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

July 30, 2019 updated by: Radboud University Medical Center

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500HB
        • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / 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: Placebo
Drug: Aspirin
Other Names:
  • ASA
  • Acetylsalicylic acid
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:
  • ASA
  • Acetylsalicylic acid
PLACEBO_COMPARATOR: Placebo group
7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge
Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Measured after the first and second LPS-challenge (on day 7 and day 14)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of MCP-1 (pg/ml)
Time Frame: Measured after the first and second LPS-challenge
measured with Luminex assay
Measured after the first and second LPS-challenge
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in monocytic HLA-DR expression (mHLA-DR)
Time Frame: Measured after the first and second LPS-challenge (on day 7 and day 14)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
Measured after the first and second LPS-challenge (on day 7 and day 14)
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)
Measured after the first and second LPS-challenge (on day 7 and day 14)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 1, 2016

Primary Completion (ACTUAL)

December 1, 2016

Study Completion (ACTUAL)

September 1, 2017

Study Registration Dates

First Submitted

September 26, 2016

First Submitted That Met QC Criteria

September 30, 2016

First Posted (ESTIMATE)

October 4, 2016

Study Record Updates

Last Update Posted (ACTUAL)

July 31, 2019

Last Update Submitted That Met QC Criteria

July 30, 2019

Last Verified

September 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SALYCENDO
  • 2016-001971-61 (EUDRACT_NUMBER)
  • NL57410.091.16 (OTHER: CCMO (Dutch))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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