EndotoxemiaPhase 4NCT02675868
Effects of Vasopressors on Immune Response
A Phase 4 study testing Norepinephrine, Phenylephrine and Vasopressins in people with Endotoxemia, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. Catecholamines exert profound immunomodulatory effects. 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
- Endotoxemia
- What is being tested?
- Norepinephrine, Phenylephrine and Vasopressins
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteNetherlands
- Study dates
- Jan 2016to Oct 2016
- Phase
- Phase 4
- 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
- Age ≥18 and ≤35 yrs
- Male
- Healthy
Who cannot join
- Use of any medication
- Smoking
- Previous spontaneous vagal collapse
- History of atrial or ventricular arrhythmia
- (Family) history of myocardial infarction or stroke under the age of 65 years
- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
Show all 19Show fewer
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
- Renal impairment (defined as plasma creatinin >120 μmol/l)
- Liver enzyme abnormalities
- Medical history of any disease associated with immune deficiency
- CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration
- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
- Use of recreational drugs within 7 days prior to experiment day
- Recent hospital admission or surgery with general anaesthesia (<3 months)
- Known anaphylaxis or hypersensitivity to the study drugs or their excipients
- Recent anaesthesia with halogenated agents
- Known cardiovascular disease (coronary artery disease)
- Known chronic nephritis
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Effects of Different Vasopressors on the Innate Immune Response During Experimental Human Endotoxemia, a Pilot Proof-of-principle Study
Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. Catecholamines exert profound immunomodulatory effects. Noradrenaline in vitro inhibits LPS-induced pro-inflammatory cytokine production, however, the actions on immune function in vivo have not been assessed. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Read the detailed description
Rationale:
Septic shock is a major medical challenge associated with a high mortality rate and increasing incidence. It has become clear that the majority of septic patients do not succumb to an initial pro-inflammatory "hit", but at a later time-point in a pronounced immunosuppressive state, so called 'immunoparalysis'. Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. However, catecholamines exert profound immunomodulatory effects which have mainly been studied for adrenaline. It profoundly inhibits LPS-induced production of TNF-α, and enhances production of anti-inflammatory IL-10 in vitro, as well as in animal and human models of inflammation. Although in vitro studies have shown that noradrenaline inhibits LPS-induced pro-inflammatory cytokine production as potently as adrenaline, the effects of noradrenaline on the immune system in vivo have not yet been studied. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Objective: To investigate whether noradrenaline exerts immunomodulatory effects in humans in vivo and to compare noradrenaline to other vasopressors (phenylephrine and vasopressin).
Study design: A randomized double-blind placebo-controlled study in healthy human volunteers during experimental endotoxemia.
Study population: 40 healthy male volunteers, aged 18-35 yrs.
Intervention:
- The noradrenaline group (n= 10): subjects that will receive intravenous infusion of noradrenaline 0.05 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
- The phenylephrine group (n=10): subjects that will receive intravenous infusion of phenylephrine 0.5 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS. .
- The vasopressin group (n = 10): subjects that will receive intravenous infusion of vasopressin 0.04 IU/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
- The placebo group (n = 10): subjects that will receive intravenous infusion of NaCl 0.9% for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
Main parameters/endpoints:
The difference of LPS-induced TNF-α plasma concentrations following endotoxemia between the noradrenaline and the placebo groups
- Conditions
- Endotoxemia
- Being tested
- Norepinephrine, Phenylephrine, Vasopressins, Placebo
- Keywords
- noradrenaline, vasopressin, phenylephrine, endotoxemia, Lipopolysaccharide, vasopressor
- Medical subject headings
- Endotoxemia, Diabetes Insipidus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NorepinephrineDrug
Also called Noradrenaline
Noradrenaline is an endogenous catecholamine with sympathomimetic effects. It has mainly α-adrenergic receptor selectivity but also β-effects in higher concentrations. It will be administered at 0.05 μg/kg/min, a clinical relevant dose on the low end of the scale.
PhenylephrineDrug
Phenylephrine is a selective α-adrenergic receptor agonist. It will be administered at 0.5 μg/kg/min, based on its relative vasopressor potency in comparison with noradrenaline.
