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

• BMS-936559 (Biological)
• Placebo (Other)

Primary outcomes

• 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 [Approximately 3 months]: 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
• Part 1: Tolerability of BMS-936559 in subjects with severe sepsis [Approximately 3 months]: 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
• Part 2: All-cause mortality within 90 days of study drug administration [Approximately 3 months]

Secondary outcomes

• 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) [Approximately 3 months]: OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.
• Organ dysfunction measured by proportion of OSFDs during index hospitalization [Approximately 3 months]: OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.
• 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 [Approximately 3 months]: 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.
• 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]

Sex: All, ages: 18 Years to any

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)

• Results publication: 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. PMID 30747773

• Bristol Myers Squibb, Study director, Bristol-Myers Squibb