<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02991508</url>
  </required_header>
  <id_info>
    <org_study_id>Adrecizumab-phase1</org_study_id>
    <secondary_id>2015-005671-24</secondary_id>
    <nct_id>NCT02991508</nct_id>
  </id_info>
  <brief_title>Adrecizumab Phase 1 Trial</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Adrenomed AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is the first clinical trial with ADRECIZUMAB. The purpose of this clinical trial to&#xD;
      identify safety and tolerability of different doses of ADRECIZUMAB in healthy volunteers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Adrenomedullin (ADM) is a natural occurring 52 amino acid peptide which is mainly expressed&#xD;
      in endothelial and smooth muscle cells. ADM plasma levels are increased in patients with&#xD;
      sepsis and related with severity of disease. ADM is a key regulator of vasotonus and of&#xD;
      endothelial integrity in sepsis.&#xD;
&#xD;
      ADRECIZUMAB is an antibody against the N-terminus of ADM which only partially inhibits the&#xD;
      bioactivity of ADM. Several septic animal studies have shown that administration of&#xD;
      ADRECIZUMAB leads to reduced catecholamine demand, improved renal function, improved fluid&#xD;
      balance and improved survival.&#xD;
&#xD;
      The administration of ADRECIZUMAB to rodents and non-human primates (NHP) has been tolerated&#xD;
      very well. Single dose and repeated administrations over 14 days to rats and NHP in the GLP&#xD;
      toxicology and safety study have not shown any clinical side-effects or histopathological&#xD;
      findings.&#xD;
&#xD;
      Based on these data the starting dose for human beings should be 0.5 mg/kg ADRECIZUMAB as&#xD;
      single infusion over 1 hour and should be increased up to 8 mg/kg.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 23, 2016</start_date>
  <completion_date type="Actual">September 22, 2016</completion_date>
  <primary_completion_date type="Actual">September 22, 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and tolerability expressed in total number of treatment related (serious) adverse events</measure>
    <time_frame>3 months follow-up period</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under the curve (AUC) of free Adrecizumab (pharmacokinetics)</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak plasma concentration (Cmax) of free Adrecizumab (pharmacokinetics)</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal t1/2 of free Adrecizumab (pharmacokinetics)</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance of free Adrecizumab (pharmacokinetics)</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of distribution of free Adrecizumab (pharmacokinetics)</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ex vivo cytokine production</measure>
    <time_frame>T=0 hours, T=1 hours, T=8 hours, T=7 days, T=14 days, T=28 days, T=90 days.</time_frame>
    <description>Whole blood will be stimulated with LPS after which cytokine production will be determined by ELISA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood levels of norepinephrin, epinephrine, dopamine and renin</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood levels of endothelin and pro-enkephalin.</measure>
    <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.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma levels of adrenomedullin and MR-proadrenomedullin</measure>
    <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.</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Vehicle (20 mM His/HCl pH 6.0)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adrecizumab 0.5 mg/kg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adrecizumab 2.0 mg/kg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adrecizumab 8.0 mg/kg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Adrecizumab</intervention_name>
    <arm_group_label>Adrecizumab 0.5 mg/kg</arm_group_label>
    <arm_group_label>Adrecizumab 2.0 mg/kg</arm_group_label>
    <arm_group_label>Adrecizumab 8.0 mg/kg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent to participate in this trial prior to any study-mandated&#xD;
             procedure.&#xD;
&#xD;
          2. Male subjects aged 18 to 35 years inclusive.&#xD;
&#xD;
          3. Subjects have to agree to use a reliable way of contraception with their partners from&#xD;
             study entry until 3 months after study drug administration.&#xD;
&#xD;
          4. BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg and a upper&#xD;
             limit of 100 kg.&#xD;
&#xD;
          5. Healthy as determined by medical history, physical examination, vital signs, 12 lead&#xD;
             electrocardiogram, and clinical laboratory parameters.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unwillingness to abstain from any medication, recreational drugs, anti-oxidant or&#xD;
             vitamin supplements during the course of the study and within 7 days prior to the&#xD;
             treatment day.&#xD;
&#xD;
