Sepsis, Septic Shock
Conditions
Brief summary
The study will evaluate the vasopressor requirement, hemodynamic response and measures of tissue perfusion in patients with septic shock receiving an infusion of drotrecogin alfa (activated) compared to patients not receiving drotrecogin alfa (activated).
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: * 18 years of age or older with a diagnosis of septic shock * presence of a pulmonary artery catheter (or central venous catheters) * requiring vasopressor support despite adequate fluid resuscitation * an intravenous steroid administered for septic shock, except for those patients who were tested and are responders to a corticotropin stimulation test, or patients who do not receive a steroid due to the clinical judgment of the treating physician, based on an alternate assessment (e.g. normal baseline cortisol). Exclusion: * Onset of first-sepsis induced organ dysfunction is greater than 24 hours from the time of informed consent * Baseline measurements of pulmonary artery occlusive pressure (PAOP) \< 12 mmHg or a central venous pressure (CVP) \< 8 mmHg * Patient requires continuous oxygen therapy by face-mask * The presence of an advanced directive to withhold life-sustaining treatment, with the exception of a directive to withhold chest compressions only * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry * Weight \> 200 kg * Are moribund (not expected to survive 24 hours) * Are pregnant or are lactating and the milk is to be ingested by the infant (pregnancy status must be verified by urine or serum testing) * Have not completed written informed consent signed by the patient or the patient's legal representative.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Vasopressor Index (CVI) | baseline to 24 hours | CVI is sum of rankings for all vasopressors being used by patient at given time. Based on relative potency and dosing range for each vasopressor, each vasopressor was assigned ranking of 1 (low dosage) to 4 (high dosage). Range of CVI is between 1 and 20. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 7 Day All-cause In-hospital Mortality | baseline to 7 days | — |
| Endogenous Protein C Level | Baseline to 24 Hours | — |
| Mixed Venous Oxygen Saturation | Baseline to 24 Hours | Cardiovascular performance measures obtained with a pulmonary catheter as assessed by mixed venous oxygen saturation. |
| Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) | Baseline, 96 hours | CVI is sum of rankings for all vasopressors being used by patient at given time. Based on relative potency and dosing range for each vasopressor, each vasopressor was assigned ranking of 1 (low dosage) to 4 (high dosage). Range of CVI is between 1 and 20. |
| Mean Arterial Pressure | baseline to 24 hours | — |
| Lactate Level | Baseline to 6 Hours | Measures of global tissue perfusion and oxygenation were assessed via lactate levels. |
| Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | Baseline to 24 Hours | Per vessel category (and per quadrant), scored flow as follows: no flow=0, intermediate flow=1, sluggish flow=2, continuous flow=3. The MFI per vessel category calculated with formula (Q1+Q2+Q3+Q4)/4. Scores could range from 0 (sluggish flow) to 3 (continuous flow). |
| Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours | Baseline and 24 Hours | The presence of 5 organ dysfunctions (cardiovascular, respiratory, renal, hepatic, coagulation) was assessed using a Sequential Organ Failure Assessment (SOFA) score. Each organ has a possible dysfunction score of 0 to 4, for a total SOFA score range of 0 (no organ dysfunction) to 20 (all organs with dysfunction). |
| Change From Baseline in Creatinine Clearance (CrCl) at 24 Hours | Baseline and 24 hours | CrCl = (urine creatinine\*urine volume)/(plasma creatinine\*time period of urine collection). Corrected CrCl = CrCl\*1.73/body surface area. Change in CrCl = Endpoint minus baseline. |
| Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index | Baseline to 24 Hours | Cardiac Index = cardiac output divided by body surface area. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Bleeding Events | baseline to 7 days | Serious bleeding event resulted in one of following outcomes, or was significant for any reason: initial/ prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly/birth defect. Intracranial hemorrhage was also considered serious bleeding event. |
Countries
United States
Participant flow
Pre-assignment details
Although 22 and 21 patients were randomized to drotrecogin alfa (activated) \[DrotA(a)\] and control, respectively, 3 patients in DrotA(a) and 2 patients in control did not receive the per-protocol treatment, and as such, they have been excluded from the baseline demographics and the per-protocol efficacy analyses.
