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NCT Number: NCT02922673

The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia

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

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Key information

Conditions

Endotoxemia Bacteremia Infections Inflammation Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Systemic Inflammatory Response Syndrome Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Aspirin

Drug

Other names: Acetylsalicylic acid, ASA

Placebo

Drug

Primary outcomes

  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 outcomes

  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)

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Acronym: SALYCENDO

Important dates

Study start
2016
Primary completion
2016
Study completion
2017
First posted
Oct 4, 2016
Registry last updated
Jul 31, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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