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

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

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.

Study Overview

• Status: Completed
• Conditions: Severe Sepsis
• Intervention / Treatment: Drug: Drotrecogin alfa (activated)

• Study Type: Interventional
• Enrollment (Actual): 486
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Gent, Belgium, 9000
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• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
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  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
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  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
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  • Ontario
    • London, Ontario, Canada, N6C 2V5
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    • Ottawa, Ontario, Canada, K1H 8L6
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    • Toronto, Ontario, Canada, M4N 3M5
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  • Quebec
    • Fleurimont, Quebec, Canada, J1H 5N4
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• Finland
  • Helsinki, Finland, 00290
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  • Kuopio, Finland, 70211
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  • Oulu, Finland, 90220
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  • Tampere, Finland, 33521
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• France
  • Angouleme, France, 16470
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  • La Roche Sur Yon, France, 85925
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  • Limoges, France, 87042
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  • Poitiers, France, 86021
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  • Tours, France, 37044
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• Germany
  • Hamburg, Germany, 21075
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  • Jena, Germany, D-07740
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  • Leipzig, Germany, D-04103
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• Puerto Rico
  • San Juan, Puerto Rico, 00921
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• Spain
  • Sabadell, Spain, 08208
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United Kingdom
  • Berkshire
    • Reading, Berkshire, United Kingdom, RG1 5AN
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 5BE
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • East Yorkshire
    • Cottingham, East Yorkshire, United Kingdom, HU16 5JQ
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Greater London
    • London, Greater London, United Kingdom, W6 8RF
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • London
    • Waterloo, London, United Kingdom, SE1 7EH
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Norfolk
    • Kings Lynn, Norfolk, United Kingdom, PE30 4ET
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B9 5SS
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
    • Scottsdale, Arizona, United States, 85258
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • California
    • Fresno, California, United States, 93701
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
    • Loma Linda, California, United States, 92350
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
    • Stanford, California, United States, 94305
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Florida
    • Orlando, Florida, United States, 32806
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Maine
    • Portland, Maine, United States, 04102
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Missouri
    • St Louis, Missouri, United States, 63141
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • North Carolina
    • Greensboro, North Carolina, United States, 27401
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • South Dakota
    • Rapid City, South Dakota, United States, 55701
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Texas
    • Houston, Texas, United States, 77030
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard therapy; 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); intravenous; Other Names: LY203638; Xigris
Experimental: Alternative therapy:moderate protein C deficiency; 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); intravenous; Other Names: LY203638; Xigris
Experimental: Alternative therapy:severe protein C deficiency; 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); intravenous; Other Names: LY203638; Xigris

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality for Severe Protein C Deficiency	Twenty-eight day mortality is the patient's mortality status at the predefined timepoint of 672 hours from the start of study drug infusion. Hospital mortality is the patient's survival status at the end of the hospital stay or study day 90 (if the patient remains in the hospital).	28 Days, up to 90 days

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Shorr AF, Janes JM, Artigas A, Tenhunen J, Wyncoll DL, Mercier E, Francois B, Vincent JL, Vangerow B, Heiselman D, Leishman AG, Zhu YE, Reinhart K; RESPOND investigators. Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated). Crit Care. 2010;14(6):R229. doi: 10.1186/cc9382. Epub 2010 Dec 21.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: October 6, 2006
• First Submitted That Met QC Criteria: October 10, 2006
• First Posted (Estimate): October 11, 2006

Study Record Updates

• Last Update Posted (Estimate): December 16, 2010
• Last Update Submitted That Met QC Criteria: November 18, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Anti-Infective Agents; Drotrecogin alfa activated
• Other Study ID Numbers: 10553 (Other Identifier: CTEP); F1K-MC-EVDK (Other Identifier: Eli Lilly and Company)