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The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

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RESPOND study design. Distribution and outcome of corresponding DrotAA (Xigris®)-treated PROWESS [9] patients. DrotAA, drotrecogin alfa (activated); EOI, end of infusion; LLN, lower limit of normal; PC, protein C; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; RESPOND, Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]. †Mortality.
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Figure 6: RESPOND study design. Distribution and outcome of corresponding DrotAA (Xigris®)-treated PROWESS [9] patients. DrotAA, drotrecogin alfa (activated); EOI, end of infusion; LLN, lower limit of normal; PC, protein C; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; RESPOND, Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]. †Mortality.

Mentions: Each patient's infusion will be administered at a single infusion rate. A data monitoring committee will review safety data from the lower dose groups before enrolling patients in the next higher dose group. Figure 6 illustrates the different arms of the trial after completion of the common lead-in period, and shows the outcomes of corresponding PROWESS patients, indicating lower mortality among patients in whom protein C levels normalized by the end of the infusion period.


The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

RESPOND study design. Distribution and outcome of corresponding DrotAA (Xigris®)-treated PROWESS [9] patients. DrotAA, drotrecogin alfa (activated); EOI, end of infusion; LLN, lower limit of normal; PC, protein C; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; RESPOND, Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]. †Mortality.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230608&req=5

Figure 6: RESPOND study design. Distribution and outcome of corresponding DrotAA (Xigris®)-treated PROWESS [9] patients. DrotAA, drotrecogin alfa (activated); EOI, end of infusion; LLN, lower limit of normal; PC, protein C; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; RESPOND, Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]. †Mortality.
Mentions: Each patient's infusion will be administered at a single infusion rate. A data monitoring committee will review safety data from the lower dose groups before enrolling patients in the next higher dose group. Figure 6 illustrates the different arms of the trial after completion of the common lead-in period, and shows the outcomes of corresponding PROWESS patients, indicating lower mortality among patients in whom protein C levels normalized by the end of the infusion period.

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

Show MeSH
Related in: MedlinePlus