[PDF] Efficacy and safety of a phospholipid emulsion (GR270773) in Gram

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Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: Results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial R. Phillip Dellinger, MD; John F. Tomayko, MD; Derek C. Angus, MD, MPH; Steven Opal, MD; Michael A. Cupo, PhD; Sharon McDermott, PhD; Annie Ducher, MD; Thierry Calandra, MD; Jonathan Cohen, MD; the Lipid Infusion and Patient Outcomes in Sepsis (LIPOS) Investigators W ith an estimated global frequency of?18 million cases of sepsis annually and mortality rates in se- vere disease making it the second leading cause of death in noncoronary intensive care units, the personal and economic burden of sepsis is substantial (1-4). De- spite major advances in our understand- ing of the complex host inflammatoryresponse to infection and general manage- ment of critically ill patients, mortality rates for severe sepsis remain unacceptably high. Investigations of numerous novel po- tential therapies over the past two decades have resulted in the regulatory approval of only one new medicine for the treat- ment of severe sepsis—recombinant hu- man activated protein C (5). Two other therapies—early goal-directed therapyfor sepsis-induced tissue hypoperfusion and stress dose steroids for septic shock—have single-center literature support for improving survival in severe sepsis (6, 7). A more recent study has questioned the role of the latter therapy (8). Mortality from sepsis remains high, leaving a large unmet medical need.

There is much recent interest in lipids

and lipid modification in critical illness.

Clinical studies revealed that reduced se-

rum lipoprotein levels are associated with poor outcomes in critically ill patients including septic patients (9-14). Numer- ousin vitroand preclinical studies have demonstrated that lipoproteins, notably high-density lipoprotein, can bind and neutralize endotoxin (15-18). A survival benefit derived from exogenous lipoprotein has been demonstrated in animal studies (17, 19, 20), and the ability of lipoproteins to bind endotoxin has been correlated with their phospholipid content (20).Objective:To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical andex vivostudies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies dem- onstrate protection from septic death when lipoproteins are ad- ministered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. Design:A three-arm, randomized, blinded, placebo-controlled trial. Setting:Conducted at 235 centers worldwide between Sep- tember 2004 and April 2006. Patients:A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse

events at the fourth interim analysis and included 182 patients.Measurements and Main Results:A 28-day all-cause mortality

and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for

28-day all-cause mortality, with rates of 25.8% (p?.329), 31.3%

(p?.879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%,

20.4% with low- and high-dose phospholipid emulsion, and placebo,

respectively (one-sidedp? .992, low vs. placebo;p?.999, high vs. placebo). Of the subjects treated, 45% had microbiologically con- firmed Gram-negative infections. Maximal changes in mean hemo- globin levels were reached on day 10 (?1.04 g/dL) and day 5 (?1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (?0.82 g/dL) with placebo. Conclusions:Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram- negative severe sepsis. (Crit Care Med 2009; 37:2929-2938) KEY WORDS: sepsis; Gram-negative severe sepsis; lipid emul- sion; endotoxin neutralization From the Cooper University Hospital and University

Medicine Dentistry New Jersey (PD), Camden, NJ;

GlaxoSmithKline Pharmaceuticals (JFT, MAC), Phila- delphia, PA; University of Pittsburgh School of Medi- cine (DCA), Pittsburgh, PA; Brown University School of Medicine (SO), Providence, RI; GlaxoSmithKline Phar- maceuticals (SM), Research Triangle Park, NC;* Glaxo-

SmithKline Pharmaceuticals (AD), Greenford, Mid-

dlesex, UK; Centre Hospitalier Universitaire Vaudois (TC), Lausanne, Switzerland; University of Lausanne (TC), Lausanne, Switzerland; and Brighton and Sussex

Medical School (JC), Brighton, Sussex, UK.

*Current address: Pharmaceutical Product Devel- opment International, Wilmington, NC.This study was funded, in part, by GlaxoSmithKline (DCA, SO).

Drs. Dellinger, Angus, Opal, Calandra, and Cohen,

or their affiliated hospitals received honoraria/ reimbursement from GlaxoSmithKline for time spent on the advisory board for this study. Drs. Tomayko, Cupo, Ducher, and McDermott are employees of GlaxoSmith-

Kline. Dr. Cohen has consulted for Disvo.

For information regarding this article, E-mail: Del- linger-Phil@cooperhealth.edu Copyright © 2009 by the Society of Critical Care

Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181b0266c2929Crit Care Med 2009 Vol. 37, No. 11

Recognition of the benefits derived

from reconstituted high-density lipopro- tein in experimental models of sepsis mo- tivated the development of a 10% phos- pholipid emulsion (containing 92.5 mg/mL of phosphatidylcholine [from soy- bean], 7.5 mg/mL of soybean oil, and 7.75 mg/mL of sodium cholate) (21). In large animal models of endotoxemia including one infection model, the phospholipid emulsion (GR270773 Emulsion; hereaf- ter, emulsion) reduced endotoxin-in- duced tumor necrosis factor production, improved cardiopulmonary function, and improved survival (22, 23).

