Severe Sepsis
Conditions
Brief summary
A study to evaluate the safety, tolerability and pharmacokinetics of Nivolumab in participants with severe sepsis or septic shock.
Interventions
BIOLOGICALNivolumab
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Men and women ages ≥ 18 years old * Documented or suspected infection * Severe sepsis or septic shock for at least 24 hours * Sepsis-induced immunosuppression * In Intensive Care Unit (ICU) with no plans to discharge in next 24 hours
Exclusion criteria
* Previous episode of severe sepsis or septic shock with ICU admission during the current hospitalization * Autoimmune disease * Organ or bone marrow transplant * Cancer treatment in the past 6 weeks * 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); Chronic hepatitis B virus (HBV) infection and not on treatment Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Half-life (T1/2) | Day 1 and subsequent days after, up to 90 days | Half-Life of nivolumab derived from serum concentration |
| Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | Day 1 and subsequent days after, up to 90 days | Area under the serum concentration-time curve from time zero to time of last quantifiable concentration |
| Total Clearance (CLT) | Day 1 and subsequent days after, up to 90 days | Total clearance of serum concentration of nivolumab |
| Volume of Distribution (Vd) | Day 1 and subsequent days after, up to 90 days | Vlume of distribution of nivolumab serum concentration |
| Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Screening, day -1, day 1 and subsequent days after, up to 90 days | — |
| Composite of Vital Signs and Electrocardiogram (ECG) | Screening up to 90 days (Discharge) | Includes body temperature, respiratory rate, blood pressure and heart rate. Blood pressure and heart rate should be measured after the participant has been resting quietly for at least 5 minutes. |
| Peak Nivolumab Serum Concentration (Cmax) | Day 1 and subsequent days after, up to 90 days | Participants peak nivolumab serum concentration |
| Trough Nivolumab Serum Concentration (Cmin) | Day 1 and subsequent days after, up to 90 days | Participant trough nivolumab serum concentration |
| Average Nivolumab Serum Concentration (Cavg) | Day 1 and subsequent days after, up to 90 days | Participant average nivolumab serum concentration |
| Time of Maximum Observed Concentration (Tmax) | Day 1 and subsequent days after, up to 90 days | Participant observed time of maximum concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Detectable Anti-nivolumab Antibodies | Baseline and subsequent days after, up to 90 days | Participant with positive anti-drug antibody detection |
| Number of Participants With Any Detectable Anti-drug Antibodies | Baseline and subsequent days after, up to 90 days | — |
| Receptor Occupancy | Day 1 and up to day 90 (discharge) | Receptor occupancy on T cells at baseline and after study treatment administration at planned sampling time points |
Countries
United States
Participant flow
Pre-assignment details
38 subjects were enrolled in the study. 31 were randomized; 7 not randomized: (5) Failed to meet study eligibility criteria, (1) died, (1) withdrew consent
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab (480 mg) the assessment of the safety and tolerability of a single dose of nivolumab 480 mg | 15 |
| Nivolumab (960 mg) the assessment of the safety and tolerability of a single dose of nivolumab 960 mg | 16 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 6 |
| Overall Study | Not Disclosed | 2 | 2 |
| Overall Study | Subject No Longer Meets Study Criteria | 1 | 0 |
| Overall Study | Subject Withdrew Consent | 0 | 1 |
Baseline characteristics
| Characteristic | Nivolumab (480 mg) | Nivolumab (960 mg) | Total |
|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 12.3 | 58.4 Years STANDARD_DEVIATION 15.16 | 57.5 Years STANDARD_DEVIATION 13.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 15 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 15 | 6 / 16 |
| other Total, other adverse events | 14 / 15 | 14 / 16 |
| serious Total, serious adverse events | 1 / 15 | 7 / 16 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)]
Area under the serum concentration-time curve from time zero to time of last quantifiable concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 18099 h*ug/mL | Geometric Coefficient of Variation 51 |
| Nivolumab (960 mg) | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-T)] | 32130 h*ug/mL | Geometric Coefficient of Variation 83 |
Primary
Average Nivolumab Serum Concentration (Cavg)
Participant average nivolumab serum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Average Nivolumab Serum Concentration (Cavg) | 42.7 ug/mL | Geometric Coefficient of Variation 28.5 |
| Nivolumab (960 mg) | Average Nivolumab Serum Concentration (Cavg) | 85.4 ug/mL | Geometric Coefficient of Variation 28.5 |
Primary
Composite of Vital Signs and Electrocardiogram (ECG)
Includes body temperature, respiratory rate, blood pressure and heart rate. Blood pressure and heart rate should be measured after the participant has been resting quietly for at least 5 minutes.
