Healthy VolunteersPhase 1NCT03083171
Adrecizumab-LPS Study
A Phase 1 study testing Endotoxin and Adrecizumab in people with Healthy Volunteers, run by Adrenomed AG at 1 site in Netherlands.
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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers
- What is being tested?
- Endotoxin and Adrecizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 24 participants
- Where
- 1 siteNetherlands
- Study dates
- 4 Jan 2017to 24 May 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Written informed consent to participate in this trial prior to any study-mandated procedure.
- Male subjects aged 18 to 35 years inclusive.
- Subjects have to agree to use a reliable way of contraception with their partners from study entry until 3 months after study drug administration.
- BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg and a upper limit of 100 kg.
- Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters.
Who cannot join
- 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.
- Unwillingness to abstain from smoking, or alcohol, within 1 day prior to the treatment day and 1 day after the treatment day.
- Previous participation in a trial where LPS was administered.
- Surgery or trauma with significant blood loss or blood donation within 3 months prior to the treatment day.
- History, signs or symptoms of cardiovascular disease, in particular:
- History of frequent vasovagal collapse or of orthostatic hypotension
Show all 20Show fewer
- 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)
- Renal impairment: plasma creatinine >120 μmol/L
- Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper limit of normal.
- History of asthma
- Atopic constitution
- CRP above 2x the upper limit of normal, or clinically significant acute illness, including infections, within 2 weeks prior to the treatment day.
- Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to the treatment day.
- Known or suspected of not being able to comply with the trial protocol.
- 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.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Dept. of Intensive Care Medicine, Research-unit, Radboud university medical center
Nijmegen, Gelderland, 6500 HB
About this study
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.
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.
Read the 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 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.
- Conditions
- Healthy Volunteers
- Being tested
- Endotoxin, Placebo, Adrecizumab
- Keywords
- Adrecizumab, Adrenomedullin, Healthy volunteers, LPS, Monoclonal recombinant antibody
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EndotoxinDrug
Also called LPS, Lipopolysaccharide
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.
PlaceboDrug
At T=1 hour, placebo will be administered intravenously over a 1 hour period. Placebo is indistinguishable from Adrecizumab.
AdrecizumabDrug
At T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Not described Receives: Drug: Endotoxin; Drug: Placebo |
| Adrecizumab 0.5 mg/kg | Active comparator | A single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period. Receives: Drug: Endotoxin; Drug: Adrecizumab |
| Adrecizumab 2.0 mg/kg | Active comparator | A single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period. Receives: Drug: Endotoxin; Drug: Adrecizumab |
| Adrecizumab 8.0 mg/kg | Active comparator | A single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period. Receives: Drug: Endotoxin; Drug: Adrecizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 months follow-up period
Secondary outcomes (8)
Area under the curve (AUC) of free Adrecizumab (pharmacokinetics)
Measured: 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
Peak plasma concentration (Cmax) of free Adrecizumab (pharmacokinetics)
Measured: 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
Terminal t1/2 of free Adrecizumab (pharmacokinetics)
Measured: 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
Clearance of free Adrecizumab (pharmacokinetics)
Measured: 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
Volume of distribution of free Adrecizumab (pharmacokinetics)
Measured: 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
Plasma levels of adrenomedullin and MR-proadrenomedullin
Measured: 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
Cytokines
Blood plasma levels of TNF-alfa, IL-6, IL-8, IL-10, MCP-1, IP-10 and G-CSF
Measured: 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
Kidney damage markers
In urine and plasma, including, but not limited to pro-enkephalin, creatinine clearance, NGAL and KIM-1
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2017
- Study start4 Jan 2017
- Primary completion24 May 2017
- Study completion24 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adrenomed AG
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Radboud University Medical Center
- Responsible party
- Sponsor
- Investigators
- Peter Pickkers, MD, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03083171
- Sponsor's protocol ID
- Adrecizumab-LPS
- Status last verified
- Mar 2017
- First submitted
- 13 Mar 2017
- Last updated
- 1 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT03083171
- Acronym / sponsor ID
- Adrecizumab-LPS
- Conditions
- Healthy Volunteers
- Keywords
- Adrecizumab, Adrenomedullin, Healthy volunteers, LPS, Monoclonal recombinant antibody
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Adrenomed AGIndustry (pharma, biotech, devices)
- Collaborators
- Radboud University Medical Center
- Study start
- 4 Jan 2017 (actual)
- Primary completion
- 24 May 2017 (actual)
- Study completion
- 24 May 2017 (actual)
- First posted
- 17 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Endotoxin, Drug: Placebo |
| Adrecizumab 0.5 mg/kg | Active comparator | Drug: Endotoxin, Drug: AdrecizumabA single intravenous dose of 0.5 mg/kg Adrecizumab given over a 1 hour period. |
| Adrecizumab 2.0 mg/kg | Active comparator | Drug: Endotoxin, Drug: AdrecizumabA single intravenous dose of 2.0 mg/kg Adrecizumab given over a 1 hour period. |
| Adrecizumab 8.0 mg/kg | Active comparator | Drug: Endotoxin, Drug: AdrecizumabA single intravenous dose of 8.0 mg/kg Adrecizumab given over a 1 hour period. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Written informed consent to participate in this trial prior to any study-mandated procedure.