Endotoxin challenge studies in human

volunteers demonstrated that infusion of the emulsion reduced clinical symptom scores and cytokine release (21, 24). These effects correlated with increasing serum phospholipid levels. In phase I studies in- cluding both healthy volunteers and septic patients, infusion of the emulsion was well tolerated, except for a mild reversible he- molytic anemia, and demonstrated a low potential for drug-drug interactions (25-28).

In this paper, we report the findings of a

multinational, randomized, dose ranging, phase II trial evaluating the efficacy and safety of a phospholipid emulsion as ad- junctive therapy for Gram-negative severe sepsis.

METHODS

Design and Patients

The Lipid Infusion and Patient Outcomes

in Sepsis (LIPOS) study was a three-arm, ran- domized, blinded, placebo-controlled trial conducted to assess two doses of the emulsion given as a 3-day continuous infusion in pa- tients with confirmed or suspected Gram- negative severe sepsis. The hypothesis was that the emulsion would increase surface phospho- lipid on plasma lipoproteins, thereby improv- ing their capacity to bind and neutralize en- dotoxin, and thus lead to improved outcomes in Gram-negative severe sepsis. The study was conducted at 235 study centers in 31 coun- tries. The standards of patient care were left to local practice.

The objective of the LIPOS study was to

estimate the size of the potential beneficial effect of the emulsion on mortality and new- onset organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

The protocol was approved by national, re-

gional, or investigational center independent

Ethics Committees or Institutional Review

Boards. Patients or their legal representative

provided informed written consent. The studywas conducted in accordance with Good Clin- ical Practice and the Declaration of Helsinki.

Patients were included if they were?18 yrs,

with a suspected or confirmed Gram-negative infection (Appendix 1) for which they were re- ceiving parenteral antibiotics for?36 hrs before the start of infusion, and had signs of new-onset severe sepsis evidenced by at least one new organ dysfunction/hypoperfusion (Appendix 2) caused by the current episode of sepsis.

Exclusion criteria were: participation in an

experimental trial within 30 days of enroll- ment; unlikelihood of remaining in hospital for a minimum of 72 hrs; neutropenia (abso- lute neutrophil count is?500/?L or expected to be within 3 days); suffering from spherocy- tosis or southeast Asian elliptocytosis; active hemolytic disease; bone marrow disorders af- fecting red cell production; allergy to any components of study drugs; do-not-resuscitate designation or equivalent; moribund or life expectancy of?3 mos due to underlying dis- ease; preexisting liver disease (e.g., cirrhosis, primary biliary cirrhosis or Child-Pugh class B or C liver dysfunction); receiving prohibited medication; pregnant or lactating. Patients with hemoglobin of?9.0 g/dL measured after adequate volume resuscitation were not eligi- ble for inclusion. At the time of screening, patients who were receiving or had orders to receive human activated protein C were not eligible although patients could receive this therapy after randomization, if deemed neces- sary by the investigator.

Treatment Assignment

Patients were randomized, in a simple ran-

domization scheme without blocking or strat- ification, to receive a 3-day continuous infu- sion of low-dose (850 mg/kg) or high-dose emulsion (1350 mg/kg) or low- or high-dose placebo. All doses were administered as a 2-hr loading infusion followed by a maintenance infusion for 70 hrs. Infusions were started within 36 hrs of starting parenteral antibiotics for the episode of sepsis and within 12 hrs of the first organ dysfunction or hypoperfusion.

Sterile 100 mg/mL batches of the emulsion

for intravenous administration were manufac- tured by Baxter (Deerfield, IL) for Glaxo-

SmithKline (Brentford, Middlesex, UK). The

placebo emulsion (manufactured by Hospira,

Lake Forest, IL) contained soybean oil to

match the opacity of the active emulsion, and egg yolk phospholipid as an emulsifier. These ingredients were not present in sufficient quan- tity to exert a physiologic effect. Active and pla- cebo emulsions were supplied ready to use.

An interactive voice response system was

used for registration and randomization. The interactive voice response system referenced the randomization code generated by the sponsor, and assigned a randomization num- ber and corresponding treatment. Study med-ication was prepared by a pharmacist (or other study personnel) not involved in patient care or assessments. The drug vial and administra- tion set was shrouded (to obscure any slight variation in color between the placebo and active emulsions). All study site personnel in- volved in assessment of patients were blinded to treatment allocation.

Enrollment was staged with an Independent

Data Monitoring Committee (IDMC) safety as-

sessment of the low dose before escalating to high dose and a safety assessment of high dose before progressing to three-way randomization.

Treatment Assessments

Baseline (preinfusion, day 1) assessments

included microbiological cultures, underlying disorders, adequacy of antimicrobial therapy, and Acute Physiology and Chronic Health

Evaluation (APACHE) II scores. Clinical as-

sessments were performed daily, including the following: evaluation of vital signs; evaluation of the need for organ support; documentation of blood products and erythropoietin use, andquotesdbs_dbs26.pdfusesText_32

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