaliximab<br>* Andecaliximab administered via subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Placebo Comparator: Placebo<br>Double-Blind Phase: Participants will receive 2 single-use PFS of placebo coadministered weekly for 8 weeks. Open-Label Phase: Participants will be eligible to enroll in the Open-Label Phase to receive andecaliximab 150 mg weekly for 44 weeks. Extended Treatment Phase: Participants who complete Week 52 assessments will be eligible to enter into the Extended Treatment Phase to continue treatment with andecaliximab 150 mg for an additional 156 weeks. | Drug: Andecaliximab<br>* Andecaliximab administered via subcutaneous (SC) injection<br>* Other names: GS-5745;Drug: Placebo<br>* Placebo to match andecaliximab administered via SC injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase | Clinical response was defined as patient-reported outcomes (PRO2) score ≤ 8 at Week 8. PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with a missing PRO2 value at the Week 8 analysis visit were imputed as not achieving the Clinical Response. | Week 8 | 
| Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase | Endoscopic response was defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 8. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD value at Week 8 analysis visit were imputed as not achieving Endoscopic Response. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase | Clinical remission was defined as Crohn's Disease Activity Index (CDAI) ≤ 150 at Week 8. CDAI is used as a measure of clinical response and remission. It includes 8 variables of patient-reported symptoms and objective variables: stool count, abdominal pain, general well-being, complications, use of anti-diarrheal medications, presence of abdominal mass, hematocrit values, and weight. It has a minimum range of 0 and no upper bound, with higher scores indicating greater disease activity. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing CDAI score at Week 8 analysis visit were imputed as not achieving CDAI Remission. | Week 8 | 
| Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase | The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The SES-CD size-of-ulcer subscore ranges from 0 (none) to 3 (very large). Mucosal healing at Week 8 was defined as the size-of-ulcer subscore for segments with non-zero baseline value changes to zero at Week 8 AND the size-of-ulcer subscore for segments with zero value at baseline remain zero at Week 8. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD size-of-ulcer subscore at Week 8 analysis visit were imputed as not achieving Mucosal Healing. | Week 8 |