Safety, Pharmacokinetics, and Pharmacodynamics of Drotrecogin Alfa (Activated) in Children With Severe Sepsis
* Department of Pediatrics, Division of Pediatric Critical Care, Children’s Hospital at Saint Francis, Tulsa, Oklahoma
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Department of Paediatrics, Imperial College School of Medicine at St. Mary’s Hospital, London, United Kingdom
|| Division of Pediatric Critical Care, Oregon Health Sciences University, Portland, Oregon
¶ Pediatric Critical Care Section, Baylor College of Medicine, Houston, Texas
# Division of Critical Care Medicine, Children’s Hospital Medical Center, Cincinnati, Ohio
** Department of Pediatrics, Division of Pediatric Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas
Department of Anesthesiology, Children’s Hospital and Regional Medical Center, Seattle, Washington
Emmanuel Hospital and Health Center, Portland, Oregon
|||| Children’s Hospital Oakland, Oakland, California
¶¶ Children’s National Medical Center, Washington, District of Columbia
## Critical Care Medical Section, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma
*** Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. In a phase 3 trial, recombinant human activated protein C (drotrecogin alfa [activated]) significantly reduced mortality in adult patients with severe sepsis. We have now performed a preliminary analysis of the safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in pediatric patients with severe sepsis.
Design and Setting. Open-label, nonrandomized, sequential, 2-part study conducted in 11 medical centers in the United States and United Kingdom.
Patients. Eighty-three pediatric patients with severe sepsis aged term newborn (
38 weeks’ gestation) to <18 years old.
Intervention. In part 1, drotrecogin alfa (activated) was administered as escalating doses of 6, 12, 24, and 36 µg/kg per hour for 6 hours for each patient (n = 21). In part 2, drotrecogin alfa (activated) was infused at a rate of 24 µg/kg per hour for 96 hours in 62 patients.
Main Outcome Measures. Plasma clearance, plasma concentration, D-dimer, protein C, and antithrombin levels were measured, and adverse events were monitored.
Results. The trial enrolled 83 pediatric patients with severe sepsis, aged term newborn (38 weeks’ gestation) to <18 years. In part 1, a dose of 24 µg/kg per hour produced steady-state plasma concentrations of activated protein C similar to those attained in equivalently dosed adult severe sepsis patients. For all pediatric patients dosed at 24 µg/kg per hour, the median weight-normalized clearance was 0.45 L/hour/kg and the median steady-state concentration was 51.3 ng/mL. The mean plasma half-life was 30 minutes. Weight-normalized clearance in pediatric and adult patients did not differ significantly with age or weight. D-dimer levels decreased 26% from baseline to end of infusion. Baseline levels of protein C and antithrombin increased 79% and 24%, respectively, over the 96-hour treatment period in part 2. The incidence of serious bleeding during infusion and during the entire study period was 2.4% and 4.8%, respectively.
Conclusions. Pediatric patients with severe sepsis manifest sepsis-induced coagulopathy including protein C deficiency comparable to that seen in adults with severe sepsis. The pharmacokinetics, pharmacodynamic effects, and safety profile of drotrecogin alfa (activated) in pediatric patients are similar to those previously published for adult patients. A large, phase 3, randomized, placebo-controlled study is ongoing to confirm these results and formally assess the safety and efficacy of drotrecogin alfa (activated) in children.