Participants by arm
| Arm | Count |
|---|---|
| Drotrecogin Cohort Group received drotrecogin alfa (activated) per physician-directed therapy | 19 |
| Control Cohort Group did not receive drotrecogin alfa (activated) per physician-directed therapy | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 2 |
Baseline characteristics
| Characteristic | Drotrecogin Cohort | Control Cohort | Total |
|---|---|---|---|
| Age Continuous | 68.0 years STANDARD_DEVIATION 11.8 | 65.8 years STANDARD_DEVIATION 15 | 66.9 years STANDARD_DEVIATION 13.3 |
| Cardiac Index | 3.5 liters/minute/meters squared STANDARD_DEVIATION 1.7 | 3.3 liters/minute/meters squared STANDARD_DEVIATION 1.4 | 3.4 liters/minute/meters squared STANDARD_DEVIATION 1.6 |
| Creatinine Clearance | 69.2 milliliter per minute STANDARD_DEVIATION 77 | 29.9 milliliter per minute STANDARD_DEVIATION 31.1 | 52.9 milliliter per minute STANDARD_DEVIATION 64.5 |
| Cumulative Vasopressor Index (CVI) | 4.3 units on a scale STANDARD_DEVIATION 2.1 | 4.4 units on a scale STANDARD_DEVIATION 2.4 | 4.4 units on a scale STANDARD_DEVIATION 2.2 |
| Lactate Levels | 2.0 millimoles per Liter STANDARD_DEVIATION 1.1 | 2.6 millimoles per Liter STANDARD_DEVIATION 2.8 | 2.3 millimoles per Liter STANDARD_DEVIATION 2.1 |
| Mean Arterial Pressure (MAP) | 73.5 mm Hg STANDARD_DEVIATION 9.9 | 72.1 mm Hg STANDARD_DEVIATION 9.4 | 72.8 mm Hg STANDARD_DEVIATION 9.5 |
| Mixed Venous Oxygen Saturation | 68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 15.6 | 68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 10.1 | 68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 12.9 |
| Number of Organ Dysfunctions | 2.5 number of organ dysfunctions STANDARD_DEVIATION 0.8 | 2.0 number of organ dysfunctions STANDARD_DEVIATION 0.9 | 2.3 number of organ dysfunctions STANDARD_DEVIATION 0.9 |
| Race/Ethnicity African | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity Caucasian | 16 participants | 15 participants | 31 participants |
| Race/Ethnicity East Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity Hispanic | 1 participants | 3 participants | 4 participants |
| Ratio of Arterial Partial Pressure of Oxygen to Fraction of Inspired Oxygen (PaO2/FiO2) | 191.8 mm Hg / percent inspired oxygen | 248.3 mm Hg / percent inspired oxygen | 222.0 mm Hg / percent inspired oxygen |
| Region of Enrollment United States | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 23 Participants |
| Total Sequential Organ Failure Assessment Score | 8.5 units on a scale STANDARD_DEVIATION 2 | 8.3 units on a scale STANDARD_DEVIATION 3.2 | 8.4 units on a scale STANDARD_DEVIATION 2.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / — | 0 / — |
| serious Total, serious adverse events | 4 / — | 3 / — |
Outcome results
Primary
Cumulative Vasopressor Index (CVI)
CVI is sum of rankings for all vasopressors being used by patient at given time. Based on relative potency and dosing range for each vasopressor, each vasopressor was assigned ranking of 1 (low dosage) to 4 (high dosage). Range of CVI is between 1 and 20.
Time frame: baseline to 24 hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Cumulative Vasopressor Index (CVI) | 24 Hour | 2.3 units on a scale | Standard Deviation 2.5 |
| Drotrecogin Cohort | Cumulative Vasopressor Index (CVI) | 24 Hour Change from Baseline | -2.0 units on a scale | Standard Deviation 2.2 |
| Control Cohort | Cumulative Vasopressor Index (CVI) | 24 Hour | 3.0 units on a scale | Standard Deviation 2.8 |
| Control Cohort | Cumulative Vasopressor Index (CVI) | 24 Hour Change from Baseline | -1.4 units on a scale | Standard Deviation 2.2 |
Comparison: 24-Hour p-valuep-value: 0.238Repeated Measures - propensity adjusted
p-value: 0.281Repeated Measures - propensity adjusted
Secondary
7 Day All-cause In-hospital Mortality
Time frame: baseline to 7 days
Population: All enrolled patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Drotrecogin Cohort | 7 Day All-cause In-hospital Mortality | Alive at 7 Days | 18 partipants |
| Drotrecogin Cohort | 7 Day All-cause In-hospital Mortality | Not Alive at 7 Days | 4 partipants |
| Control Cohort | 7 Day All-cause In-hospital Mortality | Alive at 7 Days | 13 partipants |
| Control Cohort | 7 Day All-cause In-hospital Mortality | Not Alive at 7 Days | 8 partipants |
Secondary
Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index
Cardiac Index = cardiac output divided by body surface area.
