Clinical Trial: PK/PD of EA-230 During Endotoxemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Randomized Double Blind Placebo-controlled Clinical Safety, Tolerability and Pharmacokinetic/-Dynamic Study on the Effects of Escalating Single Intravenous Doses of EA-230 on the Innate Immune Respons

Brief 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 Summary:

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 fail
Sponsor: Radboud University

Current Primary Outcome: Safety and tolerability expressed in treatment related (serious) adverse events [ Time Frame: total (S)AE's at day 14 ]

Adverse events include: clinically significant variation in vital signs compared to baseline (blood pressure and heart rate), local infusion reaction at site of i.v. IMP infusion, clinically significant changes in ECG compared to baseline and clinically significant deflections in laboratory parameters compared to baseline (Hb, Ht, Leucocytes, thrombocytes, Leucocyte differential blood count, sodium, potassium, creatinine, urea, alkaline phosphatase, ALT, AST, γGT, CK, CRP)


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Cytokines [ Time Frame: at baseline (t=-1.5 and t=0), t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Blood plasma levels of TNF-alfa, IL-6 and IL-10, IL-8, IL12-p70, IL-1RA, MCP-1, ICAM, VCAM, MIP1-alfa, MIP1-beta,
  • Pharmacokinetics - levels of EA-230 [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Blood plasma levels of EA-230 and, if possible, metabolites
  • Pharmacokinetics - AUC [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Area under the plasma concentration versus time curve (AUC) of EA-230 and, if possible, metabolites
  • Pharmacokinetics - peak plasma levels [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Cmax of EA-230 and, if possible, metabolites
  • Pharmacokinetics - half life [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    plasma terminal t1/2 levels of EA-230 and, if possible, metabolites
  • Pharmacokinetics - distribution [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Distibution volume (V) of EA-230 and, if possible, metabolites
  • Pharmacokinetics - Clearance [ Time Frame: at baseline, t=0.25, t=0.5, t=1, t=1,5 t=2, t=3, t=4, t=6, t=8 and t=24 hours after IMP and endotoxin administration ]
    Clearance (Cl) of EA-230 and, if possible, metabolites
  • Renal function - GFR [ Time Frame: one day before, during and one day after IMP en endotoxine administration ]
    GFR, measured by the clearance of iohexol, the endogenous creatinie clearance and estimated by the clearance of serum creatinine using MDRD.
  • Renal function - renal damage markers [ Time Frame: at baseline(t=-1.5 and t=0), t=3, t=6, t=9, t=12 and t=24 hours after IMP en endotoxine administration ]
    Kidney injury markers measured by urine NGAL, KIM-1, L-FABP and plasma cystatin C.


Original Secondary Outcome: Same as current

Information By: Radboud University

Dates:
Date Received: November 16, 2015
Date Started: February 2015
Date Completion:
Last Updated: June 22, 2016
Last Verified: June 2016