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Adrecizumab Phase 1 Trial

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02991508
Recruitment Status : Completed
First Posted : December 13, 2016
Last Update Posted : March 15, 2017
Sponsor:
Collaborator:
Adrenomed AG
Information provided by (Responsible Party):
Peter Pickkers, Radboud University

Tracking Information
First Submitted Date  ICMJE July 1, 2016
First Posted Date  ICMJE December 13, 2016
Last Update Posted Date March 15, 2017
Actual Study Start Date  ICMJE May 23, 2016
Actual Primary Completion Date September 22, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2016)
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: December 9, 2016)
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • Ex vivo cytokine production [ Time Frame: T=0 hours, T=1 hours, T=8 hours, T=7 days, T=14 days, T=28 days, T=90 days. ]
    Whole blood will be stimulated with LPS after which cytokine production will be determined by ELISA.
  • Blood levels of norepinephrin, epinephrine, dopamine and renin [ 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. ]
  • Blood levels of endothelin and pro-enkephalin. [ Time Frame: T=0, T=0.25, T=0.5, T=1, T=1,5, T=2, T=3, T=4, T=8, T=24 hours. T=7, T=14, T=28, T=60, T=90 days. ]
  • Plasma levels of adrenomedullin and MR-proadrenomedullin [ Time Frame: T=0, T=0.25, T=0.5, T=1, T=1,5, T=2, T=3, T=4, T=8, T=24 hours. T=7, T=14, T=28, T=60, T=90 days. ]
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 Phase 1 Trial
Official Title  ICMJE A Randomized Double-blind Placebo-controlled Phase 1 Study on the Safety, Tolerability and Pharmacokinetics/-Dynamics of Escalating Single Intravenous Doses of ADRECIZUMAB (HAM8101) in Healthy Male Subjects
Brief Summary This is the first clinical trial with ADRECIZUMAB. The purpose of this clinical trial to identify safety and tolerability of different doses of ADRECIZUMAB in healthy volunteers.
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 reduced catecholamine demand, improved renal function, improved fluid balance and improved survival.

The administration of ADRECIZUMAB to rodents and non-human primates (NHP) has been tolerated very well. Single dose and repeated administrations over 14 days to rats and NHP in the GLP toxicology and safety study have not shown any clinical side-effects or histopathological findings.

Based on these data the starting dose for human beings should be 0.5 mg/kg ADRECIZUMAB as single infusion over 1 hour and should be increased up to 8 mg/kg.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE
  • Drug: Placebo
  • Drug: Adrecizumab
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Vehicle (20 mM His/HCl pH 6.0)
    Intervention: Drug: Placebo
  • Active Comparator: Adrecizumab 0.5 mg/kg
    To assess the safety, tolerability and pharmacokinetics/-dynamics of single escalating doses of ADRECIZUMAB (0.5 mg/kg, 2,0 mg/kg and 8,0 mg/kg administered as single infusion over 1 hour) in healthy male subjects.
    Intervention: Drug: Adrecizumab
  • Active Comparator: Adrecizumab 2.0 mg/kg
    To assess the safety, tolerability and pharmacokinetics/-dynamics of single escalating doses of ADRECIZUMAB (0.5 mg/kg, 2,0 mg/kg and 8,0 mg/kg administered as single infusion over 1 hour) in healthy male subjects.
    Intervention: Drug: Adrecizumab
  • Active Comparator: Adrecizumab 8.0 mg/kg
    To assess the safety, tolerability and pharmacokinetics/-dynamics of single escalating doses of ADRECIZUMAB (0.5 mg/kg, 2,0 mg/kg and 8,0 mg/kg administered as single infusion over 1 hour) in healthy male subjects.
    Intervention: 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: December 9, 2016)
24
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE September 22, 2016
Actual Primary Completion Date September 22, 2016   (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, recreational drugs, anti-oxidant 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 1 day prior to the treatment day and during the first 24 hours of the study.
  3. Surgery or trauma with significant blood loss or blood donation within 3 months prior to the treatment day.
  4. 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)
    • Hypotension (RR systolic <100 or RR diastolic <50)
    • 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
  5. Renal impairment: plasma creatinine >120 µmol/L
  6. Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper limit of normal.
  7. History of asthma
  8. Atopic constitution
  9. CRP above 2x the upper limit of normal or clinically significant acute illness, including infections, within 2 weeks before administration of the study drug.
  10. Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to study drug administration.
  11. Known or suspected of not being able to comply with the trial protocol.
  12. 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.
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 NCT02991508
Other Study ID Numbers  ICMJE Adrecizumab-phase1
2015-005671-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Peter Pickkers, Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Adrenomed AG
Investigators  ICMJE
Principal Investigator: Peter Pickkers, MD, PhD Radboudumc department of Intensive Care
PRS Account Radboud University
Verification Date March 2017

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