Adrecizumab-LPS Study

Study Overview
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Brief Summary
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In this randomized, double-blind, placebo-controlled study, either a single dose of Adrecizumab (0.5, 2.0 or 8.0 mg/kg) or placebo will be administrated to 24 healthy male volunteers during experimental endotoxemia.

Detailed Description
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Adrenomedullin (ADM) is a natural occurring 52 amino acid peptide which is mainly expressed in endothelial and smooth muscle cells. ADM plasma levels are increased in patients with sepsis and related with severity of disease. ADM is a key regulator of vasotonus and of endothelial integrity in sepsis. Adrecizumab is an antibody against the N-terminus of ADM which only partially inhibits the bioactivity of ADM. Several septic animal studies have shown that administration of Adrecizumab leads to stabilization of hemodynamics in mice and pigs, improved renal function, reduced catecholamine demand, improved fluid balance and improved survival. The administration of Adrecizumab to rodents, non-human primates and recently humans, has been tolerated very well. The experimental human endotoxemia model, in which healthy male volunteers receive a low dose of lipopolysaccharide (LPS) derived from Escherichia coli, is widely used to study the effects of systemic inflammation in humans in vivo and is considered a safe and highly reproducible method to activate the innate immune system. Furthermore, previous data has shown that experimental human endotoxemia results in increased plasma ADM levels. In this study, the investigators wish to assess the safety, tolerability and pharmacokinetics/-dynamics of Adrecizumab under inflammatory conditions in healthy volunteers.

Official Title
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A Randomized Double-blind Placebo-controlled Phase I Study on the Safety, Tolerability and Pharmacokinetics/-Dynamics of Escalating Single Intravenous Doses of ADRECIZUMAB (HAM8101) in Healthy Male Subjects During Experimental Endotoxemia.

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Endotoxin
* Drug: Placebo
* Drug: Adrecizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to participate in this trial prior to any study-mandated procedure. Male subjects aged 18 to 35 years inclusive. Subjects have to agree to use a reliable way of contraception with their partners from study entry until 3 months after study drug administration. BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg and a upper limit of 100 kg. Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters. Exclusion Criteria: 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. Unwillingness to abstain from smoking, or alcohol, within 1 day prior to the treatment day and 1 day after the treatment day. Previous participation in a trial where LPS was administered. Surgery or trauma with significant blood loss or blood donation within 3 months prior to the treatment day. History, signs or symptoms of cardiovascular disease, in particular: History of frequent vasovagal collapse or of orthostatic hypotension Resting pulse rate ≤45 or ≥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) Renal impairment: plasma creatinine >120 μmol/L Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper limit of normal. History of asthma Atopic constitution CRP above 2x the upper limit of normal, or clinically significant acute illness, including infections, within 2 weeks prior to the treatment day. Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to the treatment day. Known or suspected of not being able to comply with the trial protocol. Known hypersensitivity to any excipients of the drug formulations used. Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Endotoxin<br>* At T=0 1 ng/kg E. Coli type O113 lipopolysaccharide is administrated intravenously as a bolus, followed by 1 ng/kg/hour for 3 hours.<br>* Other names: Lipopolysaccharide;Drug: Placebo<br>* At T=1 hour, placebo will be administered intravenously over a 1 hour period. Placebo is indistinguishable from Adrecizumab.<br>|
| Active Comparator: Adrecizumab 0.5 mg/kg<br>A single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period. | Drug: Endotoxin<br>* At T=0 1 ng/kg E. Coli type O113 lipopolysaccharide is administrated intravenously as a bolus, followed by 1 ng/kg/hour for 3 hours.<br>* Other names: Lipopolysaccharide;Drug: Adrecizumab<br>* At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.<br>|
| Active Comparator: Adrecizumab 2.0 mg/kg<br>A single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period. | Drug: Endotoxin<br>* At T=0 1 ng/kg E. Coli type O113 lipopolysaccharide is administrated intravenously as a bolus, followed by 1 ng/kg/hour for 3 hours.<br>* Other names: Lipopolysaccharide;Drug: Adrecizumab<br>* At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.<br>|
| Active Comparator: Adrecizumab 8.0 mg/kg<br>A single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period. | Drug: Endotoxin<br>* At T=0 1 ng/kg E. Coli type O113 lipopolysaccharide is administrated intravenously as a bolus, followed by 1 ng/kg/hour for 3 hours.<br>* Other names: Lipopolysaccharide;Drug: Adrecizumab<br>* At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability expressed in total number of 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. | 3 months follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of free Adrecizumab (pharmacokinetics) |  | T=0 hours, T=0.25 hours, T=0.5 hours, T=1 hours, T=1.5 hours, T=2 hours, T=3 hours, T=4 hours, T=8 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after Adrecizumab administration | 
| Peak plasma concentration (Cmax) of free Adrecizumab (pharmacokinetics) |  | T=0 hours, T=0.25 hours, T=0.5 hours, T=1 hours, T=1.5 hours, T=2 hours, T=3 hours, T=4 hours, T=8 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after Adrecizumab administration | 
| Terminal t1/2 of free Adrecizumab (pharmacokinetics) |  | T=0 hours, T=0.25 hours, T=0.5 hours, T=1 hours, T=1.5 hours, T=2 hours, T=3 hours, T=4 hours, T=8 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after Adrecizumab administration | 
| Clearance of free Adrecizumab (pharmacokinetics) |  | T=0 hours, T=0.25 hours, T=0.5 hours, T=1 hours, T=1.5 hours, T=2 hours, T=3 hours, T=4 hours, T=8 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after Adrecizumab administration | 
| Volume of distribution of free Adrecizumab (pharmacokinetics) |  | T=0 hours, T=0.25 hours, T=0.5 hours, T=1 hours, T=1.5 hours, T=2 hours, T=3 hours, T=4 hours, T=8 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after Adrecizumab administration | 
| Plasma levels of adrenomedullin and MR-proadrenomedullin |  | T=0 hours, T=1 hours, T=1.25 hours, T=1.5 hours, T=2 hours, T=2.5 hours T=3 hours, T=4 hours, T=5 hours, T=9 hours, T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90 days after LPS administration | 
| Cytokines | Blood plasma levels of TNF-alfa, IL-6, IL-8, IL-10, MCP-1, IP-10 and G-CSF | T=0 hours, T=1 hours, T=1.5 hours, T=2 hours, T=2.5 hours T=3 hours, T=4 hours, T=5 hours, T=6 hours, T=9 hours after LPS administration | 
| Kidney damage markers | In urine and plasma, including, but not limited to pro-enkephalin, creatinine clearance, NGAL and KIM-1 | Baseline, T=0 to T=3 hours, T=3 to T=6 hours, T=6 to T=9 hours, T=9 to T=12 hours, T=12 to T=24 hours after LPS administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adrecizumab, Adrenomedullin, Healthy volunteers, LPS, Monoclonal recombinant antibody