Trial Outcomes & Findings for Hemodynamic and Perfusion Response to Drotrecogin Alfa (Activated) in Patients With Septic Shock (NCT NCT00279214)

NCT ID: NCT00279214

Last Updated: 2009-09-02

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 43 participants
• Primary outcome timeframe: baseline to 24 hours
• Results posted on: 2009-09-02

Participant Flow

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.

Participant milestones

Measure	Drotrecogin Cohort Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Overall Study STARTED	22	21
Overall Study COMPLETED	19	19
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Measure	Drotrecogin Cohort Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Overall Study Physician Decision	3	2

Baseline Characteristics

Hemodynamic and Perfusion Response to Drotrecogin Alfa (Activated) in Patients With Septic Shock

Baseline characteristics by cohort

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=19 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy	Total n=38 Participants Total of all reporting groups
Age Continuous	68.0 years STANDARD_DEVIATION 11.8 • n=5 Participants	65.8 years STANDARD_DEVIATION 15.0 • n=7 Participants	66.9 years STANDARD_DEVIATION 13.3 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	12 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment United States	19 participants n=5 Participants	19 participants n=7 Participants	38 participants n=5 Participants
Race/Ethnicity African	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity Caucasian	16 participants n=5 Participants	15 participants n=7 Participants	31 participants n=5 Participants
Race/Ethnicity East Asian	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity Hispanic	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Cardiac Index	3.5 liters/minute/meters squared STANDARD_DEVIATION 1.7 • n=5 Participants	3.3 liters/minute/meters squared STANDARD_DEVIATION 1.4 • n=7 Participants	3.4 liters/minute/meters squared STANDARD_DEVIATION 1.6 • n=5 Participants
Creatinine Clearance	69.2 milliliter per minute STANDARD_DEVIATION 77.0 • n=5 Participants	29.9 milliliter per minute STANDARD_DEVIATION 31.1 • n=7 Participants	52.9 milliliter per minute STANDARD_DEVIATION 64.5 • n=5 Participants
Cumulative Vasopressor Index (CVI)	4.3 units on a scale STANDARD_DEVIATION 2.1 • n=5 Participants	4.4 units on a scale STANDARD_DEVIATION 2.4 • n=7 Participants	4.4 units on a scale STANDARD_DEVIATION 2.2 • n=5 Participants
Lactate Levels	2.0 millimoles per Liter STANDARD_DEVIATION 1.1 • n=5 Participants	2.6 millimoles per Liter STANDARD_DEVIATION 2.8 • n=7 Participants	2.3 millimoles per Liter STANDARD_DEVIATION 2.1 • n=5 Participants
Mean Arterial Pressure (MAP)	73.5 mm Hg STANDARD_DEVIATION 9.9 • n=5 Participants	72.1 mm Hg STANDARD_DEVIATION 9.4 • n=7 Participants	72.8 mm Hg STANDARD_DEVIATION 9.5 • n=5 Participants
Mixed Venous Oxygen Saturation	68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 15.6 • n=5 Participants	68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 10.1 • n=7 Participants	68.9 percent saturation mixed venous oxygen STANDARD_DEVIATION 12.9 • n=5 Participants
Number of Organ Dysfunctions	2.5 number of organ dysfunctions STANDARD_DEVIATION 0.8 • n=5 Participants	2.0 number of organ dysfunctions STANDARD_DEVIATION 0.9 • n=7 Participants	2.3 number of organ dysfunctions STANDARD_DEVIATION 0.9 • n=5 Participants
Ratio of Arterial Partial Pressure of Oxygen to Fraction of Inspired Oxygen (PaO2/FiO2)	191.8 mm Hg / percent inspired oxygen n=5 Participants	248.3 mm Hg / percent inspired oxygen n=7 Participants	222.0 mm Hg / percent inspired oxygen n=5 Participants
Total Sequential Organ Failure Assessment Score	8.5 units on a scale STANDARD_DEVIATION 2.0 • n=5 Participants	8.3 units on a scale STANDARD_DEVIATION 3.2 • n=7 Participants	8.4 units on a scale STANDARD_DEVIATION 2.6 • n=5 Participants

PRIMARY outcome

Timeframe: baseline to 24 hours

Population: Number of per-protocol participants with values at baseline and 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.