VasopressinsDrug
Also called Argipressin
Vasopressin is 8-arginine-vasopressin, a synthetic analogue of endogenous nonapeptide hormone. It exerts its action via V1 receptors (ubiquitous vasoconstriction) and V2 receptors (renal water resorption). It will be administered at 0.04 IU/min, a clinically relevant dose.
PlaceboDrug
Also called NaCl 0,9%
NaCl 0.9% infusion
| Study group | Role | What they receive |
|---|---|---|
| Norepinephrine | Experimental | The noradrenaline group: a group of 10 subjects that will receive noradrenaline 0.05 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration. Receives: Drug: Norepinephrine |
| Vasopressins | Active comparator | The vasopressin group: a group of 10 subjects that will receive vasopressin 0.04 IU/min infusion for 5 hours, starting 60 minutes before endotoxin administration. Receives: Drug: Vasopressins |
| Phenylephrine | Active comparator | The phenylephrine group: a group of 10 subjects that will receive phenylephrine 0.5 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration. Receives: Drug: Phenylephrine |
| Placebo | Placebo comparator | The placebo group: a group of 10 subjects that will receive NaCl 0.9% infusion for 5 hours, starting 60 minutes before endotoxin administration. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
comparison of subjects treated with noradrenaline compared to subjects treated with placebo
Measured: 1 day
Secondary outcomes (24)
concentration plasma IL-6 (pg/ml)
Measured with Luminex assay
Measured: 1 day
concentration plasma IL-8 (pg/ml)
Measured with Luminex assay
Measured: 1 day
Leucocyte counts and differentiation
Measured with Luminex assay
Measured: 1 day
-The phenotype of circulating leukocytes
Measured with Luminex assay
Measured: 1 day
concentration plasma IL-10 (pg/ml)
Measured with Luminex assay
Measured: 1 day
concentration plasma IL-1RA (pg/ml)
Measured with Luminex assay
Measured: 1 day
concentration plasma IL-1beta (pg/ml)
Measured with Luminex assay
Measured: 1 day
symptoms during endotoxin day
6 point likert scale
Measured: 1 day
blood pressure
mmHg
Measured: 1 day
temperature
tympanic temperature
Measured: 1 day
cytokine production after ex vivo stimulation of leukocytes
Measured: 1 day
phenotype of circulating leucocytes
Measured: 1 day
Heart rate variability
Comparison between Holter and 2 phone applications
Measured: 1 day
Breathing frequency (breaths/ min)
comparison between pulseoximeter and a health Patch device and VISI mobile device
Measured: 1 day
Stress Levels (in percentage based on heart rate and heart rate variability)
Comparison between health patch device, and 2 phone applications and a subjective stress questionaire
Measured: 1 day
Mean flow velocity of the median cerebral artery
As measured via Transcranial Doppler Ultrasound
Measured: 1 day
cerebral microcirculatory flow
As measured via Near Infrared Spectroscopy
Measured: 1 day
Tranfer function analysis
As derived from transcranial Doppler Ultrasound
Measured: 1 day
Cerebral vascular resistance
As derived from transcranial Doppler Ultrasound
Measured: 1 day
Cerebral Critical closing pressure
As derived from transcranial Doppler Ultrasound
Measured: 1 day
Microvascular flow (microvascular flow index)
Measured via Sidestream Darkfield Imaging
Measured: 1 day
Pulsatility index of the median cerebral artery
As measured via Transcranial Doppler Ultrasound
Measured: 1 day
Mean flow index
As measured via Transcranial Doppler Ultrasound
Measured: via 1 day
cerebral oxygenation
As measured via Near infrared spectroscopy
Measured: 1 day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2016 (estimated)
- Study startJan 2016
- Primary completionJul 2016
- Study completionOct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for EndotoxemiaStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- 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 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Roeland Stolk, MD, Principal investigator, Radboudumc, Intensive Care
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02675868
- Sponsor's protocol ID
- NL53411.091.015
- Status last verified
- Apr 2016
- First submitted
- 25 Jan 2016
- Last updated
- 13 Oct 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Stolk RF, Reinema F, van der Pasch E, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth M, van der Hoeven HG, van Leeuwen HJ, Pickkers P, Kox M. Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study. Br J Anaesth. 2021 Mar;126(3):652-664. doi: 10.1016/j.bja.2020.11.040. Epub 2021 Jan 20.
