Systemic inflammatory respons (SIRS) and associated acute kidney injury (AKI)
Conditions
Sponsors
Exponential Biotherapies Inc
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1.Written informed consent to participate in this trial prior to any study-mandated procedure. 2.Subjects aged 18 to 35 years inclusive, for part 2 only male subjects will be included. 3.Subjects and their partners have to agree to use a reliable way of contraception from study entry until 3 months after study drug administration. 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, 12 lead electrocardiogram, and clinical laboratory parameters 6.Negative results for hard drug use from urine drug screen at screening Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 studyDay 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 120 µmol/L 7.Liver function tests (alkaline phosphatase, AST, ALT and/or ?-GT) above 2x the upper limit of normal
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1: To assess the safety, tolerability and pharmacokinetic-dynamic response, of single escalating doses of EA-230 in healthy subjects. Part 2: To assess the dose-and plasma concentration-response relation of single escalating doses EA-230 on inflammation and LPS-induced changes in markers for renal function, and to assess safety, tolerability and PK of EA-230 under the condition of experimental endotoxemia.;Secondary Objective: Modulation by EA-230 on markers of inflammation-induced kidney injury and changes in renal function;Primary end point(s): Part 1: Safety and tolerability of EA-230 Part 2: Modulation by EA-230 of the LPS-induced inflammatory response, quantified by the change in area under the curve (AUC) of the concentration * time curve of TNF-a during endotoxemia;Timepoint(s) of evaluation of this end point: 5 timepoints: Day1 (testday), Day2, Day3, Day8, Day15 | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 6 timepoints: Day-1, Day1(testday), Day2, Day3, Day8, Day15 ;Secondary end point(s): Part 1: Pharmacokinetics of EA-230 -Blood plasma levels of EA-230 and, if possible, metabolites, AUC, Cmax, terminal t1/2, Cl, V -Urinary excretion profile of EA-230 and, if possible, metabolites. Vital signs -blood pressure -heart rate Adverse events Safety parameters -Local tolerability at the site of i.v. infusion -Safety laboratory parameters (Hb, Ht, Leucocytes, thrombocytes, Leucocyte differential blood count, sodium, potassium, creatinine, urea, alkaline phosphatase, ALT, AST, ?GT, CK, CRP) -Electrocardiogram (ECG), at baseline, just after IMP administration, and at 7 to 8 hrs after IMP administration Part 2: Modulation by EA-230 of the LPS-induced inflammatory response, quantified by the change in AUC of the concentration * time curve of other cytokines during endotoxemia (IL-6 and IL-10) Modulation by EA-230 of the LPS-induced leucocyte response, quantified by total WBC counts, neutrophil counts and monocyte counts over 24 hours after LPS challenge Modulation by EA-230 of markers of inflammation-induced kidney injury -Urinary excretion of NGAL, KIM-1, cystatin C, microalbumin, creatinine and urea -Plasma concentration of creatinine, urea, and NGAL in plasma Modulation by EA-230 of inflammation-induced changes in renal function -Glomerular filtration rate (GFR) measured by the clearance of iohexol Pharmacokinetics of EA-230 -Blood plasma levels of EA-230 and, if possible, metabolites, AUC, Cmax, terminal t1/2, Cl, V -Urinary excretion profile of EA-230 and, if possible, metabolites. Vital signs -blood pressure -heart rate Adverse events Safety parameters -Local tolerability at the site of i.v. infusion -Safety laboratory parameters (Hb, Ht, Leucocytes, thrombocytes, Leucocyte differential blood count, sodium, potassium, creatinine, urea, alkaline phosphatase, ALT, AST, ?GT, CK, CRP) -Electr | — |
Countries
Netherlands
Contacts
Public ContactLucas van Eijk
Radboud UMC, Research Intensive care
Outcome results
None listed