Outcome measures

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=19 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Cumulative Vasopressor Index (CVI) 24 Hour	2.3 units on a scale Standard Deviation 2.5	3.0 units on a scale Standard Deviation 2.8
Cumulative Vasopressor Index (CVI) 24 Hour Change from Baseline	-2.0 units on a scale Standard Deviation 2.2	-1.4 units on a scale Standard Deviation 2.2

SECONDARY outcome

Timeframe: Baseline, 96 hours

Population: Number of per-protocol participants with values at baseline and 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.

Outcome measures

Measure	Drotrecogin Cohort n=18 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=16 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Change From Baseline to 96 Hour Endpoint in Cumulative Vasopressor Index (CVI) 96 Hour	0.4 units on a scale Standard Deviation 1.3	0.5 units on a scale Standard Deviation 1.4
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	-3.3 units on a scale Standard Deviation 2.1

SECONDARY outcome

Timeframe: baseline to 24 hours

Population: Number of per-protocol participants with values at baseline and 24 hours.

Outcome measures

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=18 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Mean Arterial Pressure 24 Hours	78.2 mm Hg Standard Deviation 11.3	75.6 mm Hg Standard Deviation 9.8
Mean Arterial Pressure 24 Hour Change from Baseline	4.7 mm Hg Standard Deviation 14.6	2.5 mm Hg Standard Deviation 12.4

SECONDARY outcome

Timeframe: Baseline to 24 Hours

Population: Number of per-protocol participants with values at baseline and 24 hours.

Cardiac Index = cardiac output divided by body surface area.

Outcome measures

Measure	Drotrecogin Cohort n=17 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=13 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Cardiovascular Performance Measures Obtained With a Pulmonary Artery Catheter - Cardiac Index 24 Hours	3.3 liters/minute/meters squared Standard Deviation 0.7	3.2 liters/minute/meters squared Standard Deviation 1.0
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	0.1 liters/minute/meters squared Standard Deviation 0.9

SECONDARY outcome

Timeframe: Baseline to 6 Hours

Population: Number of per-protocol participants with values at baseline and 6 hours.

Measures of global tissue perfusion and oxygenation were assessed via lactate levels.

Outcome measures

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=15 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Lactate Level 6 Hours	1.8 millimoles per Liter Standard Deviation 1.0	2.8 millimoles per Liter Standard Deviation 4.6
Lactate Level 6 Hour Change from Baseline	-0.2 millimoles per Liter Standard Deviation 0.6	0.4 millimoles per Liter Standard Deviation 1.7

SECONDARY outcome

Timeframe: Baseline to 24 Hours

Population: Number of per-protocol participants with values at baseline, 12, and 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).

Outcome measures

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=18 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Microcirculatory Measures From Sidestream Darkfield (SDF) Microscopy - Small Vessel Microvascular Flow Index (MFI) Baseline	2.70 units on a scale Standard Deviation 0.51	2.50 units on a scale Standard Deviation 0.70
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	2.80 units on a scale Standard Deviation 0.35
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	2.65 units on a scale Standard Deviation 0.47
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	0.06 units on a scale Standard Deviation 0.27

SECONDARY outcome

Timeframe: Baseline and 24 Hours

Population: Number of per-protocol participants with values 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).

Outcome measures

Measure	Drotrecogin Cohort n=19 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=19 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours Baseline	8.5 units on a scale Standard Deviation 2.0	8.3 units on a scale Standard Deviation 3.2
Sequential Organ Failure Assessment (SOFA) Score at Baseline and 24 Hours 24 Hours	7.8 units on a scale Standard Deviation 2.3	7.8 units on a scale Standard Deviation 4.0

SECONDARY outcome

Timeframe: Baseline and 24 hours

Population: Number of per-protocol participants with values at 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.

