Safety, Pharmacokinetics and Pharmacodynamics of BMS-936559 in Severe Sepsis

A Phase 1b/2a, Randomized, Double-Blinded, Placebo-Controlled, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMS-936559 in Subjects With Severe Sepsis

The purpose of this study is to determine whether BMS-936559 is safe and has the desired pharmacologic activity in patients who have severe sepsis.

Study Overview

• Status: Terminated
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: Other: Placebo; Biological: BMS-936559

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
  • Colorado
    • Denver, Colorado, United States, 80204
      • Local Institution
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5033
      • University of Michigan, Division of Acute Care Surgery
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
    • Toledo, Ohio, United States, 43603
      • St. Vincent's Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261-2500
      • UPMC
  • Washington
    • Seattle, Washington, United States, 98104
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Severe sepsis or septic shock for at least 24 hours
• Documented or suspected infection
• Sepsis-induced immunosuppression
• Men and women ≥ 18 years old

Exclusion Criteria:

• Autoimmune disease
• Organ transplant or bone marrow transplant
• Cancer treated in the past 6 months
• Hepatitis B virus (HBV) Infection
• Human Immunodeficiency Virus (HIV) infection and not on therapy prior to this episode of sepsis
• Hepatitis C virus (HCV) infection and still has virus (not cured)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BMS-936559; BMS-936559 Intravenous infusion on specified days	Biological: BMS-936559
Other: Placebo; Placebo on specified days	Other: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Safety of BMS-936559 in subjects with severe sepsis - measured by the incidence rates of death, AEs, SAEs, AEs leading to discontinuation, AEs of special interest and laboratory abnormalities	Safety will be measured by the incidence rates of death, Adverse event (AEs), Serious adverse event (SAEs), AEs leading to discontinuation, AEs of special interest (identified from PD-L1 oncology trial), and laboratory abnormalities	Approximately 3 months
Part 1: Tolerability of BMS-936559 in subjects with severe sepsis	Tolerability will be measured by the incidence rates of death, AEs, SAEs, AEs leading to discontinuation, AEs of special interest (identified from PD-L1 oncology trial), and laboratory abnormalities	Approximately 3 months
Part 2: All-cause mortality within 90 days of study drug administration		Approximately 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed serum concentration (Cmax) of BMS-936559		Approximately 3 months
Time of maximum observed serum concentration (Tmax) of BMS-936559		Approximately 3 months
Area under the serum concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)) of BMS-936559		Approximately 3 months
Area under the serum concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-936559		Approximately 3 months
Total Body Clearance (CLT) of BMS-936559		Approximately 3 months
Volume of distribution at steady state (Vss) of BMS-936559		Approximately 3 months
Terminal serum half-life (T-HALF) of BMS-936559		Approximately 3 months
Receptor occupancy based on PD-L1 receptor occupancy levels		Approximately 3 months
Immune system function based on baseline and post-dosing assessments of mHLA-DR expression on monocytes at planned sampling timepoints		Approximately 3 months
Immune system function based on absolute lymphocyte counts at planned sampling timepoints		Approximately 3 months
Immune system function based on lipopolysaccharide (LPS)-induced whole blood TNFalpha production levels at planned sampling timepoints		Approximately 3 months
Organ dysfunction measured by organ support-free days (OSFDs)	OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.	Approximately 3 months
Organ dysfunction measured by proportion of OSFDs during index hospitalization	OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.	Approximately 3 months
Duration of mechanical ventilation, vasopressor use, and/or dialysis use separately during the index hospitalization		Approximately 3 months
Incidence of secondary infections (as adjudicated by a clinical committee) up to 90 days post administration of BMS-936559		Approximately 3 months
All-cause mortality at 28 days, 90 days, and 1 year after study drug administration	All-cause mortality at 28 days, 90 days, and 1 year post administration of BMS-936559. Time to death will also be used to assess the treatment effect.	Approximately 3 months
Immunogenicity measured by number of subjects having detectable anti-drug antibodies (ADA) at baseline and following administration of BMS-936559.		Approximately 3 months
Immunogenicity measured by percentage of subjects having detectable anti-drug antibodies (ADA) at baseline and following administration of BMS-936559.		Approximately 3 months

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, Martin GS, Coopersmith CM, Brakenridge S, Mayr FB, Park PK, Ye J, Catlett IM, Girgis IG, Grasela DM. Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559). Crit Care Med. 2019 May;47(5):632-642. doi: 10.1097/CCM.0000000000003685.

Helpful Links

• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2015
• Primary Completion (Actual): March 15, 2017
• Study Completion (Actual): March 15, 2017

Study Registration Dates

• First Submitted: October 13, 2015
• First Submitted That Met QC Criteria: October 14, 2015
• First Posted (Estimate): October 15, 2015

Study Record Updates

• Last Update Posted (Actual): September 15, 2017
• Last Update Submitted That Met QC Criteria: September 14, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Antineoplastic Agents; Antineoplastic Agents, Immunological; BMS-936559
• Other Study ID Numbers: AI471-049

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No