Adrecizumab-LPS Study

Healthy Volunteers Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03083171
• Other study ID #: Adrecizumab-LPS
• Status: Completed
• Phase: Phase 1
• Start date: January 4, 2017
• Est. completion date: May 24, 2017

Study information

• Verified date: March 2017
• Source: Adrenomed AG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: May 24, 2017
• Est. primary completion date: May 24, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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 ?-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.

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

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.
• Placebo
At T=1 hour, placebo will be administered intravenously over a 1 hour period. Placebo is indistinguishable from Adrecizumab.
• Adrecizumab
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.

Locations

Country	Name	City	State
Netherlands	Dept. of Intensive Care Medicine, Research-unit, Radboud university medical center	Nijmegen	Gelderland

Sponsors (2)

Lead Sponsor	Collaborator
Adrenomed AG	Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability expressed in total number of treatment related (serious) adverse events.	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.	3 months follow-up period
Secondary	Area under the curve (AUC) of free Adrecizumab (pharmacokinetics)		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
Secondary	Peak plasma concentration (Cmax) of free Adrecizumab (pharmacokinetics)		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
Secondary	Terminal t1/2 of free Adrecizumab (pharmacokinetics)		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
Secondary	Clearance of free Adrecizumab (pharmacokinetics)		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
Secondary	Volume of distribution of free Adrecizumab (pharmacokinetics)		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
Secondary	Plasma levels of adrenomedullin and MR-proadrenomedullin		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
Secondary	Cytokines	Blood plasma levels of TNF-alfa, IL-6, IL-8, IL-10, MCP-1, IP-10 and G-CSF	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
Secondary	Kidney damage markers	In urine and plasma, including, but not limited to pro-enkephalin, creatinine clearance, NGAL and KIM-1	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