Time frame: Baseline to 24 Hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index | 24 Hours | 3.3 liters/minute/meters squared | Standard Deviation 0.7 |
| Drotrecogin Cohort | Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index | 24 Hour Change from Baseline | -0.2 liters/minute/meters squared | Standard Deviation 1.5 |
| Control Cohort | Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index | 24 Hours | 3.2 liters/minute/meters squared | Standard Deviation 1 |
| Control Cohort | Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index | 24 Hour Change from Baseline | 0.1 liters/minute/meters squared | Standard Deviation 0.9 |
p-value: 0.704Repeated Measures - propensity adjusted
p-value: 0.702Repeated Measures - propensity adjusted
Secondary
Change From Baseline in Creatinine Clearance (CrCl) at 24 Hours
CrCl = (urine creatinine\*urine volume)/(plasma creatinine\*time period of urine collection). Corrected CrCl = CrCl\*1.73/body surface area. Change in CrCl = Endpoint minus baseline.
Time frame: Baseline and 24 hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drotrecogin Cohort | Change From Baseline in Creatinine Clearance (CrCl) at 24 Hours | -9.74 milliliter per minute | Standard Deviation 75.45 |
| Control Cohort | Change From Baseline in Creatinine Clearance (CrCl) at 24 Hours | 1.66 milliliter per minute | Standard Deviation 28.9 |
p-value: 0.165Repeated Measures - propensity adjusted
Secondary
Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI)
CVI is sum of rankings for all vasopressors being used by patient at given time. Based on relative potency and dosing range for each vasopressor, each vasopressor was assigned ranking of 1 (low dosage) to 4 (high dosage). Range of CVI is between 1 and 20.
Time frame: Baseline, 96 hours
Population: Number of per-protocol participants with values at baseline and 96 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) | 96 Hour | 0.4 units on a scale | Standard Deviation 1.3 |
| Drotrecogin Cohort | Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) | 96 Hour Change from Baseline | -3.7 units on a scale | Standard Deviation 2.5 |
| Control Cohort | Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) | 96 Hour Change from Baseline | -3.3 units on a scale | Standard Deviation 2.1 |
| Control Cohort | Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) | 96 Hour | 0.5 units on a scale | Standard Deviation 1.4 |
p-value: 0.478Mixed Models Analysis
Secondary
Endogenous Protein C Level
Time frame: Baseline to 24 Hours
Population: Number of per-protocol participants with values at baseline, 12, and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Endogenous Protein C Level | 24 Hours | 54.7 percentage of Protein C activity | Standard Deviation 20.7 |
| Drotrecogin Cohort | Endogenous Protein C Level | Baseline | 38.7 percentage of Protein C activity | Standard Deviation 25.2 |
| Drotrecogin Cohort | Endogenous Protein C Level | 24 Hour Change from Baseline | 16.3 percentage of Protein C activity | Standard Deviation 16.2 |
| Drotrecogin Cohort | Endogenous Protein C Level | 12 Hours | 48.2 percentage of Protein C activity | Standard Deviation 23 |
| Control Cohort | Endogenous Protein C Level | 24 Hour Change from Baseline | 2.4 percentage of Protein C activity | Standard Deviation 16.7 |
| Control Cohort | Endogenous Protein C Level | Baseline | 34.8 percentage of Protein C activity | Standard Deviation 19.1 |
| Control Cohort | Endogenous Protein C Level | 24 Hours | 40.0 percentage of Protein C activity | Standard Deviation 17.9 |
| Control Cohort | Endogenous Protein C Level | 12 Hours | 38.9 percentage of Protein C activity | Standard Deviation 19.6 |
p-value: 0.552Repeated Measures - propensity adjusted
p-value: 0.129Repeated Measures - propensity adjusted
p-value: 0.03Repeated Measures - propensity adjusted
p-value: 0.002Repeated Measures - propensity adjusted
Secondary
Lactate Level
Measures of global tissue perfusion and oxygenation were assessed via lactate levels.
Time frame: Baseline to 6 Hours
Population: Number of per-protocol participants with values at baseline and 6 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Lactate Level | 6 Hours | 1.8 millimoles per Liter | Standard Deviation 1 |
| Drotrecogin Cohort | Lactate Level | 6 Hour Change from Baseline | -0.2 millimoles per Liter | Standard Deviation 0.6 |
| Control Cohort | Lactate Level | 6 Hours | 2.8 millimoles per Liter | Standard Deviation 4.6 |
| Control Cohort | Lactate Level | 6 Hour Change from Baseline | 0.4 millimoles per Liter | Standard Deviation 1.7 |
p-value: 0.061Repeated Measures - propensity adjusted
p-value: 0.027Repeated Measures - propensity adjusted
Secondary
Mean Arterial Pressure
Time frame: baseline to 24 hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Mean Arterial Pressure | 24 Hours | 78.2 mm Hg | Standard Deviation 11.3 |
| Drotrecogin Cohort | Mean Arterial Pressure | 24 Hour Change from Baseline | 4.7 mm Hg | Standard Deviation 14.6 |
| Control Cohort | Mean Arterial Pressure | 24 Hours | 75.6 mm Hg | Standard Deviation 9.8 |
| Control Cohort | Mean Arterial Pressure | 24 Hour Change from Baseline | 2.5 mm Hg | Standard Deviation 12.4 |
p-value: 0.442Repeated Measures - propensity adjusted
p-value: 0.871Repeated Measures - propensity adjusted
Secondary
Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI)
Per vessel category (and per quadrant), scored flow as follows: no flow=0, intermediate flow=1, sluggish flow=2, continuous flow=3. The MFI per vessel category calculated with formula (Q1+Q2+Q3+Q4)/4. Scores could range from 0 (sluggish flow) to 3 (continuous flow).
