Primary Objective:1. To assess the safety and tolerability of single escalating doses of Adrecizumab in healthy male volunteers during experimental endotoxemia.Secondary Objectives:2. To determine the pharmacokinetics of single escalating doses of…
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Brief title
Condition
- Other condition
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Health condition
Experimentele endotoxemie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint is safety, consisting of:
- Adverse Events
- Vital signs during the first 8 hours after Adrecizumab administration and at
follow-up periods (T=24 hours, T=7 days, T=14 days, T=28 days, T=60 days, T=90
days):
o Heart rate
o Blood pressure
o Oxygen saturation
o Temperature
- Local tolerability at site of i.v. infusion.
- Safety laboratory parameters
o Hb, Ht, leukocytes, thrombocytes, leukocyte differential blood count, sodium,
potassium, creatinine, urea, alkaline phosphatase, ALT, AST, GGT, CK, CRP, PT,
APTT.
- 12-lead electrocardiogram (ECG), 2 and 8 hours after Adrecizumab
administration.
Secondary outcome
- Pharmacokinetics of Adrecizumab during experimental endotoxemia (AUC, Cmax,
Terminal T1/2, Cl, V)
- Pharmacodynamics (blood plasma levels of Adrenomedullin) during experimental
endotoxemia.
- Plasma levels of inflammatory mediators on the endotoxemia day (including but
not limited to TNFα, IL-6, IL-8, IL-10, IL-1RA).
- Symptom score.
- Kidney damage markers (including but not limited to pro-enkephalin,
creatinine clearance, NGAL, KIM-1)
Background summary
Adrenomedullin (ADM) is a natural occurring 52 amino acid peptide which is
mainly expressed in endothelial and smooth muscle cells. Plasma levels of ADM
are increased in patients with sepsis, SIRS and after surgery, and are
associated with short-term mortality and vasopressor requirement. Although the
correlation of higher ADM concentrations with impaired outcome might suggest
that ADM is deleterious, this is not necessarily the case, as is shown by
several preclinical studies both in vitro as in vivo.
Adrecizumab is a monoclonal antibody against the N-terminus of ADM which
inhibits the ADM function by approximately 20%. Compared to other antibodies,
Adrecizumab gives the least inhibition of ADM and also improves survival in
septic animals most pronounced. Administration of Adrecizumab in healthy
animals increases the total ADM plasma immediately and dose-dependently and
declines according to the t1/2 of IgG antibodies. Combined with the only
partial inhibition by the antibody, this means that the overall active ADM
level is significantly increased.
Preclinical studies have shown that Adrecizumab administration in a wide
variety of animal models of septic shock led to improved outcome: Improved
hemodynamic parameters, reduced edema, reduced catecholamine requirement,
reduced inflammation and ultimately improved survival.
Preclinical toxicology studies with single and repeated administrations of
Adrecizumab to rodents, dogs and non human primates (NHP) were tolerated very
well and showed no clinical or histopathological findings.
The safety and tolerability of Adrecizumab administration in humans was
recently investigated under *baseline circumstances* (no inflammation or
activation of the ADM system) in the Adrecizumab-phase 1 study (CMO 2016-2283).
In this randomized, double-blinded, placebo-controlled phase 1 study, 24
healthy male volunteers were recruited and randomized to receive either
Adrecizumab or placebo. Four groups (n=6 each) received study drug by i.v.
infusion over a 1 hour period (either Adrecizumab 0.5 mg/kg, 2.0 mg/kg,
8.0mg/kg or placebo). The subjects were admitted to the research unit of the
department of Intensive Care of the Radboudumc for the first 8 hours after
study drug administration for continuous monitoring, electrocardiographic
investigations and blood withdrawal. The 3 month follow-up period of this study
is still ongoing but an interim 14 day safety/tolerability report showed no
indications of any unfavorable effects of Adrecizumab, meaning no SAEs
occurred, there were no signs of local intolerability at the site of i.v.
infusion and there were no serious alterations or abnormalities in vital signs,
ECGs and safety laboratory parameters (see Adrecizumab-phase1 14 day
safety/tolerability report, a separate document for this Ethics Committee
submission).
Prior to investigating Adrecizumab efficacy in septic patients, we wish to
assess the safety, tolerability and pharmacokinetics/-dynamics of Adrecizumab
under inflammatory conditions in healthy volunteers. 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.14
Furthermore, previous data has shown that experimental human endotoxemia
results in increased plasma ADM levels (see Figure 1).
Study proposal: We propose a randomized double-blind, placebo-controlled study
in 24 healthy male volunteers who will be given single, escalating per group
doses of Adrecizumab during experimental human endotoxemia in which ADM plasma
concentrations are elevated. A similar study design and similar doses of
Adrecizumab (0.5, 2.0 and 8.0 mg/kg) will be used as in the previous
Adrecizumab phase I study.
