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Clinical Trial
. 2010;14(6):R229.
doi: 10.1186/cc9382. Epub 2010 Dec 21.

Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)

Andrew F Shorr  1 , Jonathan M Janes, Antonio Artigas, Jyrki Tenhunen, Duncan L A Wyncoll, Emmanuelle Mercier, Bruno Francois, Jean-Louis Vincent, Burkhard Vangerow, Darell Heiselman, Amy G Leishman, Yajun E Zhu, Konrad Reinhart; RESPOND investigators
Collaborators, Affiliations
Clinical Trial

Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)

Andrew F Shorr et al. Crit Care. 2010.

Abstract

Introduction: Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.

Methods: This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy.

Results: Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration.

Conclusions: The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies.

Trial registration: ClinicalTrials.gov identifier: NCT00386425.

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Figures

Figure 1
Figure 1
Patient disposition and study flow diagram of patients. *Patients who signed informed consent, but did not proceed to randomization or the nondrug-interventional arm.
Figure 2
Figure 2
Absolute mean change in protein C levels. Change in mean protein C levels from study Day 1 up to study Day 7 for different therapy groups in the primary efficacy population. Alt, alternative; std, standard
Figure 3
Figure 3
Protein C level over time by therapy in the primary efficacy population. Alt, alternative; std, standard.
Figure 4
Figure 4
Comparison between studies of 28-day mortality by Day 4 protein C level. Twenty-eight-day mortality is shown based on Day 4 protein C levels by categories: normal (> 80%); moderately deficient (41 to 80%); and severely deficient (≤40%) for PROWESS [3], ENHANCE [17] (both reported by Vangerow et al. 2007 [14]), and RESPOND. The number (n) under each column is the total number of patients in each category. DAA, drotrecogin alfa (activated).
See this image and copyright information in PMC

Comment in

References

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