Experimentele endotoxemie Sepsis
Conditions
Interventions
- All subjects will undergo experimental endotoxemia. A continuous LPS
(lipopolysaccharide) model will be used to induce experimental endotoxemia
administration of LPS in an initial bolus of 1 ng/kg followed by continuous
infusion of 1 ng/kg/hr for 3 hours.
- Single dose of study medication (Adrecizumab 0.5, 2.0, 8.0 mg/kg, or
placebo), 1 h
Sponsors
Adrenomed AG
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Written informed consent to participate in this trial prior to any study-mandated procedure. 2. Male subjects aged 18 to 35 years. 3. Subjects have to agree to use a reliable way of contraception with their partners 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 and a upper limit of 100 kg. 5. Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters.
Exclusion criteria
Exclusion criteria: A potential subject who meets any of the following criteria will be excluded from participation: 1. Unwillingness to abstain from any medication, including recreational drugs or vitamin supplements during the course of the study and within 7 days prior to the treatment day. 2. Unwillingness to abstain from smoking, or alcohol, within 1 day prior to the treatment day and 1 day after the treatment day. 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 the treatment day. 5. History, signs or symptoms of cardiovascular disease, in particular: • History of frequent vasovagal collapse or of orthostatic hypotension • Resting pulse rate =100 beats /min • Hypertension (RR systolic >160 or RR diastolic >90 mmHg) • Hypotension (RR systolic <100 or RR diastolic <50 mmHg) • Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block • Any chronic cardiac arrhythmias (except PAC*s, PVC*s) 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 prior to the treatment day. 11. Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to the treatment day. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary study endpoint is safety, consisting of: - Adverse Events - Vital signs during the first 8 hours after Adrecizumab administration and at follow-up periods (T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days): o Heart rate o Blood pressure o Oxygen saturation o Temperature - Local tolerability at site of i.v. infusion. - Safety laboratory parameters o Hb, Ht, leukocytes, thrombocytes, leukocyte differential blood count, sodium, potassium, creatinine, urea, alkaline phosphatase, ALT, AST, GGT, CK, CRP, PT, APTT. - 12-lead electrocardiogram (ECG), 2 and 8 hours after Adrecizumab administration. | — |
Secondary
| Measure | Time frame |
|---|---|
| - Pharmacokinetics of Adrecizumab during experimental endotoxemia (AUC, Cmax, Terminal T1/2, Cl, V) - Pharmacodynamics (blood plasma levels of Adrenomedullin) during experimental endotoxemia. - Plasma levels of inflammatory mediators on the endotoxemia day (including but not limited to TNFa, IL-6, IL-8, IL-10, IL-1RA). - Symptom score. - Kidney damage markers (including but not limited to pro-enkephalin, creatinine clearance, NGAL, KIM-1) | — |
Countries
The Netherlands
Outcome results
None listed