NCT02922673

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

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
30

participants targeted

Target at below P25 for not_applicable

Timeline
Completed

Started Sep 2016

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

September 1, 2016

Completed
25 days until next milestone

First Submitted

Initial submission to the registry

September 26, 2016

Completed
8 days until next milestone

First Posted

Study publicly available on registry

October 4, 2016

Completed
2 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2016

Completed
9 months until next milestone

Study Completion

Last participant's last visit for all outcomes

September 1, 2017

Completed
Last Updated

July 31, 2019

Status Verified

September 1, 2016

Enrollment Period

3 months

First QC Date

September 26, 2016

Last Update Submit

July 30, 2019

Conditions

Endotoxemia

Keywords

human endotoxemiaLPSacetylsalicylic acidplaceboendotoxin tolerance

Outcome Measures

Primary Outcomes (1)

  • Change in concentration plasma TNFalpha (pg/ml)

    measured with Luminex assay

    Measured after the first and second LPS-challenge (on day 7 and day 14)

Secondary Outcomes (25)

  • Change in concentration plasma IL-6 (pg/ml)

    Measured after the first and second LPS-challenge (on day 7 and day 14)

  • Change in concentration plasma IL-8 (pg/ml)

    Measured after the first and second LPS-challenge (on day 7 and day 14)

  • Change in plasma concentration of IL-10 (pg/ml)

    Measured after the first and second LPS-challenge (on day 7 and day 14)

  • Change in plasma concentration of IL-1RA (pg/ml)

    Measured after the first and second LPS-challenge (on day 7 and day 14)

  • Change in plasma concentration of IL-1beta (pg/ml)

    Measured after the first and second LPS-challenge (on day 7 and day 14)

  • +20 more secondary outcomes

Study Arms (3)

Treatment group

EXPERIMENTAL

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: AspirinDrug: Placebo

Prophylaxis group

ACTIVE COMPARATOR

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

Placebo group

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

AspirinDRUG
Also known as: Acetylsalicylic acid, ASA
Prophylaxis groupTreatment group
PlaceboDRUG
Placebo groupTreatment group

Eligibility Criteria

Age18 Years - 35 Years
Sexmale
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • Written informed consent
  • Age ≥18 and ≤35 yrs
  • Male
  • Healthy (as confirmed by medical history, examination, ECG, blood sampling)

You may not qualify if:

  • 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)
  • +11 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Related Publications (1)

  • 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.

    PMID: 34566840DERIVED

MeSH Terms

Conditions

Endotoxemia

Interventions

Aspirin

Condition Hierarchy (Ancestors)

BacteremiaSepsisInfectionsToxemiaSystemic Inflammatory Response SyndromeInflammationPathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

SalicylatesHydroxybenzoatesPhenolsBenzene DerivativesHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsOrganic Chemicals

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
BASIC SCIENCE
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

September 26, 2016

First Posted

October 4, 2016

Study Start

September 1, 2016

Primary Completion

December 1, 2016

Study Completion

September 1, 2017

Last Updated

July 31, 2019

Record last verified: 2016-09

Locations

NL(1)