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

• ClinicalTrials.gov Identifier: NCT02576457
• Recruitment Status: Terminated
• First Posted: October 15, 2015
• Last Update Posted: September 15, 2017
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Severe Sepsis; Septic Shock	Biological: BMS-936559; Other: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 2, 2015
• Actual Primary Completion Date: March 15, 2017
• Actual Study Completion Date: March 15, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Maximum observed serum concentration (Cmax) of BMS-936559 [ Time Frame: Approximately 3 months ]
2. Time of maximum observed serum concentration (Tmax) of BMS-936559 [ Time Frame: Approximately 3 months ]
3. Area under the serum concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)) of BMS-936559 [ Time Frame: Approximately 3 months ]
4. Area under the serum concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-936559 [ Time Frame: Approximately 3 months ]
5. Total Body Clearance (CLT) of BMS-936559 [ Time Frame: Approximately 3 months ]
6. Volume of distribution at steady state (Vss) of BMS-936559 [ Time Frame: Approximately 3 months ]
7. Terminal serum half-life (T-HALF) of BMS-936559 [ Time Frame: Approximately 3 months ]
8. Receptor occupancy based on PD-L1 receptor occupancy levels [ Time Frame: Approximately 3 months ]
9. Immune system function based on baseline and post-dosing assessments of mHLA-DR expression on monocytes at planned sampling timepoints [ Time Frame: Approximately 3 months ]
10. Immune system function based on absolute lymphocyte counts at planned sampling timepoints [ Time Frame: Approximately 3 months ]
11. Immune system function based on lipopolysaccharide (LPS)-induced whole blood TNFalpha production levels at planned sampling timepoints [ Time Frame: Approximately 3 months ]
12. Organ dysfunction measured by organ support-free days (OSFDs) [ Time Frame: Approximately 3 months ]
    OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.
13. Organ dysfunction measured by proportion of OSFDs during index hospitalization [ Time Frame: Approximately 3 months ]
    OSFD is defined as the last period of organ support-free duration during the index hospitalization stay prior to discharge.
14. Duration of mechanical ventilation, vasopressor use, and/or dialysis use separately during the index hospitalization [ Time Frame: Approximately 3 months ]
15. Incidence of secondary infections (as adjudicated by a clinical committee) up to 90 days post administration of BMS-936559 [ Time Frame: Approximately 3 months ]
16. All-cause mortality at 28 days, 90 days, and 1 year after study drug administration [ Time Frame: 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.

17. Immunogenicity measured by number of subjects having detectable anti-drug antibodies (ADA) at baseline and following administration of BMS-936559. [ Time Frame: Approximately 3 months ]
18. Immunogenicity measured by percentage of subjects having detectable anti-drug antibodies (ADA) at baseline and following administration of BMS-936559. [ Time Frame: Approximately 3 months ]

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

United States, California

Uc Davis Medical Center

Sacramento, California, United States, 95817

United States, Colorado

Local Institution

Denver, Colorado, United States, 80204

United States, Florida

University Of Florida

Gainesville, Florida, United States, 32610

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Osf Saint Francis Medical Center

Peoria, Illinois, United States, 61637

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Baystate Medical Center

Springfield, Massachusetts, United States, 01199

United States, Michigan

University of Michigan, Division of Acute Care Surgery

Ann Arbor, Michigan, United States, 48109-5033

United States, Missouri

Washington University School Of Medicine

Saint Louis, Missouri, United States, 63110

United States, Ohio

The Ohio State University

Columbus, Ohio, United States, 43210

St. Vincent'S Medical Center

Toledo, Ohio, United States, 43603

United States, Pennsylvania

UPMC

Pittsburgh, Pennsylvania, United States, 15261-2500

United States, Washington

Local Institution

Seattle, Washington, United States, 98104

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol Myers Squibb; Bristol-Myers Squibb

More Information

Additional Information:

BMS Clinical Trial Patient Recruiting 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02576457
• Other Study ID Numbers: AI471-049
• First Posted: October 15, 2015
• Last Update Posted: September 15, 2017
• Last Verified: September 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Sepsis; Toxemia; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; BMS-936559; Antineoplastic Agents, Immunological; Antineoplastic Agents