Key Words: drotrecogin alfa (activated) • activated protein C • Xigris • sepsis • pediatric
Abbreviations: SIRS, systemic inflammatory response syndrome • ICH, intracranial hemorrhage • Css, steady-state plasma concentration • PIM, pediatric index of mortality • Clp, plasma clearance • CV, coefficient of variation
Severe sepsis, defined as sepsis associated with acute organ dysfunction, remains a major cause of morbidity and mortality among children.1–3 In children, as in adults, severe sepsis arises from coordinated activation of the innate immune response.4 This response, triggered by diverse pathogens, is multifaceted.4,5 Once triggered, the response leads to secretion of pro- and antiinflammatory cytokines, activation and mobilization of leukocytes, activation of coagulation and inhibition of fibrinolysis,6,7 and increased apoptosis.8 As a result of coagulation activation, the thrombin generated not only promotes fibrin deposition in the microvasculature, but it also exacerbates ongoing inflammation via both direct and indirect mechanisms. Although evolutionarily designed to limit microbial dissemination throughout the host, these innate inflammatory processes can also be detrimental, resulting in cardiac dysfunction, vasodilation, capillary injury, and micro- and macrovascular thromboses. Despite antibiotics and intensive care, these processes frequently lead to organ dysfunction, gangrenous extremities, long-term neurologic morbidity, or death.2,9
Activated protein C is a critical, endogenous regulator of coagulation and inflammation. After activation of plasma protein C by the thrombin-thrombomodulin complex, activated protein C exerts antithrombotic10,11 and profibrinolytic effects.12–15 The antiinflammatory effects of activated protein C are indirect because of the inhibition of thrombin formation16 and direct via blockage of cytokine formation,17–19 inhibition of selectin activity,20 and nuclear factor 
B translocation.8,21
In children and adults, acquired deficiencies in protein C are found in most patients with severe sepsis and are associated with an increased risk of mortality.22 Moreover, the diminished or even absent expression of endothelial thrombomodulin during severe sepsis in children imposes an additional severe restriction on activated protein C generation.23,24 Altogether, both the levels and activation of protein C are considerably diminished during severe sepsis.
Drotrecogin alfa (activated), a recombinant form of human activated protein C, was shown recently to significantly improve survival of adults with severe sepsis.25 The PROWESS trial was a multicenter, randomized, double-blind, placebo-controlled trial in adults with severe sepsis and at least one sepsis-induced organ dysfunction. In PROWESS, the infusion of drotrecogin alfa (activated) resulted in a highly statistically significant reduction in 28-day all-cause mortality (relative risk reduction: 19.4%; P = .005) in adults with severe sepsis compared with patients receiving placebo. The results of PROWESS led regulatory authorities to approve drotrecogin alfa (activated) or Xigris (Eli Lilly, Indianapolis, IN) for the treatment of severe sepsis in adults at high risk of death or with multiple organ dysfunction.
The pediatric trial described in this report was initiated after the first interim analysis (n = 760 patients) of the PROWESS trial by an independent data safety monitoring board. The data safety monitoring board’s decision to continue the PROWESS trial signaled that there were no major safety concerns that would prevent evaluation of drotrecogin alfa (activated) in children. The primary objectives of the pediatric trial were to investigate the safety and pharmacokinetics of drotrecogin alfa (activated) in children, aged term newborn (38 weeks’ gestation) to 18 years. The secondary objective was to evaluate whether the baseline coagulation activation and pharmacodynamic responses to drotrecogin alfa (activated) were similar in children and adults with severe sepsis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Population
From March 2000 through June 2001, eligible pediatric patients aged term newborn (
38 weeks’ gestation) to <18 years were enrolled in an open-label trial conducted at 11 centers located in the United States and United Kingdom. The institutional review board at each center approved the protocol, and written informed consent was obtained from the patient’s parent or legal guardian. Assent was obtained from patients according to age and if their clinical condition allowed.
Study Entry Criteria
Eligible patients had a diagnosis of severe sepsis that was defined as 1) suspected or proven infection based on clinical data at the time of screening or the presence of a clinical syndrome associated with a high probability of infection (eg, purpura fulminans); 2) presence of at least 2 of the 4 criteria defining the systemic inflammatory response syndrome (SIRS), as detailed in Appendix 1, within the 24-hour period immediately preceding the time of entry into the study; and 3) evidence of one or more sepsis-induced organ dysfunctions (Appendix 1) within the 12-hour period immediately preceding entry into the study. The initial organ dysfunction criteria for the pediatric study were conservative and included only cardiovascular and respiratory dysfunction. Once the adult PROWESS trial was stopped for efficacy, the decision was made by study investigators and the sponsor to broaden the organ dysfunction criteria to match those used in PROWESS. Hematologic and renal organ dysfunction criteria were added, and the respiratory organ dysfunction criteria were modified. Daily organ dysfunction assessments (Appendix 2) were used to determine the severity of illness at baseline. Patients were required to begin study drug infusion within 12 hours of meeting inclusion criteria. Exclusion criteria are summarized in Appendix 3.