Time frame: Screening up to 90 days (Discharge)
Population: All treated participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Heart Rate (beats/min) Screening | 80.1 Percentage | Standard Deviation 21.34 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Temperature (C) Screening | 37.19 Percentage | Standard Deviation 0.79 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | ECG Change from Baseline (Discharge) | -18.0 Percentage | Standard Deviation 31.68 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Diastolic Pressure (mmHg) Discharge | 79.7 Percentage | Standard Deviation 16.49 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Diastolic Pressure (mmHg) Screening | 61.5 Percentage | Standard Deviation 20.37 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Systolic Pressure (mmHg) Discharge | 129.0 Percentage | Standard Deviation 25.06 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Heart Rate (beats/min) Discharge | 85.3 Percentage | Standard Deviation 18.89 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Resp. Rate (breaths/min) Discharge | 18.8 Percentage | Standard Deviation 2.71 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Systolic Pressure (mmHg) Screening | 116.5 Percentage | Standard Deviation 21.48 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Temperature (C) Discharge | 36.60 Percentage | Standard Deviation 0.276 |
| Nivolumab (480 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Resp. Rate (breaths/min) Screening | 23.0 Percentage | Standard Deviation 6.08 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Temperature (C) Discharge | 36.90 Percentage | Standard Deviation 0.337 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Heart Rate (beats/min) Screening | 94.6 Percentage | Standard Deviation 16.64 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Systolic Pressure (mmHg) Discharge | 110.0 Percentage | Standard Deviation 16.47 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | ECG Change from Baseline (Discharge) | -29.0 Percentage | Standard Deviation 3.46 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Diastolic Pressure (mmHg) Screening | 58.5 Percentage | Standard Deviation 9 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Resp. Rate (breaths/min) Screening | 24.4 Percentage | Standard Deviation 8.83 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Temperature (C) Screening | 37.11 Percentage | Standard Deviation 0.77 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Diastolic Pressure (mmHg) Discharge | 70.5 Percentage | Standard Deviation 16.28 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Heart Rate (beats/min) Discharge | 86.5 Percentage | Standard Deviation 19.76 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Resp. Rate (breaths/min) Discharge | 17.5 Percentage | Standard Deviation 3.32 |
| Nivolumab (960 mg) | Composite of Vital Signs and Electrocardiogram (ECG) | Vital Signs - Systolic Pressure (mmHg) Screening | 105.5 Percentage | Standard Deviation 14.65 |
Primary
Half-life (T1/2)
Half-Life of nivolumab derived from serum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Half-life (T1/2) | 353 hours | Standard Deviation 126.5 |
| Nivolumab (960 mg) | Half-life (T1/2) | 378 hours | Standard Deviation 189.6 |
Primary
Peak Nivolumab Serum Concentration (Cmax)
Participants peak nivolumab serum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Peak Nivolumab Serum Concentration (Cmax) | 123 ug/mL | Geometric Coefficient of Variation 85.4 |
| Nivolumab (960 mg) | Peak Nivolumab Serum Concentration (Cmax) | 246 ug/mL | Geometric Coefficient of Variation 85.4 |
Primary
Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths
Time frame: Screening, day -1, day 1 and subsequent days after, up to 90 days
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nivolumab (480 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Adverse Events (AEs) | 93.3 Percentage |
