PK/PD of EA-230 During Endotoxemia

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 Response During Experimental Human Endotoxemia

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.

Study Overview

• Status: Completed
• Conditions: Endotoxemia; Systemic Inflammatory Response
• Intervention / Treatment: Drug: Placebo; Drug: EA-230; Drug: Endotoxin

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Intensive care, research unit, Radboud University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 18 to 35 years inclusive
2. For part 2 only male
3. Subjects and their partners use a reliable way of contraception
4. BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg
5. Healthy as determined by medical history, physical examination, vital signs, ECG, and clinical laboratory parameters

Exclusion Criteria:

1. Unwillingness to abstain from any medication, recreational drugs or anti-oxidant vitamin supplements during the course of the study and within 7 days prior to study Day 1.
2. Unwillingness to abstain from nicotine, or alcohol or within 1 day prior to study Day 1
3. Previous participation in a trial where LPS was administered
4. Surgery or trauma with significant blood loss or blood donation within 3 months prior to study Day 1

5. History, signs or symptoms of cardiovascular disease, in particular:

   • History of frequent vaso-vagal collapse or of orthostatic hypotension
   • Resting pulse rate ≤45 or ≥100 beats / min
   • Hypertension (RR systolic >160 or RR diastolic >90)
   • Hypotension (RR systolic <100 or RR diastolic <50)
   • conduction abnormalities on the ECG
6. Renal impairment: plasma creatinine >120 µmol/L
7. Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper limit of normal.
8. History of asthma
9. Atopic constitution
10. CRP above 2x the upper limit of normal, or clinically significant acute illness, including infections, within 2 weeks before administration of the study drug.
11. Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to study drug administration.
12. Known or suspected of not being able to comply with the trial protocol.
13. Known hypersensitivity to any excipients of the drug formulations used.
14. Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: EA-230 (30mg/kg); Subjects will receive EA-230, 30 mg/kg	Drug: EA-230; at t=0 30, 90 or 180 mg/kg EA-230 will be administered intravenously over 2 hours.; Other Names: AQGV; Drug: Endotoxin; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously; Other Names: LPS, lipopolysaccharide
Active Comparator: EA-230 (90mg/kg); Subjects will receive EA-230, 90 mg/kg	Drug: EA-230; at t=0 30, 90 or 180 mg/kg EA-230 will be administered intravenously over 2 hours.; Other Names: AQGV; Drug: Endotoxin; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously; Other Names: LPS, lipopolysaccharide
Active Comparator: EA-230 (180mg/kg); Subjects will receive EA-230, 180 mg/kg	Drug: EA-230; at t=0 30, 90 or 180 mg/kg EA-230 will be administered intravenously over 2 hours.; Other Names: AQGV; Drug: Endotoxin; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously; Other Names: LPS, lipopolysaccharide
Placebo Comparator: Placebo; subjects receive placebo	Drug: Placebo; Drug: Endotoxin; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously; Other Names: LPS, lipopolysaccharide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability expressed in treatment related (serious) adverse events	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)	total (S)AE's at day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokines	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,	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
Pharmacokinetics - levels of EA-230	Blood plasma levels of EA-230 and, if possible, metabolites	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
Pharmacokinetics - AUC	Area under the plasma concentration versus time curve (AUC) of EA-230 and, if possible, metabolites	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
Pharmacokinetics - peak plasma levels	Cmax of EA-230 and, if possible, metabolites	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
Pharmacokinetics - half life	plasma terminal t1/2 levels of EA-230 and, if possible, metabolites	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
Pharmacokinetics - distribution	Distibution volume (V) of EA-230 and, if possible, metabolites	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
Pharmacokinetics - Clearance	Clearance (Cl) of EA-230 and, if possible, metabolites	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
Renal function - GFR	GFR, measured by the clearance of iohexol, the endogenous creatinie clearance and estimated by the clearance of serum creatinine using MDRD.	one day before, during and one day after IMP en endotoxine administration
Renal function - renal damage markers	Kidney injury markers measured by urine NGAL, KIM-1, L-FABP and plasma cystatin C.	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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Exponential Biotherapies Inc.
• Investigators: Principal Investigator: P Pickkers, MD, Prof., Radboud University Medical Center

Publications and helpful links

General Publications

• van Groenendael R, Kox M, Leijte G, Koeneman B, Gerretsen J, van Eijk L, Pickkers P. A randomized double-blind, placebo-controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA-230 during experimental human endotoxaemia. Br J Clin Pharmacol. 2019 Jul;85(7):1559-1571. doi: 10.1111/bcp.13941. Epub 2019 May 23.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 16, 2015
• First Submitted That Met QC Criteria: December 10, 2015
• First Posted (Estimate): December 14, 2015

Study Record Updates

• Last Update Posted (Estimate): June 23, 2016
• Last Update Submitted That Met QC Criteria: June 22, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Inflammatory response; Endotoxemia; Kidney Injury; EA-230
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia
• Other Study ID Numbers: EBI-EA230-LPS-2014