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Study Design
The trial was an open-label, nonrandomized, sequential, 2-part study based on recommendations in the Food and Drug Administration guidance document26 for pharmacokinetic studies in children and the intracranial hemorrhage (ICH) guidelines27 for extrapolating efficacy from studies in adults. Patients were divided into 3 age groups: term newborn to <1 year old, 1 to <8 years old, and 8 to <18 years old. Within each age group a 2-part, sequential study was conducted. Each part was conducted independently within each age group, with a provision to alter the study protocol for other age groups should any issue arise within one age group.
Part 1 was a dose-escalation, safety, and pharmacokinetic analysis planned for 6 to 8 patients per age group. Drotrecogin alfa (activated) (Xigris, Eli Lilly, Indianapolis, IN) was administered as a 6-hour constant-rate infusion once daily on 4 consecutive days. Infusion rates were 6, 12, 24, and 36 µg/kg per hour on study days 1, 2, 3, and 4, respectively. The doses selected were based on safety information available from healthy subjects and a phase 2 clinical study in adult severe sepsis patients.28 Safety and pharmacokinetic data were assessed at each infusion rate for each dose administered. These data were used to calculate the age group-specific infusion rate expected to produce a steady-state plasma activated protein C concentration of 
50 ng/mL. This was the approximate concentration produced by infusions of 24 µg/kg per hour in the phase 2 trial in adults with severe sepsis and was therefore the target steady-state plasma concentration (Css) in pediatric patients.
Part 2 was a safety, pharmacokinetic, and pharmacodynamic analysis of drotrecogin alfa (activated) administered as a 96-hour continuous infusion at the age group-specific infusion rate calculated from part 1 data. The age group-specific infusion rate was the rate expected to produce the targeted Css of 50 ng/mL. Safety, pharmacokinetic, and pharmacodynamic data were obtained from all patients enrolled in part 2.
Evaluation of Patients
Patients were followed for 14 days after the start of the infusion or until hospital discharge, whichever came first. Baseline characteristics including demographic information and preexisting conditions were assessed within 6 hours before the start of infusion. Organ function was assessed daily from preinfusion through study day 14 by using criteria modified from Wilkinson et al29 (Appendix 2). Available clinical and laboratory data were used to calculate the pediatric index of mortality (PIM).30 A complete blood cell count and platelet count were obtained before the start of drug infusion and daily during infusion. Other laboratory data (eg, chemistry data, microbiologic culture results, and urinalysis) were recorded at baseline and, if available, recorded postbaseline.
Pharmacokinetic Analyses
Pharmacokinetic analyses were based on plasma activated protein C concentrations measured by using an immunocapture amidolytic assay validated in human plasma over a concentration range of 10 to 200 ng/mL.31 Endogenous concentrations of activated protein C are usually well below the quantitation limit of the assay, and therefore pharmacokinetic parameters based on this assay reflect those of drotrecogin alfa (activated).31
In all patients, blood samples for measurement of baseline endogenous activated protein C concentrations were collected within 2 hours before the start of drug infusion. Concentrations in plasma samples collected during infusion after at least 2 hours of continuous infusion were used to calculate Css and plasma clearance (Clp). Clp was calculated as k0/Css, where k0 is the infusion rate.
In part 1, Css and Clp were summarized by infusion rate and age group. Age group-specific infusion rates were calculated for part 2 as Clavg x Ctarget, where Clavg was the average age group-specific Clp in part 1 and Ctarget was the targeted Css of 50 ng/mL.
In part 2, plasma samples were collected during and after infusion according to age group-specific sampling schedules that were more extensive than those used in part 1. Css and Clp were summarized by age group based on all data from parts 1 and 2 at an infusion rate of 24 µg/kg per hour. The apparent elimination half-life (t1/2) of drotrecogin alfa (activated) was calculated in part 2 patients as –ln(2)/k, where k is the slope of ln(concentration) versus time after stopping infusion.
