Clinical trial NCT01831427: Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of GS-5745 (Andecaliximab) in Adults With Moderate to Severe Active Ulcerative Colitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Ulcerative Colitis
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2013-04-15
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants Who Experienced Any Treatment-Emergent Adverse Events (TEAEs) (SAD/MAD)
timeFrame: 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
measure: Pharmacokinetic (PK) Parameter: Cmax (SAD)
timeFrame: Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43
measure: PK Parameter: Cmax (MAD)
timeFrame: 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
measure: PK Parameter: Ctau (MAD)
timeFrame: 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
measure: PK Parameter: AUCinf (SAD)
timeFrame: Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43
measure: PK Parameter: AUCtau (MAD)
timeFrame: 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
measure: PK Parameter: AUClast (SAD)
timeFrame: Predose and 1, 2, and 6 hours postdose on Day 1; Days 2, 3, 8, 15, 29, and 43
Secondary outcomes:
Other outcomes:
Locations:
city: Monroe
country: United States
facility: Delta Research Partners LLC
state: Louisiana
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Chesterfield Township, MI 48047
country: United States
facility: Clinical Research Institute of Michigan
state: Michigan
city: Belton
country: United States
facility: Ehrhardt Clinical Research, LLC
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Community Research
state: Ohio
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: GIRI
state: British Columbia
city: London
country: Canada
facility: LHSC University Campus
state: Ontario
city: Debrecen
country: Hungary
facility: Clinical Pharma Center of Kenezy Gyula Korhaz Rendelointezet
state: Hajdú-Bihar
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Altalanos Orvostudomanyi Kar
state: Pest
city: Balatonfured
country: Hungary
facility: Drug Research Centre
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Bucharest
country: Romania
facility: Institute of Pulmonology "Marius Nasta"
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Bhandari BR, Fogel R, Onken J, Yen EH, Kanwar B, Subramanian GM, McHutchison GJ, et al. Safety and Efficacy of GS-5745 an Anti-Matrix Metalloproteinase 9 (MMP) Monoclonal Antibody in Patients with Moderately to Severely Active Ulcerative Colitis. Gastroenterology 2015;148 (4): S-1196.