| Nivolumab (480 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | AEs leading to discontinuation | 0.0 Percentage |
| Nivolumab (480 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Immune-Mediated Adverse Events | 53.3 Percentage |
| Nivolumab (480 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Deaths | 40.0 Percentage |
| Nivolumab (480 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Serious Adverse Events (SAEs) | 6.7 Percentage |
| Nivolumab (960 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Deaths | 38.7 Percentage |
| Nivolumab (960 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Serious Adverse Events (SAEs) | 43.8 Percentage |
| Nivolumab (960 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Adverse Events (AEs) | 87.5 Percentage |
| Nivolumab (960 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | Immune-Mediated Adverse Events | 81.3 Percentage |
| Nivolumab (960 mg) | Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths | AEs leading to discontinuation | 0.0 Percentage |
Primary
Time of Maximum Observed Concentration (Tmax)
Participant observed time of maximum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab (480 mg) | Time of Maximum Observed Concentration (Tmax) | 1.67 hours |
| Nivolumab (960 mg) | Time of Maximum Observed Concentration (Tmax) | 1.53 hours |
Primary
Total Clearance (CLT)
Total clearance of serum concentration of nivolumab
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Total Clearance (CLT) | 0.025 L/h | Geometric Coefficient of Variation 50 |
| Nivolumab (960 mg) | Total Clearance (CLT) | 0.027 L/h | Geometric Coefficient of Variation 85 |
Primary
Trough Nivolumab Serum Concentration (Cmin)
Participant trough nivolumab serum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All treated participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Trough Nivolumab Serum Concentration (Cmin) | 21.6 ug/mL | Geometric Coefficient of Variation 39 |
| Nivolumab (960 mg) | Trough Nivolumab Serum Concentration (Cmin) | 43.2 ug/mL | Geometric Coefficient of Variation 39 |
Primary
Volume of Distribution (Vd)
Vlume of distribution of nivolumab serum concentration
Time frame: Day 1 and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nivolumab (480 mg) | Volume of Distribution (Vd) | 12.0 L | Geometric Coefficient of Variation 42 |
| Nivolumab (960 mg) | Volume of Distribution (Vd) | 13.3 L | Geometric Coefficient of Variation 54 |
Secondary
Number of Participants With Any Detectable Anti-drug Antibodies
Time frame: Baseline and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab (480 mg) | Number of Participants With Any Detectable Anti-drug Antibodies | 26.7 Percentage |
| Nivolumab (960 mg) | Number of Participants With Any Detectable Anti-drug Antibodies | 56.3 Percentage |
Secondary
Number of Participants With Detectable Anti-nivolumab Antibodies
Participant with positive anti-drug antibody detection
Time frame: Baseline and subsequent days after, up to 90 days
Population: All Treated Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab (480 mg) | Number of Participants With Detectable Anti-nivolumab Antibodies | 73.3 Percentage |
| Nivolumab (960 mg) | Number of Participants With Detectable Anti-nivolumab Antibodies | 75.0 Percentage |
Secondary
Receptor Occupancy
Receptor occupancy on T cells at baseline and after study treatment administration at planned sampling time points
Time frame: Day 1 and up to day 90 (discharge)
Population: All Treated Participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nivolumab (480 mg) | Receptor Occupancy | Baseline | 0.00 Percentage | Standard Deviation 0 |
| Nivolumab (480 mg) | Receptor Occupancy | Study Discharge | 81.272 Percentage | Standard Deviation 27.69 |
| Nivolumab (960 mg) | Receptor Occupancy | Study Discharge | 71.14 Percentage | Standard Deviation 34.83 |
| Nivolumab (960 mg) | Receptor Occupancy | Baseline | 0.00 Percentage | Standard Deviation 0 |