Time frame: Baseline to 24 Hours
Population: Number of per-protocol participants with values at baseline, 12, and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | Baseline | 2.70 units on a scale | Standard Deviation 0.51 |
| Drotrecogin Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 12 Hour | 2.95 units on a scale | Standard Deviation 0.13 |
| Drotrecogin Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 24 Hour | 2.56 units on a scale | Standard Deviation 0.83 |
| Drotrecogin Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 24 Hour Change from Baseline | -0.21 units on a scale | Standard Deviation 0.61 |
| Control Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 24 Hour Change from Baseline | 0.06 units on a scale | Standard Deviation 0.27 |
| Control Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | Baseline | 2.50 units on a scale | Standard Deviation 0.7 |
| Control Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 24 Hour | 2.65 units on a scale | Standard Deviation 0.47 |
| Control Cohort | Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) | 12 Hour | 2.80 units on a scale | Standard Deviation 0.35 |
p-value: 0.242Repeated Measures - propensity adjusted
p-value: 0.083Repeated Measures - propensity adjusted
p-value: 0.81Repeated Measures - propensity adjusted
p-value: 0.623Repeated Measures - propensity adjusted
Secondary
Mixed Venous Oxygen Saturation
Cardiovascular performance measures obtained with a pulmonary catheter as assessed by mixed venous oxygen saturation.
Time frame: Baseline to 24 Hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Mixed Venous Oxygen Saturation | 24 Hours | 69.6 percent saturation mixed venous oxygen | Standard Deviation 8.3 |
| Drotrecogin Cohort | Mixed Venous Oxygen Saturation | 24 Hour Change from Baseline | 3.7 percent saturation mixed venous oxygen | Standard Deviation 14.5 |
| Control Cohort | Mixed Venous Oxygen Saturation | 24 Hours | 75.0 percent saturation mixed venous oxygen | Standard Deviation 11.1 |
| Control Cohort | Mixed Venous Oxygen Saturation | 24 Hour Change from Baseline | 6.5 percent saturation mixed venous oxygen | Standard Deviation 13.3 |
p-value: 0.128Repeated Measures - propensity adjusted
p-value: 0.234Repeated Measures - propensity adjusted
Secondary
Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours
The presence of 5 organ dysfunctions (cardiovascular, respiratory, renal, hepatic, coagulation) was assessed using a Sequential Organ Failure Assessment (SOFA) score. Each organ has a possible dysfunction score of 0 to 4, for a total SOFA score range of 0 (no organ dysfunction) to 20 (all organs with dysfunction).
Time frame: Baseline and 24 Hours
Population: Number of per-protocol participants with values at baseline and 24 hours.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drotrecogin Cohort | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours | Baseline | 8.5 units on a scale | Standard Deviation 2 |
| Drotrecogin Cohort | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours | 24 Hours | 7.8 units on a scale | Standard Deviation 2.3 |
| Control Cohort | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours | Baseline | 8.3 units on a scale | Standard Deviation 3.2 |
| Control Cohort | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours | 24 Hours | 7.8 units on a scale | Standard Deviation 4 |
p-value: 0.686Repeated Measures - propensity adjusted
p-value: 0.575Repeated Measures - propensity adjusted
Other Pre-specified
Number of Participants With Bleeding Events
Serious bleeding event resulted in one of following outcomes, or was significant for any reason: initial/ prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly/birth defect. Intracranial hemorrhage was also considered serious bleeding event.
Time frame: baseline to 7 days
Population: All enrolled patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Drotrecogin Cohort | Number of Participants With Bleeding Events | Serious Bleeding Event | 2 participants |
| Drotrecogin Cohort | Number of Participants With Bleeding Events | Intracranial Hemorrhage | 0 participants |
| Control Cohort | Number of Participants With Bleeding Events | Serious Bleeding Event | 0 participants |
| Control Cohort | Number of Participants With Bleeding Events | Intracranial Hemorrhage | 0 participants |