- Male subjects aged 18 to 35 years inclusive.
- Subjects have to agree to use a reliable way of contraception with their partners from study entry until 3 months after study drug administration.
- BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg and a upper limit of 100 kg.
- Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters.
Key exclusion criteria (20 listed)
- 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.
- Unwillingness to abstain from smoking, or alcohol, within 1 day prior to the treatment day and 1 day after the treatment day.
- Previous participation in a trial where LPS was administered.
- Surgery or trauma with significant blood loss or blood donation within 3 months prior to the treatment day.
- History, signs or symptoms of cardiovascular disease, in particular:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EndotoxinAlso: LPS, LipopolysaccharideAt 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. | Drug | Adrecizumab 0.5 mg/kg, Adrecizumab 2.0 mg/kg, Adrecizumab 8.0 mg/kg, Placebo |
| PlaceboAt T=1 hour, placebo will be administered intravenously over a 1 hour period. Placebo is indistinguishable from Adrecizumab. | Drug | Placebo |
| AdrecizumabAt T=1 hour, Adrecizumab will be administered intravenously over a 1 hour period. | Drug | Adrecizumab 0.5 mg/kg, Adrecizumab 2.0 mg/kg, Adrecizumab 8.0 mg/kg |
Primary outcome
Safety and tolerability expressed in total number of treatment related (serious) adverse events.
Time frame: 3 months follow-up period
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.
8 secondary outcomes
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 after Adrecizumab administration
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 after Adrecizumab administration
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 after Adrecizumab administration
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 after Adrecizumab administration
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 after Adrecizumab administration
Plasma levels of adrenomedullin and MR-proadrenomedullin
Time frame: 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
Cytokines
Time frame: 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
Kidney damage markers
Time frame: 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2021.
- Individual participant dataSharing planned: Undecided
Related trials for Healthy Volunteers
Active, not recruitingPhase 1/2
Novel Biomarkers of Non-IgE Immediate Hypersensitivity Drug Reactions
Healthy Volunteer, Hypersensitivity Reactions
Active, not recruitingPhase 1/2
Study Evaluating ABCL635 for Vasomotor Symptoms of Menopause
Vasomotor Symptoms Associated With Menopause, Healthy Volunteers
Enrolling by invitationObservational study
Establishing Fibroblast-Derived Cell Lines From Skin Biopsies of Patients With Immunodeficiency or Immunodysregulation Disorders
Primary Immunodeficiency, DOCK8
Not yet recruiting
Positron Emission Tomography and Organ-Specific Changes in Participants Co-Enrolled in NIH Studies of Plasmodium Vivax Controlled Human Malaria Infection
Healthy Volunteer, Malaria
Enrolling by invitation
Development and Evaluation of Magnetic Resonance Imaging Acquisition and Analysis Methods
Healthy
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Pickkers, MD, PhD principal investigator
Radboud University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Endotoxin and Adrecizumab in people with Healthy Volunteers, run by Adrenomed AG at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and tolerability expressed in total number of treatment related (serious) adverse events. (time frame: 3 months follow-up period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2021.