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Trial record 72 of 87 for:    ASPIRIN AND thromboxane

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

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ClinicalTrials.gov Identifier: NCT02922673
Recruitment Status : Completed
First Posted : October 4, 2016
Last Update Posted : July 31, 2019
Sponsor:
Information provided by (Responsible Party):
Radboud University

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:

  1. Treatment group: 7 days placebo / first endotoxemia / 7 days ASA 80 mg (loading dose on first day of 160mg) / second endotoxemia
  2. Prophylaxis group: 7 days ASA 80 mg (loading dose on first day of 160mg) / first endotoxemia / 7 days ASA 80 mg / second endotoxemia
  3. Placebo group: 7 days placebo / first endotoxemia / 7 days placebo / second endotoxemia

Condition or disease Intervention/treatment Phase
Endotoxemia Drug: Aspirin Drug: Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia
Actual Study Start Date : September 2016
Actual Primary Completion Date : December 2016
Actual Study Completion Date : September 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

Arm Intervention/treatment
Experimental: Treatment group
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
Drug: Aspirin
Other Names:
  • Acetylsalicylic acid
  • ASA

Drug: Placebo
Active Comparator: Prophylaxis group
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
Drug: Aspirin
Other Names:
  • Acetylsalicylic acid
  • ASA

Placebo Comparator: Placebo group
7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge
Drug: Placebo



Primary Outcome Measures :
  1. Change in concentration plasma TNFalpha (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay


Secondary Outcome Measures :
  1. Change in concentration plasma IL-6 (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  2. Change in concentration plasma IL-8 (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  3. Change in plasma concentration of IL-10 (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  4. Change in plasma concentration of IL-1RA (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  5. Change in plasma concentration of IL-1beta (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  6. Change in plasma concentration of MCP-1 (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge ]
    measured with Luminex assay

  7. Change in plasma concentration of MIP-1alpha (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  8. Change in plasma concentration of MIP-1beta (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  9. Change in monocytic HLA-DR expression (mHLA-DR) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  10. Change in symptoms during endotoxin day [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  11. Change in blood pressure [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  12. Change in temperature [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  13. Change in heart rate [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  14. 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) ]
  15. Arterial bloodgas [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  16. Change in platelet monocyte complexes [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  17. 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) ]
  18. Thromboxane B2 [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  19. Prostaglandin E2 (PGE-M) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  20. Change in plasma enkephalin [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  21. 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) ]
  22. Change in leukocyte count (and differentiation) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  23. Change in transcriptional activity of leukocytes [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
  24. Change in plasma concentration of IFN-gamma (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
    measured with Luminex assay

  25. 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02922673


Locations
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Netherlands
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02922673     History of Changes
Other Study ID Numbers: SALYCENDO
2016-001971-61 ( EudraCT Number )
NL57410.091.16 ( Other Identifier: CCMO (Dutch) )
First Posted: October 4, 2016    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Radboud University:
human endotoxemia
LPS
acetylsalicylic acid
placebo
endotoxin tolerance
Additional relevant MeSH terms:
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Aspirin
Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics