Clinical Trial: The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia

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 (

Detailed Summary:
Sponsor: Radboud University

Current Primary Outcome: Change in concentration plasma TNFalpha (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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
• 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
• 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
• 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
• 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
• Change in plasma concentration of MCP-1 (pg/ml) [ Time Frame: Measured after the first and second LPS-challenge ]
  measured with Luminex assay
• 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
• 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
• Change in monocytic HLA-DR expression (mHLA-DR) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in symptoms during endotoxin day [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in blood pressure [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in temperature [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in heart rate [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 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) ]
• Arterial bloodgas [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in platelet monocyte complexes [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• 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) ]
• Thromboxane B2 [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Prostaglandin E2 (PGE-M) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in plasma enkephalin [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• 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) ]
• Change in leukocyte count (and differentiation) [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• Change in transcriptional activity of leukocytes [ Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14) ]
• 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
• 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) ]

Original Secondary Outcome: Same as current

Information By: Radboud University

Dates:
Date Received: September 26, 2016
Date Started: September 2016
Date Completion: October 2017
Last Updated: April 24, 2017
Last Verified: September 2016