PubMed 33483132van Loon LM, Stolk RF, van der Hoeven JG, Veltink PH, Pickkers P, Lemson J, Kox M. Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo. Shock. 2020 Feb;53(2):171-174. doi: 10.1097/SHK.0000000000001357.
PubMed 31008870
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Different Vasopressors on the Innate Immune Response During Experimental Human Endotoxemia, a Pilot Proof-of-principle Study
- ClinicalTrials.gov ID
- NCT02675868
- Acronym / sponsor ID
- NL53411.091.015
- Conditions
- Endotoxemia
- Keywords
- noradrenaline, vasopressin, phenylephrine, endotoxemia, Lipopolysaccharide, vasopressor
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Jan 2016
- Primary completion
- Jul 2016 (actual)
- Study completion
- Oct 2016 (actual)
- First posted
- 5 Feb 2016 (estimated)
- 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.
Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. Catecholamines exert profound immunomodulatory effects. Noradrenaline in vitro inhibits LPS-induced pro-inflammatory cytokine production, however, the actions on immune function in vivo have not been assessed. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Detailed description
Rationale:
Septic shock is a major medical challenge associated with a high mortality rate and increasing incidence. It has become clear that the majority of septic patients do not succumb to an initial pro-inflammatory "hit", but at a later time-point in a pronounced immunosuppressive state, so called 'immunoparalysis'. Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. However, catecholamines exert profound immunomodulatory effects which have mainly been studied for adrenaline. It profoundly inhibits LPS-induced production of TNF-α, and enhances production of anti-inflammatory IL-10 in vitro, as well as in animal and human models of inflammation. Although in vitro studies have shown that noradrenaline inhibits LPS-induced pro-inflammatory cytokine production as potently as adrenaline, the effects of noradrenaline on the immune system in vivo have not yet been studied. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Objective: To investigate whether noradrenaline exerts immunomodulatory effects in humans in vivo and to compare noradrenaline to other vasopressors (phenylephrine and vasopressin).
Study design: A randomized double-blind placebo-controlled study in healthy human volunteers during experimental endotoxemia.
Study population: 40 healthy male volunteers, aged 18-35 yrs.
Intervention:
- The noradrenaline group (n= 10): subjects that will receive intravenous infusion of noradrenaline 0.05 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
- The phenylephrine group (n=10): subjects that will receive intravenous infusion of phenylephrine 0.5 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS. .
- The vasopressin group (n = 10): subjects that will receive intravenous infusion of vasopressin 0.04 IU/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
- The placebo group (n = 10): subjects that will receive intravenous infusion of NaCl 0.9% for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
Main parameters/endpoints:
The difference of LPS-induced TNF-α plasma concentrations following endotoxemia between the noradrenaline and the placebo groups
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Norepinephrine | Experimental | Drug: NorepinephrineThe noradrenaline group: a group of 10 subjects that will receive noradrenaline 0.05 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration. |
| Vasopressins | Active comparator | Drug: VasopressinsThe vasopressin group: a group of 10 subjects that will receive vasopressin 0.04 IU/min infusion for 5 hours, starting 60 minutes before endotoxin administration. |
| Phenylephrine | Active comparator | Drug: PhenylephrineThe phenylephrine group: a group of 10 subjects that will receive phenylephrine 0.5 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration. |
| Placebo | Placebo comparator | Drug: PlaceboThe placebo group: a group of 10 subjects that will receive NaCl 0.9% infusion for 5 hours, starting 60 minutes before endotoxin administration. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy
Key exclusion criteria (19 listed)
- Use of any medication
- Smoking
- Previous spontaneous vagal collapse
- History of atrial or ventricular arrhythmia
- (Family) history of myocardial infarction or stroke under the age of 65 years
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 |
|---|---|---|
