PK/PD of EA-230 During Endotoxemia
Condition: Endotoxemia; Systemic Inflammatory Response
MeSH terms: Endotoxemia
Study type: Interventional
Phase: Phase 1

Summary: 
      EA-230 is a newly developed synthetic compound with anti-inflammatory properties.
      Pre-clinical data indicate that EA-230 may be a valuable treatment for systemic inflammation
      resulting from a variety of causes such as surgery, trauma, infection, irradiation and
      others. Although previous studies in healthy volunteers have shown an excellent safety
      profile, the safety and tolerability of higher doses administered per continuous infusion
      need to be investigated. Also, the dose-effect relation on systemic inflammation needs to be
      further elucidated before a phase II trial in patients can be commenced.
    

Detailed description: 
      Although the immune system is essential to survival, a variety of diseases originate from
      inappropriate activation of the immune response. Besides a range of auto-inflammatory disease
      like rheumatoid arthritis, inappropriate or undesirable activation of the immune system can
      occur during infectious diseases like sepsis, after major surgery like cardiac artery bypass
      grafting, after radiation therapy in the treatment of cancer, or after organ transplantation.

      For auto-inflammatory diseases, in the last decades therapies have come available that
      specifically target parts of the immune system. The development of 'biologicals', recombinant
      antibodies that specifically block one antigen or receptor, has had an enormous impact on the
      treatment of chronic autoimmune diseases. However, these treatments have been shown not to be
      effective in other types of (acute) systemic inflammation, like sepsis.

      Of the many downstream consequences of exaggerated inflammatory response, organ injury and
      failure is the most serious, most often involving the kidneys. This also holds true for
      cardiac surgery with cardiopulmonary bypass, in which various factors, including the
      inflammatory cascade, cause a temporarily decline or even permanent loss of renal function.
      As kidney failure is an independent prognostic factor for mortality in critically ill
      patients, treatments aimed at preventing acute kidney injury are warranted.

      EA-230 is a novel pharmacological compound being developed for the treatment of systemic
      inflammatory states like sepsis, and for the treatment of inflammation associated organ
      dysfunction like acute kidney injury (AKI). It's a linear tetrapeptide derived from the human
      chorionic gonadotropin hormone (hCG). It has shown anti-inflammatory properties and protects
      against organ failure in several pre-clinical models of sepsis or systemic inflammation which
      will be described in more detail below. Most notably, EA-230 has shown marked protective
      effects in the kidney during abdominal sepsis in animals. As EA-230 attenuates the
      pro-inflammatory response in neutrophils and monocytes ex vivo, and neutrophil influx in
      tissues during systemic inflammation in vivo is abrogated, it is thought that EA-230 acts by
      protecting the host against the detrimental effects of neutrophils during acute systemic
      inflammatory diseases, thereby preventing organ damage, especially in the kidney.

      Having performed extensive research into the pharmacology, pharmacokinetics and toxicology of
      EA-230, a first in human study was previously conducted with escalating single doses of
      EA-230, which showed that EA-230 was well tolerated up to i.v. doses of 30 mg/kg three times
      a day (daily dose of 90 mg/kg) for three days, and did not result in adverse events that were
      related to the study treatment. In a human model of systemic inflammation elicited by the
      administration of a low dose of endotoxin, EA-230 showed to attenuate the innate immune
      response at a single i.v. dose of 10 mg/kg, even though EA-230 was administered 30 minutes
      after endotoxin administration. A full dose- and concentration-response profile was not
      collected in that study. In addition, until now, only bolus administrations of EA-230 were
      tested, whereas in view of the short terminal half life of less than 15 minutes, a continuous
      administration of EA-230 over a longer time interval may be more effective.

      For that reason, an additional phase I study in healthy volunteers is required to complete
      the profile of EA-230 response in inflammation before a dose or dose range can be chosen for
      a first 'prove-of-concept' study in patients. The safety profile of EA-230 has to be extended
      beyond the daily dose of 90 mg/kg addressed to date; the dose- and concentration response
      information collected during escalation will provide the dose for proof-of-concept testing in
      patients.
    

Intervention name(s): EA-230; Endotoxin; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): at t=0 30, 90 or 180 mg/kg EA-230 will be administered intravenously over 2 hours.; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
Other intervention name(s): AQGV; LPS, lipopolysaccharide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: EA-230; Inflammatory response; Kidney Injury; Endotoxemia