Study objective
Primary Objective:
1. To assess the safety and tolerability of single escalating doses of
Adrecizumab in healthy male volunteers during experimental endotoxemia.
Secondary Objectives:
2. To determine the pharmacokinetics of single escalating doses of Adrecizumab
during experimental endotoxemia.
3. To determine the effects of Adrecizumab on Adrenomedullin concentrations
(pharmacodynamics) during experimental endotoxemia.
4. To determine whether Adrecizumab modulates the absolute plasma cytokine
levels upon experimental endotoxemia.
5. To determine the effects of Adrecizumab on LPS-induced clinical symptoms
(illness score) as well as hemodynamic and temperature changes.
6. To determine the effects of Adrecizumab on LPS-induced markers of kidney
damage.
Study design
A randomized, double-blind, placebo-controlled phase I study in healthy male
volunteers during experimental endotoxemia with single, escalating per group
doses of Adrecizumab administered as i.v. infusion over a 1 hour period. A
continuous LPS (lipopolysaccharide) model is used to induce experimental
endotoxemia; administration of LPS in an initial bolus of 1 ng/kg followed by
continuous infusion at 1 ng/kg/hr for 3 hours. Subject will receive one course
of treatment with study medication (Adrecizumab or placebo), 1 hour after start
of LPS administration.
Intervention
- All subjects will undergo experimental endotoxemia. A continuous LPS
(lipopolysaccharide) model will be used to induce experimental endotoxemia;
administration of LPS in an initial bolus of 1 ng/kg followed by continuous
infusion of 1 ng/kg/hr for 3 hours.
- Single dose of study medication (Adrecizumab 0.5, 2.0, 8.0 mg/kg, or
placebo), 1 hours after start of LPS administration.
Study burden and risks
Total time burden for the study is approx. 12.5 hours: 1 hour for screening, 10
hours for the admission day, and six 15-minutes follow-up visits. Volunteers
will be recruited and are subject to a medical examination (including
interview, medical history, blood withdrawal and physical examination). Blood
withdrawal during the study is restricted to a smaller volume (<500 mL) than is
withdrawn during routine phlebotomy at the blood bank, and is not associated
with relevant risks. Venipunctures and vascular access at the several study
visits carries the risk of hematoma at the puncture sites, which will resolve
spontaneously, should they occur. Blood loss from puncture sites after removal
of cannulas will be stopped by applying pressure. A pressure bandage will be
applied to the site of arterial cannulation. Also, vasovagal reactions can
occur during a puncture procedure, which can be adequately treated.
Adrecizumab was generated by CDR grafting of a murine IgG and has a composition
of 92.5% amino acid sequence of human IgG1. This means that it has a high level
of humanization. Antibodies with a high level of humanization are better
tolerated by humans then antibodies with a low level of humanization. Also, the
administration of Adrecizumab to rodents, non-human primates has been tolerated
very well. Single dose administration up to 800 mg/kg ADRECIZUMAB to rats and
100 mg/kg to NHP have not shown any clinical adverse effects and no
histopathological findings. Even the repeated administrations (day 1 / 4 / 8 /
14) of 400 mg/kg over 14 days to rats and 100 mg/kg over 14 days to NHP within
the regulatory pre-clinical toxicity and safety study have not shown any
clinical or histopathological findings. No effect on blood pressure could be
observed in healthy conscious telemetered beagle dogs when up to 50 mg/ kg
Adrecizumab were administered. In humans, the safety- and tolerability of
Adrecizumab has recently been explored in a phase I study. Single escalating
doses of Adrecizumab (up to 8.0 mg/kg) were administered i.v. over a 1 hour
period and tolerated well. Although the study is still blinded, it is already
known that the administration of a single dose of Adrecizumab to healthy
volunteers was associated with NO moderate or serious adverse events and was
very well tolerated.
The administration of a lipopolysaccharide (LPS) induces flu-like symptoms.
This model of systemic inflammation has been applied for more than 10 years in
our department and thousands of subjects worldwide have participated in
endotoxemia trials. During the endotoxemia experiment day, subjects will be
under constant supervision of a physician with continuous monitoring of blood
pressure and heart rate. The endotoxemia protocol and associated risks are
identical to earlier endotoxemia studies performed in our institute.
The combination of Adrecizumab and LPS has not been investigated before.
Placing the arterial cannula can hurt, this is why it is placed under local
anesthesia.
Time burden: screening (1hr), 1 experimental day, 6 follow-up visists.
Subjects will not benefit directly from participation to the study. The total
risks to the subjects in this study is classified as an *intermediate
risk* (low risk on minor harms). A subject fee is provided.
Neuendorfstr. 15a
Hennigsdorf 16761
DE
Neuendorfstr. 15a
Hennigsdorf 16761
DE
Listed location countries
Age
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.
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
A potential subject who meets any of the following criteria will be excluded from participation:
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003218-29-NL |
| CCMO | NL58811.091.16 |