| NorepinephrineAlso: NoradrenalineNoradrenaline is an endogenous catecholamine with sympathomimetic effects. It has mainly α-adrenergic receptor selectivity but also β-effects in higher concentrations. It will be administered at 0.05 μg/kg/min, a clinical relevant dose on the low end of the scale. | Drug | Norepinephrine |
| PhenylephrinePhenylephrine is a selective α-adrenergic receptor agonist. It will be administered at 0.5 μg/kg/min, based on its relative vasopressor potency in comparison with noradrenaline. | Drug | Phenylephrine |
| VasopressinsAlso: ArgipressinVasopressin is 8-arginine-vasopressin, a synthetic analogue of endogenous nonapeptide hormone. It exerts its action via V1 receptors (ubiquitous vasoconstriction) and V2 receptors (renal water resorption). It will be administered at 0.04 IU/min, a clinically relevant dose. | Drug | Vasopressins |
| PlaceboAlso: NaCl 0,9%NaCl 0.9% infusion | Drug | Placebo |
Primary outcome
concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
Time frame: 1 day
comparison of subjects treated with noradrenaline compared to subjects treated with placebo
24 secondary outcomes
concentration plasma IL-6 (pg/ml)
Time frame: 1 day
concentration plasma IL-8 (pg/ml)
Time frame: 1 day
Leucocyte counts and differentiation
Time frame: 1 day
-The phenotype of circulating leukocytes
Time frame: 1 day
concentration plasma IL-10 (pg/ml)
Time frame: 1 day
concentration plasma IL-1RA (pg/ml)
Time frame: 1 day
concentration plasma IL-1beta (pg/ml)
Time frame: 1 day
symptoms during endotoxin day
Time frame: 1 day
blood pressure
Time frame: 1 day
temperature
Time frame: 1 day
cytokine production after ex vivo stimulation of leukocytes
Time frame: 1 day
phenotype of circulating leucocytes
Time frame: 1 day
Heart rate variability
Time frame: 1 day
Breathing frequency (breaths/ min)
Time frame: 1 day
Stress Levels (in percentage based on heart rate and heart rate variability)
Time frame: 1 day
Mean flow velocity of the median cerebral artery
Time frame: 1 day
cerebral microcirculatory flow
Time frame: 1 day
Tranfer function analysis
Time frame: 1 day
Cerebral vascular resistance
Time frame: 1 day
Cerebral Critical closing pressure
Time frame: 1 day
Microvascular flow (microvascular flow index)
Time frame: 1 day
Pulsatility index of the median cerebral artery
Time frame: 1 day
Mean flow index
Time frame: via 1 day
cerebral oxygenation
Time frame: 1 day
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 13 Oct 2016.
- Derived from this study: PubMed 33483132Stolk RF, Reinema F, van der Pasch E, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth M, van der Hoeven HG, van Leeuwen HJ, Pickkers P, Kox M. Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study. Br J Anaesth. 2021 Mar;126(3):652-664. doi: 10.1016/j.bja.2020.11.040. Epub 2021 Jan 20.
- Derived from this study: PubMed 31008870van Loon LM, Stolk RF, van der Hoeven JG, Veltink PH, Pickkers P, Lemson J, Kox M. Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo. Shock. 2020 Feb;53(2):171-174. doi: 10.1097/SHK.0000000000001357.
- Individual participant dataSharing planned: No
Related trials for Endotoxemia
Recruiting
Short-Chain Fatty Acids in Lypopolysaccharide-Induced Inflammation and Executive Function
Endotoxemia, Inflammation
Not yet recruiting
Hemoadsorpion in Patients With Septic Shock: Efficacy and Safety Evaluation
Septic Shock
Not yet recruitingObservational study
Intestinal Endotoxemia and Beta- Cell Dysfunction in Prediabetics
Prediabetic State (IGT), Prediabetic State
RecruitingObservational study
OxiCLEAR (Oxiris Cytokines and Endotoxin Adsorption Rate) Study
Sepsis, Septic Shock
Active, not recruiting
Assessing Gut Microbiota Mediated Health Outcomes of Whole Wheat and Its Major Bioactive Components
PreDiabetes, Dysbiosis
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.
Roeland Stolk, MD principal investigator
Radboudumc, Intensive Care
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Norepinephrine, Phenylephrine and Vasopressins in people with Endotoxemia, run by Radboud University Medical Center 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 4 inclusion and 19 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 13 Oct 2016. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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?
concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups (time frame: 1 day). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02675868, which also lists 2 linked publications.
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 13 Oct 2016.