Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial

doi:10.1016/S0140-6736(07)60411-5

The Lancet

Volume 369, Issue 9564, 10–16 March 2007, Pages 836-843

https://doi.org/10.1016/S0140-6736(07)60411-5 Get rights and content

Summary

Background

Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children.

Methods

Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 μg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov, number NCT00049764.

Findings

477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0·72) or in 28-day mortality (placebo 17·5%; DrotAA, 17·2%; p=0·93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6·8%; DrotAA 6·7%; p=0·97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4·6%], vs 5 [2·1%] in placebo, p=0·13), particularly in children younger than 60 days. For CTCOFR score days 1–14, correlation coefficient was −0·016 (95% CI −0·106 to 0·74); relative risk for 28-day mortality was 1·06 (95% CI 0·66 to 1·46) for DrotAA compared with placebo.

Interpretation

Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.

Introduction

Up to one-fifth of the estimated 42 000 children with severe sepsis in the developed world die each year, and the illness is the second leading cause of death in children ages 1–14 years.1, 2, 3, 4, 5 The financial burden of severe sepsis in children is estimated to be $1·97 billion per year in the USA.⁵ Apart from antibiotics and supportive care, there are no approved adjunctive therapies for children.

Drotrecogin alfa (activated) (DrotAA), a recombinant form of human activated protein C, has been approved in over 50 countries for treatment of severe sepsis in adults at high risk of death. Approval was based on a highly significant reduction in 28-day mortality shown in the PROWESS trial,⁶ which excluded patients younger than 18 years.

An open-label study (called EVAO) in children with severe sepsis indicated that pharmacokinetics and pharmacodynamics of DrotAA are similar to that in adults.⁷ Children in the EVAO study had higher rates of cardiovascular dysfunction and two or more organ dysfunctions (93% and 85%, respectively) than did adults in the PROWESS study (72% and 75%, respectively). The most common infection in the EVAO study was that from Neisseria meningitidis (26·5%), which was documented in only 1% of PROWESS patients.

Before approval of DrotAA and completion of EVAO, a global open-label trial in adults and children with severe sepsis (ENHANCE) was initiated to gather additional data for mortality and safety.⁸ In ENHANCE (n=188), 25 (13·4%) children had died by day 28, and 11 (5·9%) had serious bleeding events during DrotAA infusion.⁹ Five (2·7%) children had a CNS bleed.

This randomised placebo-controlled trial, RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE), was implemented to determine the efficacy and safety of DrotAA in children.

Section snippets

Participants

Between November, 2002, and April, 2005, we enrolled participants from 104 study sites in 18 countries. Participants were eligible if they were aged between 38 weeks' corrected gestational age and 17 years, and fulfilled all the following criteria: a suspected or proven infection, and systemic inflammation, sepsis-induced cardiovascular, and respiratory organ dysfunction within 12 h before entering the study. Exclusion criteria included high risk of intracranial bleeding, expected to die before

Results

We enrolled 477 patients between November, 2002, and March, 2005 (figure 1). In March 2005, enrollment was suspended after the second planned interim analysis suggested there was little chance of reaching the efficacy endpoint by completion of the trial. Follow-up of enrolled patients continued until April 3, 2005.

Baseline characteristics are shown in table 1. There were significantly more male patients in the DrotAA group. Also, the number of organ failures, patients with renal, hepatic,

Discussion

RESOLVE was the largest randomised placebo-controlled trial so far in critically ill children, and the only placebo-controlled study of DrotAA in children. There was no significant difference in either CTCOFR or mortality between patients on DrotAA compared with those on placebo. Nor were there any significant differences between groups in serious adverse events, serious bleeding, or CNS bleeding.

The background serious bleeding rate in paediatric severe sepsis had not been defined until this

References (16)

MR Anderson et al.
Advances in the therapy for sepsis in children
Pediatr Clin North Am
(1997)
JF Dhainaut et al.
Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation
J Thromb Haemost
(2004)
W Butt
Septic shock
Pediatr Clin North Am
(2001)
JA Hazelzet et al.
Age-related differences in outcome and severity of DIC in children with septic shock and purpura
Thromb Haemost
(1996)
A Martinot et al.
Sepsis in neonates and children: definitions, epidemiology, and outcome
Pediatr Emerg Care
(1997)
RS Watson et al.
The epidemiology of severe sepsis in children in the United States
Am J Respir Crit Care Med
(2003)
GR Bernard et al.
Efficacy and safety of recombinant human activated protein C for severe sepsis
N Engl J Med
(2001)
P Barton et al.
Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis
Pediatr
(2004)

There are more references available in the full text version of this article.

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ArticlesDrotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Results

Discussion

Pediatr Clin North Am

J Thromb Haemost

Septic shock

Pediatr Clin North Am

Age-related differences in outcome and severity of DIC in children with septic shock and purpura

Thromb Haemost

Sepsis in neonates and children: definitions, epidemiology, and outcome

Pediatr Emerg Care

The epidemiology of severe sepsis in children in the United States

Am J Respir Crit Care Med

Efficacy and safety of recombinant human activated protein C for severe sepsis

N Engl J Med

Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis

Pediatr

Articles
Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial