Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of GS-5745 (Andecaliximab) in Adults With Moderate to Severe Active Ulcerative Colitis

Study Overview
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Brief Summary
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The primary objectives of this study are as follows: To assess the safety and tolerability of escalating single and multiple doses of GS-5745 (andecaliximab) in participants with moderate to severe ulcerative colitis (UC) as assessed by adverse events (AEs) and laboratory abnormalities To assess the pharmacokinetics (PK) of GS-5745 (andecaliximab) in participants with moderate to severe UC.

Detailed Description
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The study will test the safety of the drug. Participants will be given different concentrations of the drug in Cohorts, starting from a lower dose to a higher dose. Single-Dose Treatment: A thorough assessment of safety and tolerability will be performed before escalating to the next higher dose. For example, the first 2 participants will be dosed in a staggered fashion 24 hours apart. Provided that there are no significant safety signals up to 24 hours post-dose for the first 2 participants, the remaining 4 participants will be dosed. A thorough assessment of safety and tolerability (through Day 14 post-dose) will be performed by the safety review committee before escalating to the next higher dose. Participants enrolled in a SAD cohort will be eligible to participate in a MAD or adaptive MAD cohort if eligibility criteria are met. Multiple-Dose Treatment: This design follows the same set-up as the Single-Dose Treatment. Dosing will not commence in the first MAD cohort until safety data from the second dose level SAD cohort has been reviewed through Day 15. Successive MAD cohorts will only be dosed after safety data from the previous, lower dose MAD cohort through Day 43 and the next higher dose SAD cohort through Day 15, have been reviewed by the safety review committee. An additional Adaptive MAD cohort will explore a subcutaneous dosing of andecaliximab 150 mg prefilled syringe once a week for 5 weeks.

Official Title
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A Phase 1 Double-blind, Randomized, Placebo-Controlled, Staggered, Single and Multiple Ascending Dose, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of GS-5745 in Subjects With Moderate to Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Andecaliximab
* Drug: Placebo to match Andecaliximab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or Female, 18 to 65 years of age Negative pregnancy test at screening Documented diagnosis of UC with a minimum disease extent of 15 centimeters (cm) from the anal verge Mayo Score of at least 3 for the SAD cohort and Mayo Score of at least 6 for the MAD cohorts Hepatic panel (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, direct bilirubin, alkaline phosphatase, lactate dehydrogenase [LDH] ≤ 2 times the upper limit of the normal range [ULN]) Serum creatinine ≤ 1.5 times the ULN Hemoglobin ≥ 10 grams per deciliter (g/dL) (both males and females) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1,500 milli meters [mm]^3) Platelets ≥ 100 x 10^9/L. Key Exclusion Criteria: Pregnant or lactating females Exhibit severe UC/ clinically significant active infection Current use of oral corticosteroids at a dose equivalent to > 20 mg/day of prednisone Any dose adjustment in oral corticosteroids or oral immunosuppressants (6-MP, Azathioprine), or oral 5-aminosalicylate (5-ASA) compounds within 30 days of Baseline Use of rectal formulations of 5-ASA compounds or corticosteroids within 2 weeks prior to randomization Crohn's disease or indeterminate colitis History of colectomy, partial colectomy, or dysplasia on biopsy Stool sample positive for Clostridium difficile (C. difficile) toxin, E. coli, Salmonella, Shigella, Campylobacter or Yersinia Treatment with Infliximab, Adalimumab, Natalizumab, Golimumab, Vedolizumab or Certolizumab within 8 weeks of randomization 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
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Minimum Age: 18 Years
Maximum Age: 65 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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Andecaliximab 0.3 mg/kg IV single ascending dose (SAD)<br>Participants will receive andecaliximab 0.3 milligrams per kilogram (mg/kg) on Day 1. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 1.0 mg/kg IV (SAD)<br>Participants will receive andecaliximab 1.0 mg/kg on Day 1. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 2.5 mg/kg IV (SAD)<br>Participants will receive andecaliximab 2.5 mg/kg on Day 1. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 5.0 mg/kg IV (SAD)<br>Participants will receive andecaliximab 5.0 mg/kg on Day 1. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Placebo Comparator: Placebo Pooled (SAD)<br>Participants will receive placebo on Day 1. | Drug: Placebo to match Andecaliximab<br>* Placebo to match andecaliximab administered by IV infusion<br>|
| Experimental: Andecaliximab 0.3 mg/kg IV multiple ascending doses (MAD)<br>Participants will receive andecaliximab 0.3 mg/kg on Days 1, 15, and 29. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 1.0 mg/kg IV (MAD)<br>Participants will receive andecaliximab 1.0 mg/kg on Days 1, 15, and 29. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 2.5 mg/kg IV (MAD)<br>Participants will receive andecaliximab 2.5 mg/kg on Days 1, 15, and 29. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 5.0 mg/kg IV (MAD)<br>Participants will receive andecaliximab 5.0 mg/kg on Days 1, 15, and 29. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Experimental: Andecaliximab 150 mg SC (Adaptive MAD)<br>Participants will receive andecaliximab 150 mg on Days 1, 8, 15, 22, and 29. | Drug: Andecaliximab<br>* Andecaliximab administered by intravenous (IV) infusion or subcutaneous (SC) injection<br>* Other names: GS-5745;|
| Placebo Comparator: Placebo Pooled (MAD)<br>Participants will receive placebo on Days 1, 15, and 29. | Drug: Placebo to match Andecaliximab<br>* Placebo to match andecaliximab administered by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Any Treatment-Emergent Adverse Events (TEAEs) (SAD/MAD) | TEAEs are any AEs with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. | SAD Cohorts: First dose date (Day 1) plus 30 days, MAD/Adaptive MAD Cohort: First dose date up to last dose date (Maximum: Day 29) plus 30 days | 
| Pharmacokinetic (PK) Parameter: Cmax (SAD) | Cmax is defined as the maximum concentration of drug. | Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 | 
| PK Parameter: Cmax (MAD) | Cmax is defined as the maximum concentration of drug over the dosing interval. Data for Day 1 was based on the data collected from Day 1 through Day 8. Data for Day 29 was based on the data collected from Day 29 through Day 36. | MAD Cohorts: Predose and 1, 2, and 6 hours postdose on Days 1 and 29, Predose on Days 8 and 36; Adaptive MAD Cohort: Predose and 6 hours postdose on Days 1, and 29, Predose on Days 8 and 36 | 
| PK Parameter: Ctau (MAD) | Ctau is defined as the observed drug concentration at the end of the dosing interval. | MAD Cohorts: Predose and 1, 2, and 6 hours postdose on Day 29; Predose on Day 36; Adaptive MAD Cohort: Predose and 6 hours postdose on Day 29; Predose on Day 36 | 
| PK Parameter: AUCinf (SAD) | AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time. | Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 | 
| PK Parameter: AUCtau (MAD) | AUCtau is defined as the area under the plasma concentration versus time curve over the dosing interval. Data for Day 1 was based on the data collected from Day 1 through Day 8. Data for Day 29 was based on the data collected from Day 29 through Day 36. | MAD Cohorts: Predose and 1, 2, and 6 hours postdose on Days 1 and 29; Predose on Days 8 and 36; Adaptive MAD Cohort: Predose and 6 hours postdose on Days 1, and 29; Predose on Days 8 and 36 | 
| PK Parameter: AUClast (SAD) | AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last observable concentration. | Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 |