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Adrecizumab-LPS Study

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ClinicalTrials.gov Identifier: NCT03083171
Recruitment Status : Completed
First Posted : March 17, 2017
Last Update Posted : February 1, 2021
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Adrenomed AG

Tracking Information
First Submitted Date  ICMJE March 13, 2017
First Posted Date  ICMJE March 17, 2017
Last Update Posted Date February 1, 2021
Actual Study Start Date  ICMJE January 4, 2017
Actual Primary Completion Date May 24, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2017)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2017)
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adrecizumab-LPS Study
Official Title  ICMJE 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.
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE
  • 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.
  • Drug: Adrecizumab
    At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Interventions:
    • Drug: Endotoxin
    • Drug: Placebo
  • Active Comparator: Adrecizumab 0.5 mg/kg
    A single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period.
    Interventions:
    • Drug: Endotoxin
    • Drug: Adrecizumab
  • Active Comparator: Adrecizumab 2.0 mg/kg
    A single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period.
    Interventions:
    • Drug: Endotoxin
    • Drug: Adrecizumab
  • Active Comparator: Adrecizumab 8.0 mg/kg
    A single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period.
    Interventions:
    • Drug: Endotoxin
    • Drug: Adrecizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 13, 2017)
24
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 24, 2017
Actual Primary Completion Date May 24, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03083171
Other Study ID Numbers  ICMJE Adrecizumab-LPS
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Adrenomed AG
Study Sponsor  ICMJE Adrenomed AG
Collaborators  ICMJE Radboud University
Investigators  ICMJE
Principal Investigator: Peter Pickkers, MD, PhD Radboud University
PRS Account Adrenomed AG
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP