Evaluate Protein C Levels in Severe Sepsis Patients on Drotrecogin Alfa (Activated)

Study Overview
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Brief Summary
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In this trial, patients with severe sepsis and low protein C levels will receive drotrecogin alfa (activated) at the normal, approved dose and time of administration [24 microgram/kilogram/hour (mcg/kg/hour) for 96 hours] or will receive the normal, approved dose or higher doses than the approved dose for a longer administration time. After the drug administration is complete, the protein C levels from the patients receiving the normal, approved dose will be compared to protein C levels from patients receiving the normal, approved dose or higher dose for a longer duration to determine if the protein C levels improve faster if given higher dose and/or longer administration time. Note: The protocol was amended to remove the option of shorter infusion durations.

Official Title
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A Phase 2 Study to Evaluate Dose and Duration of Treatment of Drotrecogin Alfa (Activated) Using Serial Measurements of Protein C in Patients With Severe Sepsis and Multiple Organ Dysfunction

Conditions
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Severe Sepsis

Intervention / Treatment
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* Drug: Drotrecogin alfa (activated)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be 18 years or older Must have a suspected or proven infection Must have two or more sepsis-associated organ dysfunctions Exclusion Criteria: Documented multiple organ dysfunction greater than 24 hours prior to start of study drug Actual body weight less than 30 kg or more than 135 kg Platelet count less than 30,000/mm^3 Active internal bleeding or at increased risk of bleeding Not expected to survive 28 days given the patient's pre-existing uncorrectable medical condition

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard therapy<br>24 microgram/kilogram/hour (mcg/kg/hr) for 24 hours, followed by 24 mcg/kg/hr for an additional 72 hours | Drug: Drotrecogin alfa (activated)<br>* intravenous<br>* Other names: LY203638;|
| Experimental: Alternative therapy:moderate protein C deficiency<br>24 mcg/kg/hr for 24 hours, followed by 24 mcg/kg/hr for an additional 48 to 144 hours (original protocol) or an additional 72 to 144 hours (amended protocol) | Drug: Drotrecogin alfa (activated)<br>* intravenous<br>* Other names: LY203638;|
| Experimental: Alternative therapy:severe protein C deficiency<br>24 mcg/kg/hr for 24 hours, followed by 30 or 36 mcg/kg/hr for 48 to 144 hours (original protocol) or an additional 72 to 144 hours (amended protocol) | Drug: Drotrecogin alfa (activated)<br>* intravenous<br>* Other names: LY203638;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Protein C Levels From Day 1 to Day 7 | Mean change in protein C from Study Day 1 to Study Day 7 was tested using an unadjusted two-sample t-test with a two-sided alpha of 0.05. To be included in the primary analysis, Intention-to-Treat (ITT) patients must have at least 1 protein C value available at 24 hours or earlier and at least 1 protein C value at a post-24-hour timepoint. | Day 1, Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Protein C Level From Study Day 1 to Study Day 7 in Patients With Moderate and Severe Protein C Deficiency | Moderate Protein C Deficiency: A protein C level greater than half the lower limit of normal. Severe Protein C Deficiency: A protein C level less than or equal to half the lower limit of normal. | Day 1, Day 7 | 
| Day 28 All-Cause Mortality |  | Day 0 through Day 28 | 
| Hospital Mortality (up to Day 90) |  | Day 0 to hospital discharge or Day 90 | 
| 28-Day Time Averaged Sequential Organ Failure (SOFA) Score | 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). SOFA scores were time-averaged. | Day 0, Day 28 | 
| Number of Participants With Serious Adverse Events (SAE) and Serious Bleeding Events (SBE) by Time Period | Serious bleeding events (SBE): intracranial hemorrhage, life-threatening or fatal bleed, or bleeding event assessed as an SAE. Patients may have multiple events with onset in different time periods. SAEs include SBEs. The 3 SBEs in Alternative-Moderate Deficiency arm (days 5-8) occurred after completion of study drug infusion. One event (pleural haemorrhage) occurred same day of completion of infusion and 2 events (cerebral haemorrhage, shock haemorrhagic) occurred day after completion. | Day 0 through Day 28 | 
| Mortality by Protein C Normalized Versus Not-normalized | Normalization was defined as having 2 consecutive protein C measurements above the lower limit of normal through Study Day 7. | 28 days |