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The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia (SALYCENDO)

Primary Purpose

Endotoxemia

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Aspirin
Placebo
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Endotoxemia focused on measuring human endotoxemia, LPS, acetylsalicylic acid, placebo, endotoxin tolerance

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Written informed consent
  • Age ≥18 and ≤35 yrs
  • Male
  • Healthy (as confirmed by medical history, examination, ECG, blood sampling)

Exclusion Criteria:

  • Use of any medication
  • Use of COX-inhibitors within 6 weeks prior to the first endotoxemia day
  • Smoking
  • Known anaphylaxis or hypersensitivity to acetylsalicylic acid or non-investigational products
  • History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema)
  • History of peptic ulcer disease
  • History or signs of hematological disease
  • Thrombocytopenia (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L)
  • History of glucose-6-phosphate dehydrogenase deficiency
  • History of intracranial hemorrhage
  • History, signs or symptoms of cardiovascular disease, in particular:
  • Previous spontaneous vagal collapse
  • History of atrial or ventricular arrhythmia
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block
  • 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 creatinine >120 μmol/l)
  • Liver enzyme abnormalities (above 2x the upper limit of normal)
  • Medical history of any disease associated with immune deficiency
  • CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L or clinically significant acute illness, including infections, within 4 weeks before the first endotoxemia day
  • Previous (participation in a study with) LPS administration
  • Participation in a drug trial or donation of blood 3 months prior to first endotoxemia day
  • Any vaccination within 3 months prior to first endotoxemia day until the end of the study
  • Recent hospital admission or surgery with general anesthesia (<3 months to endotoxemia day)
  • Use of recreational drugs within 21 days prior to the first endotoxemia day
  • Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study

Sites / Locations

  • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Treatment group

Prophylaxis group

Placebo group

Arm Description

7 day treatment with placebo - first LPS challenge - 7 day treatment with ASA 80 mg (with a loading dose of 160 mg on the first day) - second LPS challenge

7 day treatment with ASA 80 mg (with a loading dose of 160 mg on the first day) - first LPS challenge - 7 day treatment with ASA (no loading dose on first day) - second LPS challenge

7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge

Outcomes

Primary Outcome Measures

Change in concentration plasma TNFalpha (pg/ml)
measured with Luminex assay

Secondary Outcome Measures

Change in concentration plasma IL-6 (pg/ml)
measured with Luminex assay
Change in concentration plasma IL-8 (pg/ml)
measured with Luminex assay
Change in plasma concentration of IL-10 (pg/ml)
measured with Luminex assay
Change in plasma concentration of IL-1RA (pg/ml)
measured with Luminex assay
Change in plasma concentration of IL-1beta (pg/ml)
measured with Luminex assay
Change in plasma concentration of MCP-1 (pg/ml)
measured with Luminex assay
Change in plasma concentration of MIP-1alpha (pg/ml)
measured with Luminex assay
Change in plasma concentration of MIP-1beta (pg/ml)
measured with Luminex assay
Change in monocytic HLA-DR expression (mHLA-DR)
Change in symptoms during endotoxin day
Change in blood pressure
Change in temperature
Change in heart rate
Change in cerebral blood flow using Transcranial Doppler (TCD) measurements and Near Infrared Spectroscopy (NIRS)
Arterial bloodgas
Change in platelet monocyte complexes
Change in monocyte surface antigen expression of PD-L1
Thromboxane B2
Prostaglandin E2 (PGE-M)
Change in plasma enkephalin
Kidney damage markers in urine (NGAL, KIM-1 and L-FABP)
Change in leukocyte count (and differentiation)
Change in transcriptional activity of leukocytes
Change in plasma concentration of IFN-gamma (pg/ml)
measured with Luminex assay
Change in lymphocyte surface antigen expression of PD-1 and IL7-RA

Full Information

First Posted
September 26, 2016
Last Updated
July 30, 2019
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02922673
Brief Title
The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia
Acronym
SALYCENDO
Official Title
The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale: The last years, research focus has moved to immunostimulatory agents in order to restore or increase the functionality of the immune system during sepsis-induced immunoparalysis. Epidemiologic data show that prehospital use of low dose acetylsalicylic acid (ASA) is associated with improved outcome of sepsis. Experimental data indicate that ASA exerts pro-inflammatory effects during systemic inflammation. However, it remains to be determined whether treatment with ASA improves immune function once immunoparalysis has developed and whether prehospital use of low dose ASA prevents the development of immunoparalysis. In the former case, ASA is a potential immunostimulatory therapy that can treat sepsis-induced immunoparalysis. In the latter case, ASA may have a broader indication as an immunomodulating agent. Taken together, ASA might be a promising, cheap, well-known, and globally available agent to reduce the incidence of secondary infections and improve patient outcome in sepsis. Objective: To determine whether acetylsalicylic acid treatment can reverse endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge. To determine whether acetylsalicylic acid prophylaxis can prevent endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge. Study design: Double-blind randomized placebo-controlled pilot study in 30 healthy male volunteers during repeated experimental endotoxemia. All subjects will receive a 14 day course of study medication (low-dose ASA or placebo) and undergo experimental endotoxemia (lipopolysacharide (LPS), E.Coli type O113) on day 7 and on day 14. LPS is administrated using an initial bolus of 1ng/kg followed by continuous infusion at 1ng/kg/hr during 3 hours. Subjects are randomized in three study arms: Treatment group: 7 days placebo / first endotoxemia / 7 days ASA 80 mg (loading dose on first day of 160mg) / second endotoxemia Prophylaxis group: 7 days ASA 80 mg (loading dose on first day of 160mg) / first endotoxemia / 7 days ASA 80 mg / second endotoxemia Placebo group: 7 days placebo / first endotoxemia / 7 days placebo / second endotoxemia