Pharmacodynamic Analyses
Blood samples for measurement of D-dimer (Liatest D-DI, latex immunoassay, Diagnostica Stago, Asnieres, France), protein C (Staclot Protein C, Diagnostica Stago), and antithrombin (Stachrom ATIII, Diagnostica Stago) levels were obtained within 2 hours before drug infusion in all patients in parts 1 and 2 and at various times during and after infusion only in part 2 of the study. D-dimer, protein C, and antithrombin analyses were performed by a central laboratory. D-dimer, protein C, and antithrombin levels from adult PROWESS patients are presented for comparison purposes.
Safety Analyses
An adverse event was defined as any untoward medical occurrence in a patient administered study drug regardless of a causal relationship. The adverse events recorded for this study were those events that occurred or worsened (if present at baseline) after the start of study drug administration even if the event was an outcome of the course of the severe sepsis. A serious adverse event was defined as any event that resulted in one of the following outcomes or was significant for any other clinically relevant reason: 1) death; 2) a life-threatening experience, defined as an experience in which the patient was at risk of death at the time of the event and not an experience that hypothetically might have caused death if it were more severe; 3) prolonged inpatient hospitalization; or 4) severe or permanent disability. Bleeding events were reported as serious adverse events if they were associated with the outcome of a serious adverse event or if they required treatment by transfusion therapy greater than or equal to the following: newborn to <1 year old, 20 mL of packed red blood cells/kg per 24 hours; 1 to 12 years old, 10 mL of packed red blood cells/kg per 24 hours; 12 to <18 years old, 3 units of packed red blood cells/day for 2 consecutive days or 6 units of packed red blood cells/48 hours.
Statistical Analysis
In general, only descriptive statistics were computed, because this was an open-label study. The Wilcoxon signed-rank test was used to analyze the percent change from baseline to end of infusion for D-dimer, protein C, and antithrombin levels. Patients had to have a baseline value and at least one postbaseline value to be included in the analysis. The last-observation-carried-forward method of data imputation was used in the cases of a missing end of infusion values.
Summary statistics were calculated for all pharmacokinetic parameters. A linear mixed-effects 2-way analysis of variance model with an interaction effect was used to study the effects of infusion rate and age group on weight-normalized Clp in part 1 of the study. In combined data from parts 1 and 2, a linear mixed-effects one-way analysis of variance model was used to compare weight-normalized Clp at an infusion rate of 24 µg/kg per hour in various age ranges across the overall range of ages studied.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Population and Baseline Characteristics
After informed consent was obtained, 89 patients were entered into the study (23 patients in part 1 and 66 patients in part 2). Of these 89 patients, 83 received study drug. Six patients never received study drug because of the development of an exclusion criterion before study drug initiation.
In part 1 of the study, all 21 patients were enrolled under the original protocol, which allowed enrollment of patients only on the basis of cardiovascular or respiratory organ dysfunction. In part 2, 30 patients were enrolled under the original protocol. Of these 30, there were 5 patients <1 year old, 19 patients 1 to 8 years old, and 6 patients 8 to 18 years old. Approximately 90% of all patients enrolled under the original protocol in part 1 and 2 had cardiovascular organ dysfunction. Another 32 patients were enrolled in part 2 under the amended protocol, which also allowed entry of patients on the basis of renal or hematologic dysfunction in addition to those with cardiovascular and respiratory organ dysfunction. Of these 32 patients, 14 were <1 year old, 7 were 1 to 8 years old, and 11 were 8 to 18 years old. Similar to the original protocol, a majority of these patients presented with cardiovascular dysfunction (n = 29, 90.6%). Of these 32 patients, 8 (25.0%) presented with hematologic dysfunction, 4 (12.5%) presented with with renal dysfunction, and 12 (37.5%) presented with respiratory dysfunction. Overall, the majority of the patients presented with cardiovascular organ dysfunction at study entry and had 2 baseline organ dysfunctions as defined by daily organ dysfunction assessment criteria (Table 1), indicating that implementation of the protocol amendment did not significantly alter the type of patient enrolled in the study. Approximately 50% of the patients presented with 4 SIRS criteria, and the mean number of organ dysfunctions at baseline was 2.7.
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The most common site of infection (Table 1) identified in patients was blood (34.9%). At least one pathogen was detected in 71.1% of all patients (part 1: n = 12, 57.1%; part 2: n = 47, 75.8%), and pure Gram-positive and pure Gram-negative organisms were identified in 21.7% and 37.3% of patients (Table 2), respectively. The most common microorganism was Neisseria meningitidis (26.5% patients).