          2. Unwillingness to abstain from smoking or alcohol 1 day prior to the treatment day and&#xD;
             during the first 24 hours of the study.&#xD;
&#xD;
          3. Surgery or trauma with significant blood loss or blood donation within 3 months prior&#xD;
             to the treatment day.&#xD;
&#xD;
          4. History, signs or symptoms of cardiovascular disease, in particular:&#xD;
&#xD;
               -  History of frequent vasovagal collapse or of orthostatic hypotension&#xD;
&#xD;
               -  Resting pulse rate ≤45 or ≥100 beats / min&#xD;
&#xD;
               -  Hypertension (RR systolic &gt;160 or RR diastolic &gt;90)&#xD;
&#xD;
               -  Hypotension (RR systolic &lt;100 or RR diastolic &lt;50)&#xD;
&#xD;
               -  Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular&#xD;
                  block or a complex bundle branch block&#xD;
&#xD;
               -  Any chronic cardiac arrhythmias, except PAC's, PVC's&#xD;
&#xD;
          5. Renal impairment: plasma creatinine &gt;120 µmol/L&#xD;
&#xD;
          6. Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper&#xD;
             limit of normal.&#xD;
&#xD;
          7. History of asthma&#xD;
&#xD;
          8. Atopic constitution&#xD;
&#xD;
          9. CRP above 2x the upper limit of normal or clinically significant acute illness,&#xD;
             including infections, within 2 weeks before administration of the study drug.&#xD;
&#xD;
         10. Treatment with investigational drugs or participation in any other clinical trial&#xD;
             within 30 days prior to study drug administration.&#xD;
&#xD;
         11. Known or suspected of not being able to comply with the trial protocol.&#xD;
&#xD;
         12. Known hypersensitivity to any excipients of the drug formulations used. Inability to&#xD;
             personally provide written informed consent (e.g. for linguistic or mental reasons)&#xD;
             and/or take part in the study.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Pickkers, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboudumc department of Intensive Care</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Radboudumc</name>
      <address>
        <city>Nijmegen</city>
        <state>Gelderland</state>
        <zip>6500HB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>July 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 13, 2016</study_first_posted>
  <last_update_submitted>March 13, 2017</last_update_submitted>
  <last_update_submitted_qc>March 13, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Radboud University Medical Center</investigator_affiliation>
    <investigator_full_name>Peter Pickkers</investigator_full_name>
    <investigator_title>Prof. dr.</investigator_title>
  </responsible_party>
  <keyword>Adrecizumab</keyword>
  <keyword>Phase 1 clinical trial</keyword>
  <keyword>Adrenomedullin</keyword>
  <keyword>Healthy volunteers</keyword>
  <keyword>Monoclonal recombinant antibody</keyword>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02991508
org study id: Adrecizumab-phase1
secondary id: 2015-005671-24
nct id: NCT02991508
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Safety and tolerability expressed in total number of treatment related (serious) adverse events
time frame: 3 months follow-up period
description: 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.
measure: 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.
measure: 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.
measure: 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.
measure: 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.
measure: 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.
measure: 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.
description: Whole blood will be stimulated with LPS after which cytokine production will be determined by ELISA.
measure: 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.
measure: 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.
measure: 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.
arm group label: Placebo
arm group type: Placebo Comparator
description: Vehicle (20 mM His/HCl pH 6.0)
arm group label: Adrecizumab 0.5 mg/kg
arm group type: Active Comparator
description: 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.
arm group label: Adrecizumab 2.0 mg/kg
arm group type: Active Comparator
description: 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.
arm group label: Adrecizumab 8.0 mg/kg
arm group type: Active Comparator
description: 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 type: Drug
intervention name: Placebo
arm group label: Placebo
intervention type: Drug
intervention name: Adrecizumab
arm group label: Adrecizumab 0.5 mg/kg
arm group label: Adrecizumab 2.0 mg/kg
arm group label: Adrecizumab 8.0 mg/kg
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Peter Pickkers, MD, PhD
role: Principal Investigator
affiliation: Radboudumc department of Intensive Care
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Radboud University Medical Center
investigator full name: Peter Pickkers
investigator title: Prof. dr.
sharing ipd: Undecided