A Phase 2 Randomized, Double-Blind, Placebo–Controlled Study of the Safety and Efficacy of Talactoferrin in Patients With Severe Sepsis

Kalpalatha Guntupalli, MD; Nathan Dean, MD; Peter E. Morris, MD; Venkata Bandi, MD; Benjamin Margolis, MD; Emanuel Rivers, MD; Mitchell Levy, MD, FCCM; Robert F. Lodato, MD, PhD; Preeti M. Ismail, PhD, MBA; Amber Reese; John P. Schaumberg, PhD; Rajesh Malik, MD; R. Phillip Dellinger, MD, MCCM

Disclosures

Crit Care Med. 2013;41(3):706-716. 

In This Article

Abstract and Introduction

Abstract

Objectives: Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety.

Design: Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial.

Setting: Adult ICUs and emergency departments in the United States.

Patients: One hundred ninety-four adults within 24 hrs of the onset of severe sepsis.

Interventions: Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU.

Measurements and Main Results: Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo.

Conclusions: Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

Introduction

Sepsis is a clinical syndrome defined by the presence of both infection and a systemic inflammatory response. Severe sepsis is defined as sepsis with the addition of one or more organ dysfunctions.[1,2] Approximately 750,000 cases of severe sepsis occur each year in the United States.[3] The conventional management of sepsis consists of eradicating the underlying infection and providing supportive care for associated organ dysfunction.[4,5] Despite the advances in treatment, severe sepsis has a mortality of approximately 30%, leading to the loss of about 220,000 lives each year while adding $16 billion in healthcare costs.[3]

Lactoferrins are members of the transferrin family of nonheme iron binding proteins.[6] They are normally found in serum and in exocrine secretions such as milk, seminal fluid, intestinal secretions, tears, sweat, saliva, and nasal secretions in mammals[7–9] and in secretory granules of neutrophils.[10] They are synthesized in epithelial cells and polymorphonuclear cell precursors.[10]

Talactoferrin alfa (TLF) is a recombinant human form of lactoferrin produced in Aspergillus niger var awamori.[11] Talactoferrin is equivalent to native lactoferrin from human milk in 3D structure, molecular weight, biological activity, and other physicochemical properties, differing only in the nature of glycosylation.[12] Like the native protein, TLF displays anti-infective[11,13–15] and anti-inflammatory[16–18] properties, which have been demonstrated in in vitro and preclinical studies. Talactoferrin has also been shown to attenuate indomethacin-induced enteropathy in healthy volunteers, suggesting that it helps maintain the barrier properties of gastrointestinal (GI) mucosa.[19] In animal models of sepsis, enterally administered talactoferrin protects against mortality induced by bacteria[15,20] and endotoxin administration (Agennix data on file).

Oral TLF acts locally at the level of the intestinal enterocytes and the gut-associated lymphoid tissue (GALT). Talactoferrin has been observed to protect against gut damage in both preclinical[21] and clinical studies,[19] and to reduce translocation of bacteria across the gut mucosa. These effects are consistent with the demonstrated ability of lactoferrin and oral TLF to reduce mortality in bacterial[22,23] and lipopolysaccharide (Agennix data on file) models of sepsis, respectively. The safety and efficacy of TLF has also been evaluated in other clinical trials in humans,[24–27] enabling this study to explore TLF effects in human sepsis. This phase 2 trial was carried out to extend the preclinical sepsis results and to evaluate the safety and efficacy of TLF in severe sepsis in humans.

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