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Most patients exhibited baseline coagulopathy as evidenced by elevated D-dimer levels and protein C and antithrombin activity below the lower limit of normal (Table 3).
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Pharmacokinetics
Preinfusion plasma concentrations of endogenous activated protein C were below the quantitation limit of 10 ng/mL in 88% of patients, similar to the rate observed in adult patients in PROWESS.31
In part 1, mean Css across age groups ranged from 22.1 ng/mL at a dose of 12 µg/kg per hour to 59.3 ng/mL at a dose of 36 µg/kg per hour. Because of a number of plasma concentrations below the assay quantitation limit at the infusion rate of 6 µg/kg per hour, the pharmacokinetics of drotrecogin alfa (activated) could not be characterized at that infusion rate. The overall mean Clp was 0.53 L/hour/kg across all infusion rates and age groups (n = 63 infusions). No significant interaction effect between infusion rate and age group was detected (P = .22), suggesting that infusion rate and age did not affect Clp. Based on these data, an infusion rate of 24 µg/kg per hour was selected for part 2 of the study.
Based on data from parts 1 and 2 combined, the overall mean and median Clp were each 0.45 L/hour/kg (coefficient of variation [CV] for mean = 5.6%) across all pediatric patients receiving drotrecogin alfa (activated) infusion at a rate of 24 µg/kg per hour (Table 4). The mean and median Css were 51.03 (CV = 5.0%) and 51.3 ng/mL, respectively. Adult values from PROWESS are included for comparison.31
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Weight-normalized Clp declined significantly with age (P = .0001) in patients <18 years old, although combined pediatric and adult weight-normalized Clp at 24 µg/kg per hour did not depend significantly on age (P = .17; Fig 1) or body weight (P = .15). Prompted by the statistically significant age dependency in weight-normalized Clp in pediatric patients <18 years old, we examined Clp in the youngest evaluable age group of pediatric patients to identify any pharmacokinetic concerns that could affect the safety of drotrecogin alfa (activated) administration to those patients. In patients <3 months old (N = 11), mean weight-normalized Clp (0.608 L/hour/kg, CV = 8.6%) was 22% higher than that in all patients
3 months old (0.497 L/hour/kg; CV = 2.5%; P = .027) and 19% higher than that in adult patients 18 years old (P = .048). The higher Clp in these patients would be expected to produce slightly lower Css than that produced in older patients, and therefore the difference in Clp does not prompt a safety concern based on differences in clearance. The mean apparent plasma elimination t1/2 calculated from all part 2 patients was 30 minutes.
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Pharmacodynamics
All age groups including the infant subgroup (term newborn to <1 year) responded similarly with regard to D-dimer, protein C, and antithrombin levels (Table 5). D-dimer levels decreased steadily from baseline to end of infusion. The overall median percent decrease in D-dimer levels from baseline to end of infusion was 26% (P = .11). There was a significant overall median percent increase in protein C and antithrombin levels from baseline to end of infusion (79% and 24%; both P < .001).
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Safety Analyses
Deaths
A total of 8 (9.6%) of 83 patients died during study participation in the pediatric open-label safety trial. The mean predicted mortality (PIM) was 10.8%. All 8 patients were enrolled in part 2 of the study. Clinically, patients in part 2 presented with considerably more disease severity based on number of organ dysfunctions, mechanical ventilation status, and PIM score (Table 1). One death was assessed by the investigator to be possibly related to administration of drotrecogin alfa (activated). This death was associated with an ICH in an adolescent with fulminant meningococcemia. The other deaths in the study were reported to be caused by sepsis-related complications.
