Clinical trial NCT02991508: Adrecizumab Phase 1 Trial
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Adrecizumab
Phase 1 clinical trial
Adrenomedullin
Healthy volunteers
Monoclonal recombinant antibody
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Adrenomed AG
First posted: 2016-12-13
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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, 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.

Primary outcomes:
measure: Safety and tolerability expressed in total number of treatment related (serious) adverse events
timeFrame: 3 months follow-up period
Secondary outcomes:
measure: Area under the curve (AUC) of free Adrecizumab (pharmacokinetics)
timeFrame: 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)
timeFrame: 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)
timeFrame: 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)
timeFrame: 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)
timeFrame: 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
timeFrame: T=0 hours, T=1 hours, T=8 hours, T=7 days, T=14 days, T=28 days, T=90 days.
measure: Blood levels of norepinephrin, epinephrine, dopamine and renin
timeFrame: 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.
timeFrame: 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
timeFrame: 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.
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
Study officials:
affiliation: Radboudumc department of Intensive Care
name: Peter Pickkers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: