The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia

NCT ID: NCT02922673

Last Updated: 2019-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-30
• Study Completion Date: 2017-09-30

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

Conditions

Endotoxemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

Aspirin

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

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

Group Type: ACTIVE_COMPARATOR

Aspirin

Intervention Type: DRUG

Placebo group

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Aspirin

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Acetylsalicylic acid; ASA

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

References

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.

Reference Type: DERIVED

PMID: 34566840 (View on PubMed)

Other Identifiers

2016-001971-61

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL57410.091.16

Identifier Type: OTHER

Identifier Source: secondary_id

SALYCENDO

Identifier Type: -

Identifier Source: org_study_id