Bleeding Events
During the entire study period of the pediatric trial, 4 patients (4.8%) experienced a serious bleeding event. Two of these events occurred in the 8- to 18-year-olds group, one occurred in the 1- to 8-year-olds group, and one occurred in the <1-year-olds group. Two of these patients (2.4%) had a serious bleeding event reported during the study drug infusion period. These events were nasopharyngeal hemorrhage and petechial cerebral hemorrhage, neither of which was considered by the investigator as related to drotrecogin alfa (activated) administration. The patient suffering a nasopharyngeal hemorrhage was the only patient in the study whose need for transfusion met the definition of a serious adverse event. Two additional patients had serious bleeding events [ICH and a gastrointestinal hemorrhage] that were reported during the remaining study period. The clinical investigator assessed the ICH occurring in the adolescent patient with fulminant meningococcemia as possibly related to infusion of drotrecogin alfa (activated). Although this event was diagnosed after the drug infusion period by postmortem CT scan, it is likely that the ICH occurred during the drotrecogin alfa (activated) infusion period. All but one of these events (nasopharyngeal hemorrhage) occurred in part 2 of the trial in patients receiving the 24 µg/kg per hour infusion. The nasopharyngeal hemorrhage, which was procedure-induced after multiple unsuccessful attempts to place a weighted nasogastric tube, occurred in part 1 approximately 1 hour after the patient had completed the 12 µg/kg per hour infusion of study drug. The last Css levels of activated protein C measured before the serious bleeding events described during study drug infusion were not unusually high (48.6 and 76.6 ng/mL) and not unexpected. Blood samples drawn for measurement of activated protein C levels did not correspond to the exact onset time of the serious bleeding event. Based on the short half-life of activated protein C, levels at time points >2 hours after completion of study drug infusion would be minimal.
Overall, 17 (20.5%) of 83 patients experienced bleeding events classified as adverse events (includes serious bleeding events previously discussed). Two of these events (not classified as serious bleeding events), retroperitoneal hematoma and oozing from arterial line, which occurred during part 2 with a 24 µg/kg per hour infusion, were considered possibly related to drotrecogin alfa (activated) infusion by the clinical investigator. The retroperitoneal hematoma occurred in the 8- to 18-year-olds group and the oozing from arterial line occurred in the 1- to 8-year-olds group. The retroperitoneal hematoma occurred in a child with severe coagulopathy and meningitis who was also receiving heparin for hemodialysis. Additional bleeding events, the majority considered mild to moderate in severity, included minor oozing and bruising near incision and catheter insertion sites, hematuria, epistaxis, and blood-tinged secretions from mucous membranes. None of these events were considered by the clinical investigators as related to infusion of drotrecogin alfa (activated).
Additional Safety Information
Three of 21 patients (14.3%) in part 1 and 13 (21.0%) of 62 patients in part 2 experienced at least one serious adverse event during drotrecogin alfa (activated) infusion, which includes the serious bleeding events already described. Other serious adverse events reported included choreoathetosis, respiratory disorder, and progressive cardiovascular dysfunction secondary to septic shock.
Serious adverse events experienced by patients during the entire study period were choreoathetosis, respiratory disorder, abscess, gangrene, necrosis, cerebral ischemia, and intestinal perforation, progressive cardiovascular dysfunction secondary to septic shock, and cardiac arrest. None of these events were considered by the investigator to be related to infusion of drotrecogin alfa (activated).
Overall, at least one adverse event during the entire study period was experienced by 78 (94.0%) of 83 patients. The most frequently occurring adverse events during the entire study period were fever (19.3%), generalized edema (15.7%), agitation, lung edema, oliguria, pleural effusion, and thrombocytopenia (all 14.5%). All the adverse events recorded in the study typically occur in pediatric severe sepsis patients, and none of these adverse events were considered related to drotrecogin alfa (activated) infusion.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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This is the first reported use of drotrecogin alfa (activated) in pediatric patients. In this study, children with severe sepsis manifested coagulation abnormalities including D-dimer elevation and acquired protein C deficiency that were similar to coagulation abnormalities documented in adults with severe sepsis.25 Pharmacokinetic analyses of multiple infusion rates across the entire pediatric age spectrum indicate that the infusion rate of drotrecogin alfa (activated) required to achieve target pharmacological plasma concentrations in children is the same as that in adults (24 µg/kg/hour). Furthermore, administration of drotrecogin alfa (activated) to children with severe sepsis was associated with an improvement in coagulopathy including D-dimer, protein C, and antithrombin levels. These data suggest that drotrecogin alfa (activated) could potentially be useful in pediatric severe sepsis patients who have the clinical characteristics of patients enrolled in this trial. Given the potential for bleeding complications, a randomized, placebo-controlled trial is currently planned to formally assess the safety and efficacy of drotrecogin alfa (activated) in children.
