Adrecizumab-LPS Study

Adrenomed

Status and phase: Completed; Phase 1

Conditions: Healthy Volunteers

Treatments: Drug: Adrecizumab; Drug: Endotoxin; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03083171

Adrecizumab-LPS

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: Male

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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24 participants in 4 patient groups, including a placebo group

Placebo

Placebo Comparator group

Treatment:

Drug: Placebo

Drug: Endotoxin

Adrecizumab 0.5 mg/kg

Active Comparator group

Description:

A single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period.

Treatment:

Drug: Endotoxin

Drug: Adrecizumab

Adrecizumab 2.0 mg/kg

Active Comparator group

Description:

A single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period.

Treatment:

Drug: Endotoxin

Drug: Adrecizumab

Adrecizumab 8.0 mg/kg

Active Comparator group

Description:

A single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period.

Treatment:

Drug: Endotoxin

Drug: Adrecizumab