Outcome measures

Measure	Drotrecogin Cohort n=15 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=8 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Change From Baseline in Creatinine Clearance (CrCl) at 24 Hours	-9.74 milliliter per minute Standard Deviation 75.45	1.66 milliliter per minute Standard Deviation 28.90

SECONDARY outcome

Timeframe: baseline to 7 days

Population: All enrolled patients

Outcome measures

Measure	Drotrecogin Cohort n=22 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=21 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
7 Day All-cause In-hospital Mortality Alive at 7 Days	18 partipants	13 partipants
7 Day All-cause In-hospital Mortality Not Alive at 7 Days	4 partipants	8 partipants

SECONDARY outcome

Timeframe: Baseline to 24 Hours

Population: Number of per-protocol participants with values at baseline, 12, and 24 hours.

Outcome measures

Measure	Drotrecogin Cohort n=16 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=18 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Endogenous Protein C Level Baseline	38.7 percentage of Protein C activity Standard Deviation 25.2	34.8 percentage of Protein C activity Standard Deviation 19.1
Endogenous Protein C Level 12 Hours	48.2 percentage of Protein C activity Standard Deviation 23.0	38.9 percentage of Protein C activity Standard Deviation 19.6
Endogenous Protein C Level 24 Hours	54.7 percentage of Protein C activity Standard Deviation 20.7	40.0 percentage of Protein C activity Standard Deviation 17.9
Endogenous Protein C Level 24 Hour Change from Baseline	16.3 percentage of Protein C activity Standard Deviation 16.2	2.4 percentage of Protein C activity Standard Deviation 16.7

SECONDARY outcome

Timeframe: Baseline to 24 Hours

Population: Number of per-protocol participants with values at baseline and 24 hours.

Cardiovascular performance measures obtained with a pulmonary catheter as assessed by mixed venous oxygen saturation.

Outcome measures

Measure	Drotrecogin Cohort n=15 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=14 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Mixed Venous Oxygen Saturation 24 Hours	69.6 percent saturation mixed venous oxygen Standard Deviation 8.3	75.0 percent saturation mixed venous oxygen Standard Deviation 11.1
Mixed Venous Oxygen Saturation 24 Hour Change from Baseline	3.7 percent saturation mixed venous oxygen Standard Deviation 14.5	6.5 percent saturation mixed venous oxygen Standard Deviation 13.3

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline to 7 days

Population: All enrolled patients

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.

Outcome measures

Measure	Drotrecogin Cohort n=22 Participants Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort n=21 Participants Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Number of Participants With Bleeding Events Serious Bleeding Event	2 participants	0 participants
Number of Participants With Bleeding Events Intracranial Hemorrhage	0 participants	0 participants

Adverse Events

Drotrecogin Cohort

Serious events: 4 serious events

Other events: 4 other events

Deaths: 0 deaths

Control Cohort

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Drotrecogin Cohort Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Cardiac disorders Bradycardia	0.00% 0/22	9.5% 2/21 • Number of events 2
Cardiac disorders Cardiac arrest	4.5% 1/22 • Number of events 1	0.00% 0/21
Cardiac disorders Ventricular tachycardia	4.5% 1/22 • Number of events 1	9.5% 2/21 • Number of events 2
Injury, poisoning and procedural complications Right sided hemothorax	4.5% 1/22 • Number of events 2	0.00% 0/21
Vascular disorders Hemorrage intraperitoneal	4.5% 1/22 • Number of events 1	0.00% 0/21

Other adverse events

Measure	Drotrecogin Cohort Group received drotrecogin alfa (activated) per physician-directed therapy	Control Cohort Group did not receive drotrecogin alfa (activated) per physician-directed therapy
Cardiac disorders Atrial fibrilation	4.5% 1/22 • Number of events 1	0.00% 0/21
Gastrointestinal disorders Gastrointestinal bleeding	4.5% 1/22 • Number of events 1	0.00% 0/21
Renal and urinary disorders Gross hematuria	4.5% 1/22 • Number of events 1	0.00% 0/21
Skin and subcutaneous tissue disorders Oropharynx blood and ecchymoses	4.5% 1/22 • Number of events 1	0.00% 0/21

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 1-800-545-5979

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: GT60