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endotoxemia
Keywords
human endotoxemia, LPS, acetylsalicylic acid, placebo, endotoxin tolerance

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment group
Arm Type
Experimental
Arm Description
7 day treatment with placebo - first LPS challenge - 7 day treatment with ASA 80 mg (with a loading dose of 160 mg on the first day) - second LPS challenge
Arm Title
Prophylaxis group
Arm Type
Active Comparator
Arm Description
7 day treatment with ASA 80 mg (with a loading dose of 160 mg on the first day) - first LPS challenge - 7 day treatment with ASA (no loading dose on first day) - second LPS challenge
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge
Intervention Type
Drug
Intervention Name(s)
Aspirin
Other Intervention Name(s)
Acetylsalicylic acid, ASA
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change in concentration plasma TNFalpha (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Secondary Outcome Measure Information:
Title
Change in concentration plasma IL-6 (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in concentration plasma IL-8 (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of IL-10 (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of IL-1RA (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of IL-1beta (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of MCP-1 (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge
Title
Change in plasma concentration of MIP-1alpha (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of MIP-1beta (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in monocytic HLA-DR expression (mHLA-DR)
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in symptoms during endotoxin day
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in blood pressure
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in temperature
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in heart rate
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in cerebral blood flow using Transcranial Doppler (TCD) measurements and Near Infrared Spectroscopy (NIRS)
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Arterial bloodgas
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in platelet monocyte complexes
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in monocyte surface antigen expression of PD-L1
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Thromboxane B2
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Prostaglandin E2 (PGE-M)
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma enkephalin
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Kidney damage markers in urine (NGAL, KIM-1 and L-FABP)
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in leukocyte count (and differentiation)
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in transcriptional activity of leukocytes
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in plasma concentration of IFN-gamma (pg/ml)
Description
measured with Luminex assay
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)
Title
Change in lymphocyte surface antigen expression of PD-1 and IL7-RA
Time Frame
Measured after the first and second LPS-challenge (on day 7 and day 14)

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Written informed consent Age ≥18 and ≤35 yrs Male Healthy (as confirmed by medical history, examination, ECG, blood sampling) Exclusion Criteria: Use of any medication Use of COX-inhibitors within 6 weeks prior to the first endotoxemia day Smoking Known anaphylaxis or hypersensitivity to acetylsalicylic acid or non-investigational products History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema) History of peptic ulcer disease History or signs of hematological disease Thrombocytopenia (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L) History of glucose-6-phosphate dehydrogenase deficiency History of intracranial hemorrhage History, signs or symptoms of cardiovascular disease, in particular: Previous spontaneous vagal collapse History of atrial or ventricular arrhythmia Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block 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 creatinine >120 μmol/l) Liver enzyme abnormalities (above 2x the upper limit of normal) Medical history of any disease associated with immune deficiency CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L or clinically significant acute illness, including infections, within 4 weeks before the first endotoxemia day Previous (participation in a study with) LPS administration Participation in a drug trial or donation of blood 3 months prior to first endotoxemia day Any vaccination within 3 months prior to first endotoxemia day until the end of the study Recent hospital admission or surgery with general anesthesia (<3 months to endotoxemia day) Use of recreational drugs within 21 days prior to the first endotoxemia day Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study
Facility Information:
Facility Name
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6500HB
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34566840
Citation
Eleveld N, Hoedemaekers CWE, van Kaam CR, Leijte GP, van den Brule JMD, Pickkers P, Aries MJH, Maurits NM, Elting JWJ. Near-Infrared Spectroscopy-Derived Dynamic Cerebral Autoregulation in Experimental Human Endotoxemia-An Exploratory Study. Front Neurol. 2021 Sep 10;12:695705. doi: 10.3389/fneur.2021.695705. eCollection 2021.
Results Reference
derived

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The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia

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