The enrollment criteria and study procedures for the pediatric trial were highly analogous to those of the PROWESS study in adults.25 The major differences included adjustment of study parameters for age-specific norms (eg, heart rate, blood pressure, and analysis of transfusion volumes) and a limitation of blood sampling for experimental studies given the relatively small blood volume of children. The analogous entry and exclusion criteria yielded a pediatric population with a high percentage of coagulation abnormalities including D-dimer elevation (100% of patients) and acute acquired protein C deficiency (81% of patients). The percentages of children with these sepsis-induced coagulopathies at baseline were nearly identical to the percentages of adults (99.7% with abnormal D-dimer; 87.6% with abnormal protein C levels) with these abnormalities in the PROWESS study.25
The majority (92.8%) of the patients in the pediatric trial presented with cardiovascular organ dysfunction at study entry, and 85% of the patients had 2 or more baseline organ dysfunctions as defined by daily organ dysfunction assessment criteria. These baseline disease severity characteristics were also similar to those in the adult PROWESS trial where, at baseline, 71.8% of patients had cardiovascular organ dysfunction32 and the majority of patients (75.2%) presented with 2 or more organ dysfunctions at entry.25
Pharmacokinetic analyses indicated that no dosage adjustment was required for age: the same per-kilogram dose and duration in adults (24 µg/kg per hour for 96 hours) resulted in desired pharmacological plasma concentrations of drotrecogin alfa (activated) in children. Given the magnitude of difference in the mean Css observed only in the 8- to 18-year-old group compared with adults (Table 4), considered against the range of individual Css values observed in pediatric and adult patients and the absence of any correlation between bleeding events and adverse events in adult patients,31 it is unlikely that this difference is clinically relevant. Furthermore, across all age groups, treatment of children with drotrecogin alfa (activated) was associated with similar pharmacodynamic effects as those in adults, specifically a reduction in D-dimer levels and an increase in the levels of plasma protein C33 (Table 5). Although we cannot identify the threshold concentration for efficacy from the pediatric or adult studies, we know that adult patients in PROWESS in the lowest Css quartile benefited from treatment.31
In the PROWESS trial, the only adverse effect of drotrecogin alfa (activated) identified was a statistically significant increase in serious bleeding during infusion (placebo: n = 8, 1%; drotrecogin alfa (activated): n = 20, 2.4%; P = .02). This effect was consistent with the pharmacological antithrombotic properties of activated protein C. In the pediatric study, the severe bleeding (n = 2) rate that occurred during infusion was 2.4%. If the patient with meningococcal sepsis and ICH is also included as a bleed that occurred during the infusion, the serious bleeding rate during infusion would be 3.6%. Whether 2.4% or 3.6%, the bleeding rate seems consistent with the bleeding rate observed in adults. The incidence of all serious bleeding events during the trial (4.8%) is also consistent with the incidence of all serious bleeding events (3.5%) observed in PROWESS. The precise quantification of a potential bleeding risk cannot be accomplished until the randomized, placebo-controlled trial in pediatrics is completed. There did not seem to be a correlation between plasma concentrations of activated protein C and occurrence of a serious bleeding event. However, collection of blood samples for measurement of activated protein C did not coincide with the onset of the serious bleeding event and may not reflect the actual concentrations of activated protein C immediately before or during the bleeding event.
The major limitation of the pediatric study was the lack of a placebo arm. Therefore, given the severity of illness of children enrolled in the pediatric trial, the observed rate of serious bleeding may or may not represent an increase over the expected bleeding rate during the natural course of severe sepsis in the pediatric population. Any potential increase in bleeding could potentially be more significant for pediatrics, because there is a relatively low baseline mortality rate in this population (10%–15%), and the benefit-risk assessment could be significantly different from that in adults.
