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

Arroliga, Alejandro C.; Balk, R.A.; Cannon, Chad; Dean, Nathan C.; Dellinger, Phil; Dennen, Paula; Figueroa, Juan Manuel; Fletcher, Eugene C.; Guntupalli, Kalpalatha K.; Huang, Defeng; Levy, Mitchell M.; Lo, Takkin; Malik, Imrana; Margolis, Benjamin D.; Matuschak, George M.; Moore, Laura J.; Moran, Gregory J.; Moretti, Eugene W.; Morris, Peter E.; Panacek, Edward A.; Rivers, E. P.; Schmidt, Greg; Seneff, Michael G.; Steingrub, Jay S.; Taylor, Robert W.

doi:10.1097/ccm.0b013e3182741551

Cited by 63 publications

(40 citation statements)

References 43 publications

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“…The talactoferrin group had a 28-day all-cause mortality of 14.4%, and the better survival was maintained up to 6 mo. The lactoferrin was given enterally, and it is believed that the compound helps maintain the integrity of the gut mucosal barrier (144). Yet, a subsequent phase II/III trial of talactoferrin in severe sepsis was discontinued by Agennix AG after the treatment group had worse outcomes than placebo (237).…”

Section: New Experimental Interventionsmentioning

confidence: 99%

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Iskander

Osuchowski

Stearns-Kurosawa

et al. 2013

Physiological Reviews

361

335

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Sepsis represents the host's systemic inflammatory response to a severe infection. It causes substantial human morbidity resulting in hundreds of thousands of deaths each year. Despite decades of intense research, the basic mechanisms still remain elusive. In either experimental animal models of sepsis or human patients, there are substantial physiological changes, many of which may result in subsequent organ injury. Variations in age, gender, and medical comorbidities including diabetes and renal failure create additional complexity that influence the outcomes in septic patients. Specific system-based alterations, such as the coagulopathy observed in sepsis, offer both potential insight and possible therapeutic targets. Intracellular stress induces changes in the endoplasmic reticulum yielding misfolded proteins that contribute to the underlying pathophysiological changes. With these multiple changes it is difficult to precisely classify an individual's response in sepsis as proinflammatory or immunosuppressed. This heterogeneity also may explain why most therapeutic interventions have not improved survival. Given the complexity of sepsis, biomarkers and mathematical models offer potential guidance once they have been carefully validated. This review discusses each of these important factors to provide a framework for understanding the complex and current challenges of managing the septic patient. Clinical trial failures and the therapeutic interventions that have proven successful are also discussed.

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Section: New Experimental Interventionsmentioning

confidence: 99%

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Iskander

Osuchowski

Stearns-Kurosawa

et al. 2013

Physiological Reviews

361

335

View full text Add to dashboard Cite

show abstract

“…In a large, multicenter randomized trial (ACCESS trial), eritoran failed to show any benefit in 28-day mortality over placebo 6 . Other strategies that aim to modify the immune response and are in various stages of development include: drugs targeting bacterial superantigens (AB103) 129,130 , immunomodulatory proteins (talactoferrin) 131 http://agennix.com/index.php?option=com_content&view=article&id=205%3Aagennix-ag-halts-phase-iiiii-oasis-trial-in-severe-sepsis&catid=23%3Apress-releases-2012&Itemid=56&lang=en (accessed May 18, 2014), and anticoagulant pathways (ART-123) 132 , as well as blocking complement activation (C1-esterase inhibitor) 133 , and inhibiting inflammatory cytokines (CytoFab against tumor necrosis alpha) 134 . Trials for these agents are in various stages (Table 2).…”

Section: Ongoing Clinical Trials In Sepsismentioning

confidence: 99%

Emerging Therapeutic Targets of Sepsis-Associated Acute Kidney Injury

Swaminathan¹,

Rosner²,

Okusa³

2015

Seminars in Nephrology

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Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. Thus far singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobial and target specific and time dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including temporal nature of pro- and anti-inflammatory processes. In this review, we will discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes as well as therapeutics that may enhance cellular survival and recovery. Lastly we include ongoing clinical trials in sepsis.

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“…Talactoferrin-α, a recombinant human form of lactoferrin, was associated with a trend towards a decreased 28-day mortality rate, especially in patients with APACHE II (Acute Physiology and Chronic Health Evaluation II) scores of > 25 in a phase II trial [46]. However, it was negative in a subsequent phase II/III trial that was prematurely terminated (NCT 01273779).…”

Section: Management Of Organism and Organism Toxicity In Septic Shockmentioning

confidence: 99%

“…AMPs have been studied in sepsis and septic shock [46, 47]. Talactoferrin-α, a recombinant human form of lactoferrin, was associated with a trend towards a decreased 28-day mortality rate, especially in patients with APACHE II (Acute Physiology and Chronic Health Evaluation II) scores of > 25 in a phase II trial [46].…”

Section: Management Of Organism and Organism Toxicity In Septic Shockmentioning

confidence: 99%

The Understanding and Management of Organism Toxicity in Septic Shock

Genga¹,

Shimada²,

Boyd

et al. 2018

J Innate Immun

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The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells’ pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored.

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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*

Abstract: 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.

Cited by 63 publications

References 43 publications

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Emerging Therapeutic Targets of Sepsis-Associated Acute Kidney Injury

The Understanding and Management of Organism Toxicity in Septic Shock

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