- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03083171
Adrecizumab-LPS Study
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Gelderland
-
Nijmegen, Gelderland, Netherlands, 6500 HB
- Dept. of Intensive Care Medicine, Research-unit, Radboud university medical center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
|
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.
Other Names:
At T=1 hour, placebo will be administered intravenously over a 1 hour period.
Placebo is indistinguishable from Adrecizumab.
|
Active Comparator: Adrecizumab 0.5 mg/kg
A single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period.
|
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.
Other Names:
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.
|
Active Comparator: Adrecizumab 2.0 mg/kg
A single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period.
|
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.
Other Names:
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.
|
Active Comparator: Adrecizumab 8.0 mg/kg
A single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period.
|
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.
Other Names:
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety and tolerability expressed in total number of treatment related (serious) adverse events.
Time Frame: 3 months follow-up period
|
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)
Time Frame: 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
|
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)
Time Frame: 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
|
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)
Time Frame: 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
|
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)
Time Frame: 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
|
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)
Time Frame: 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
|
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
Time Frame: 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
|
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
Time Frame: 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
|
Blood plasma levels of TNF-alfa, IL-6, IL-8, IL-10, MCP-1, IP-10 and G-CSF
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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
Time Frame: 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
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In urine and plasma, including, but not limited to pro-enkephalin, creatinine clearance, NGAL and KIM-1
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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
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- Adrecizumab-LPS
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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