EndotoxemiaSALYCENDONCT02922673
The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia
A study testing Aspirin in people with Endotoxemia, run by Radboud University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Endotoxemia
- What is being tested?
- Aspirin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteNetherlands
- Study dates
- Sep 2016to Sep 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy (as confirmed by medical history, examination, ECG, blood sampling)
Who cannot join
- 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
Show all 26Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, 6500HB
About this study
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.
Read more
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
- Conditions
- Endotoxemia
- Being tested
- Aspirin, Placebo
- Keywords
- human endotoxemia, LPS, acetylsalicylic acid, placebo, endotoxin tolerance
- Medical subject headings
- Endotoxemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AspirinDrug
Also called Acetylsalicylic acid, ASA
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Aspirin; Drug: 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 Receives: Drug: Aspirin |
| Placebo group | Placebo comparator | 7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in concentration plasma TNFalpha (pg/ml)
measured with Luminex assay
Measured: 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 with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in concentration plasma IL-8 (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of IL-10 (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of IL-1RA (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of IL-1beta (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of MCP-1 (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge
Change in plasma concentration of MIP-1alpha (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of MIP-1beta (pg/ml)
measured with Luminex assay
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in monocytic HLA-DR expression (mHLA-DR)
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in symptoms during endotoxin day
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in blood pressure
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in temperature
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in heart rate
Measured: 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)
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Arterial bloodgas
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in platelet monocyte complexes
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in monocyte surface antigen expression of PD-L1
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Thromboxane B2
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Prostaglandin E2 (PGE-M)
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma enkephalin
Measured: 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)
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in leukocyte count (and differentiation)
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in transcriptional activity of leukocytes
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Change in plasma concentration of IFN-gamma (pg/ml)
measured with Luminex assay
Measured: 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
Measured: Measured after the first and second LPS-challenge (on day 7 and day 14)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Oct 2016 (estimated)
- Study startSep 2016
- Primary completionDec 2016
- Study completionSep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EndotoxemiaStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02922673
- Sponsor's protocol ID
- SALYCENDO
- Other IDs
- 2016-001971-61, NL57410.091.16, 2016
- Acronym
- SALYCENDO
- Status last verified
- Sep 2016
- First submitted
- 26 Sep 2016
- Last updated
- 31 Jul 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 34566840
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Acetylsalicylic Acid on Immunoparalysis Following Human Endotoxemia
- ClinicalTrials.gov ID
- NCT02922673
- Acronym / sponsor ID
- SALYCENDO / SALYCENDO
- Conditions
- Endotoxemia
- Keywords
- human endotoxemia, LPS, acetylsalicylic acid, placebo, endotoxin tolerance
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Sep 2016 (actual)
- Primary completion
- Dec 2016 (actual)
- Study completion
- Sep 2017 (actual)
- First posted
- 4 Oct 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Treatment group | Experimental | Drug: Aspirin, Drug: Placebo7 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 |
| Prophylaxis group | Active comparator | Drug: Aspirin7 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 |
| Placebo group | Placebo comparator | Drug: Placebo7 day treatment with placebo - first LPS challenge - 7 day treatment with placebo - second LPS challenge |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy (as confirmed by medical history, examination, ECG, blood sampling)
Key exclusion criteria (26 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AspirinAlso: Acetylsalicylic acid, ASA | Drug | Prophylaxis group, Treatment group |
| Placebo | Drug | Placebo group, Treatment group |
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)
measured with Luminex assay
25 secondary outcomes
Change in concentration plasma IL-6 (pg/ml)
Time frame: 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)
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)
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)
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)
Change in plasma concentration of MCP-1 (pg/ml)
Time frame: 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)
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)
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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2019.
- Derived from this study: PubMed 34566840Eleveld 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Aspirin in people with Endotoxemia, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in concentration plasma TNFalpha (pg/ml) (time frame: Measured after the first and second LPS-challenge (on day 7 and day 14)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02922673, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2019.