In addition to bleeding events during the course of the infusion, bleeding events also occurred after the infusion throughout the entire study period. Although one cannot exclude a relationship between these events and drotrecogin alfa (activated), the very short t1/2 of activated protein C in patients makes it unlikely that these events were causally related to drug infusion. Although no additional external review of bleeding events was performed in this study, in the opinion of the study investigators, only one serious bleeding event, an ICH in an adolescent patient with fulminant meningococcemia, possibly occurred as a result of drotrecogin alfa (activated) administration. Of importance, the high adverse event rate reported here reflects all adverse events that typically occur in a pediatric severe sepsis population (eg, generalized edema, fever, agitation, thrombocytopenia, hypokalemia, oliguria, and lung edema). There was no adverse event aside from bleeding that was possibly attributed to drotrecogin alfa (activated). Additional safety information for use of drotrecogin alfa (activated) in children with severe sepsis is currently being collected in ongoing open-label trials enrolling pediatric patients. In addition, a placebo-controlled trial to evaluate the efficacy of drotrecogin alfa (activated) in pediatric patients is ongoing.
The initiation of a pediatric trial during the course of an adult randomized trial is, to the knowledge of the investigators, unique in the history of clinical trials with novel biological agents for the treatment of sepsis. This concurrent study in children reaffirms that the coagulopathy and protein C deficiency documented in adults is at least as severe, if not more so, in children. Furthermore, pharmacokinetic analyses demonstrate that an infusion rate of 24 µg/kg/hour may be considered in children, because this dose is associated with a pharmacodynamic and safety profile in children that is similar to adults. We suggest that the early, concurrent initiation of pediatric trials should become the standard for all trials of novel agents that are foreseen to have widespread applicability for critically ill children.
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ACKNOWLEDGMENTS |
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This study (F1K-MC-EVAO) was funded by Eli Lilly and Company (Indianapolis, IN).
This study would not have been possible without the considerable effort of all subinvestigators, study coordinators, and pharmacists at the clinical sites and the product development team at Eli Lilly and Company. The following investigators also participated in this study: Saul N. Faust, MRCP, MBMS, St. Mary’s Hospital (London, United Kingdom); Vivienne Newman, BBCh, Pediatric Critical Care, Children’s Hospital of Oakland (Oakland, CA); Larry S. Jefferson, MD, Pediatric Critical Care Section, Texas Children’s Hospital (Houston, TX); and Brian Jacobs, MD, Pediatric Critical Care, Children’s Hospital Medical Center (Cincinnati, OH). The following individuals served as study coordinators for the conduct of this study: Desiree D. Hollemon, BSN, Oregon Health Sciences University (Portland, OR); Dena R. Lipsky, Pediatric Intensive Care, Texas Children’s Hospital (Houston, TX); Kim A. Lyons, BSN, and Melissa L. Rickey, Division of Critical Care Medicine, Children’s Hospital Medical Center (Cincinnati, OH); Gwen Y. Shang-Feaster, MD, Critical Care Services, Children’s Medical Center (Dallas, TX); William Ramsey, BS, Department of Anesthesiology, Children’s Hospital and Regional Medical Center (Seattle, WA); Bette J. Manulich, MPH, Emmanuel Hospital and Health Center (Portland, OR); Mary McIIroy, MS, Pediatric Critical Care, Children’s Hospital Oakland (Oakland, CA); Jean Reardon, BSN, Children’s National Medical Center (Washington, DC); and Jeana M. Fansier, BA, Department of Pediatrics, University of Oklahoma Health Sciences Center (Oklahoma City, OK).
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FOOTNOTES |
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Received for publication Nov 20, 2002; Accepted May 13, 2003.
Address correspondence to Brett P. Giroir, MD, Children’s Medical Center of Dallas, 1935 Motor St, Dallas, TX 75235. E-mail: Brett.Giroir{at}childrens.com
Dr Kalil’s present address: University of Nebraska Medical Center, Omaha, NE.
Dr Yeh’s present address: Division of Pediatric Critical Care Medicine, Children’s Hospital of New Jersey at Newark Beth Israel Medical Center, Newark, NJ.
Dr Giroir had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of its analysis.
Dr Giroir has served as a consultant for Eli Lilly and Company; Dr Kalil is a past employee and stockholder of Eli Lilly and Company; and Dr Macias, Dr Small, Ms Bates, Ms Wyss, and Ms Utterback are employees and stockholders of Eli Lilly and Company.
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