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Adrecizumab-LPS Study

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ClinicalTrials.gov Identifier: NCT03083171
Recruitment Status : Active, not recruiting
First Posted : March 17, 2017
Last Update Posted : March 21, 2017
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Adrenomed AG

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Endotoxin Drug: Placebo Drug: Adrecizumab Phase 1

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 : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : January 4, 2017
Estimated Primary Completion Date : June 25, 2017
Estimated Study Completion Date : June 25, 2017

Arm Intervention/treatment
Placebo Comparator: Placebo Drug: Endotoxin
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:
  • LPS
  • Lipopolysaccharide

Drug: Placebo
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.
Drug: Endotoxin
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:
  • LPS
  • Lipopolysaccharide

Drug: Adrecizumab
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.
Drug: Endotoxin
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:
  • LPS
  • Lipopolysaccharide

Drug: Adrecizumab
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.
Drug: Endotoxin
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:
  • LPS
  • Lipopolysaccharide

Drug: Adrecizumab
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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

  8. 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 ]
    In urine and plasma, including, but not limited to pro-enkephalin, creatinine clearance, NGAL and KIM-1



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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 inclusive.
  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:

  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 ≤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)
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03083171


Locations
Netherlands
Dept. of Intensive Care Medicine, Research-unit, Radboud university medical center
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Adrenomed AG
Radboud University
Investigators
Principal Investigator: Peter Pickkers, MD, PhD Radboud University

Responsible Party: Adrenomed AG
ClinicalTrials.gov Identifier: NCT03083171     History of Changes
Other Study ID Numbers: Adrecizumab-LPS
First Posted: March 17, 2017    Key Record Dates
Last Update Posted: March 21, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adrenomed AG:
Adrecizumab
Adrenomedullin
Healthy volunteers
LPS
Monoclonal recombinant antibody