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

Guntupalli, Kalpalatha MD1; Dean, Nathan MD2; Morris, Peter E. MD3; Bandi, Venkata MD1; Margolis, Benjamin MD4; Rivers, Emanuel MD5; Levy, Mitchell MD, FCCM6; Lodato, Robert F. MD, PhD7; Ismail, Preeti M. PhD, MBA8; Reese, Amber8; Schaumberg, John P. PhD8; Malik, Rajesh MD8; Dellinger, R. Phillip MD, MCCM9

doi: 10.1097/CCM.0b013e3182741551
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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.

1 Department of Medicine, Baylor College of Medicine, Ben Taub General, Hospital Houston, TX.

2 Intermountain Medical Center and the University of Utah, Salt Lake City, UT.

3 Wake Forest University, Winston-Salem, NC.

4 West Suburban Medical Center, Oak Park, IL.

5 Departments of Surgery and Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI.

6 Brown University, Providence, RI.

7 Division of Pulmonary, Critical Care, and Sleep Medicine, The University of Texas Medical School, Houston, TX.

8 Agennix, Houston, TX.

9 Robert Wood Johnson/Cooper University Hospital, Critical Care Medicine, Camden, NJ.

* See also p. 908.

The TLF LF-0801 Investigator Group is listed in Appendix 1.

Currently listed as NCT 00630656.

Supported, in part, by NIH grant R44GM077816 and Agennix, Houston, TX.

The authors have not disclosed any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins