Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of GS-5745 (Andecaliximab) in Adults With Moderate to Severe Active Ulcerative Colitis
- Conditions
- Ulcerative Colitis
- Interventions
- Registration Number
- NCT01831427
- Lead Sponsor
- Gilead Sciences
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 74
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Andecaliximab 0.3 mg/kg IV single ascending dose (SAD) Andecaliximab Participants will receive andecaliximab 0.3 milligrams per kilogram (mg/kg) on Day 1. Andecaliximab 150 mg SC (Adaptive MAD) Andecaliximab Participants will receive andecaliximab 150 mg on Days 1, 8, 15, 22, and 29. Andecaliximab 1.0 mg/kg IV (MAD) Andecaliximab Participants will receive andecaliximab 1.0 mg/kg on Days 1, 15, and 29. Andecaliximab 2.5 mg/kg IV (MAD) Andecaliximab Participants will receive andecaliximab 2.5 mg/kg on Days 1, 15, and 29. Placebo Pooled (SAD) Placebo to match Andecaliximab Participants will receive placebo on Day 1. Placebo Pooled (MAD) Placebo to match Andecaliximab Participants will receive placebo on Days 1, 15, and 29. Andecaliximab 5.0 mg/kg IV (SAD) Andecaliximab Participants will receive andecaliximab 5.0 mg/kg on Day 1. Andecaliximab 1.0 mg/kg IV (SAD) Andecaliximab Participants will receive andecaliximab 1.0 mg/kg on Day 1. Andecaliximab 2.5 mg/kg IV (SAD) Andecaliximab Participants will receive andecaliximab 2.5 mg/kg on Day 1. Andecaliximab 0.3 mg/kg IV multiple ascending doses (MAD) Andecaliximab Participants will receive andecaliximab 0.3 mg/kg on Days 1, 15, and 29. Andecaliximab 5.0 mg/kg IV (MAD) Andecaliximab Participants will receive andecaliximab 5.0 mg/kg on Days 1, 15, and 29.
- Primary Outcome Measures
Name Time Method PK Parameter: Ctau (MAD) 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 Ctau is defined as the observed drug concentration at the end of the dosing interval.
Pharmacokinetic (PK) Parameter: Cmax (SAD) Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 Cmax is defined as the maximum concentration of drug.
Percentage of Participants Who Experienced Any Treatment-Emergent Adverse Events (TEAEs) (SAD/MAD) 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 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.
PK Parameter: AUCtau (MAD) 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 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.
PK Parameter: Cmax (MAD) 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 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.
PK Parameter: AUCinf (SAD) Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time.
PK Parameter: AUClast (SAD) Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43 AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last observable concentration.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (16)
Ehrhardt Clinical Research, LLC
🇺🇸Belton, Missouri, United States
Delta Research Partners LLC
🇺🇸Monroe, Louisiana, United States
Institute of Pulmonology "Marius Nasta"
🇷🇴Bucharest, Romania
Community Research
🇺🇸Cincinnati, Ohio, United States
Clinical Research Institute of Michigan
🇺🇸Chesterfield Township, MI 48047, Michigan, United States
Semmelweis Egyetem Altalanos Orvostudomanyi Kar
🇭🇺Budapest, Pest, Hungary
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
UZ Leuven
🇧🇪Leuven, Belgium
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Republican Clinical Hospital
🇲🇩Chisinau, Moldova, Republic of
GIRI
🇨🇦Vancouver, British Columbia, Canada
LHSC University Campus
🇨🇦London, Ontario, Canada
Drug Research Centre
🇭🇺Balatonfured, Hungary
Academic Medical Center
🇳🇱Amsterdam, Netherlands
Academisch Ziekenhuis Maastricht
🇳🇱Maastricht, Netherlands
Clinical Pharma Center of Kenezy Gyula Korhaz Rendelointezet
🇭🇺Debrecen, Hajdú-Bihar, Hungary