Primary objective:To determine whether endotoxin tolerance can be prevented by acetylsalicylic acid prophylaxis or can be reversed by acetylsalicylic acid treatment, expressed as an augmentation of pro-inflammatory cytokine levels during the second…
ID
Source
Brief title
Condition
- Immune disorders NEC
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study endpoint, endotoxin tolerance, is the decrease in the area
under the curve (AUC) of the plasma TNF* concentration between the first and
second endotoxin challenge in the control group compared to the treatment
group.
Secondary outcome
- Plasma levels of other inflammatory mediators on the first and second
endotoxemia day (including but not limited to TNF*, IL-6, IL-8, IL-10, IL-1RA)
- Ex vivo production of inflammatory mediators and reactive oxygen species
(ROS) by whole blood and peripheral blood mononuclear cells (PBMCs) stimulated
by LPS and several pathogens (including but not limited to S. aureus, M.
tuberculosis, C. albicans)
- Monocyte surface antigen expression (including but not limited to mHLA-DR,
Programmed Death Ligand (PDL)-1, Programmed cell Death protein (PD)-1, IL-7R)
- Plasma thromboxane B2 levels, as an expression of thromboxane A2
- Prostaglandin E2 urine metabolites (PGE-M)
- Kidney damage markers (including but not limited to NGAL, KIM-1, L-FABP)
- Transcriptional activity of leukocytes
- Symptom score
- Mean arterial pressure
- Heart rate
- Temperature
Background summary
Sepsis is a major health care burden with increasing incidence and high
mortality rates. The immune response in sepsis is highly variable between
patients and can comprise both a hyperinflammatory and immunosuppressive state
(immunoparalysis). The field of sepsis research has seen many pharmacological
trials, mainly aimed at inhibition of pro-inflammatory responses, fail to have
any effect on sepsis outcome. This might be due to the fact that the majority
of septic patients do not succumb to the early pro-inflammatory phase, but die
at a later time-point in a protracted immunosuppressive state that renders them
very vulnerable towards secondary infections. The last years, research focus
has moved to immunostimulatory agents in order to restore/increase the
functionality of the immune system during this sepsis-induced immunoparalysis.
Epidemiologic data show that chronic use of ASA is associated with improved
outcome during sepsis. Experimental data by our group and others indicates that
ASA, perhaps counter-intuitively, exerts pro-inflammatory effects during
systemic inflammation. Therefore, ASA may be an immunostimulatory agent that
could reverse the immunosuppressive state in sepsis. To this end, it might be a
promising, cheap, well-known, and globally available agent to reduce the
incidence of secondary infections and improve patient outcome in sepsis.
However, whether ASA is indeed capable of reversing immunoparalysis in vivo in
humans is unknown.
Study objective
Primary objective:
To determine whether endotoxin tolerance can be prevented by acetylsalicylic
acid prophylaxis or can be reversed by acetylsalicylic acid treatment,
expressed as an augmentation of pro-inflammatory cytokine levels during the
second endotoxemia one week after the first challenge.
Secondary objectives:
- To determine the effects of prophylaxis and treatment with acetylsalicylic
acid on ex vivo responsiveness of monocytes and whole blood to various
inflammatory stimuli.
- To determine the effects of prophylaxis and treatment with acetylsalicylic
acid on cell surface expression of markers of immunoparalysis on circulating
leukocytes, including but not limited to HLA-DR, PD-L1, PD-1, and IL-7R.
- To determine the effects of prophylaxis and treatment with acetylsalicylic
acid on plasma and urine levels of prostaglandin E2.
- To determine the effects of prophylaxis and treatment with acetylsalicylic
acid on inflammatory transcriptional pathways in monocytes.
- To determine the effects of prophylaxis and treatment with acetylsalicylic
acid on LPS-induced clinical symptoms (symptom score), hemodynamic or
temperature changes.
Study design
Double-blind randomized placebo-controlled pilot study in healthy male
volunteers during repeated experimental endotoxemia. We will enrol 30 subjects
which will be randomized in three study groups. Groups differ in allocated
study medication (ASA or placebo) in the first and second treatment course
(Table 1). The first course is the 7-day period before the first endotoxemia
(also referred to as prophylaxis) and the second course is the 7-day period
in-between first and second endotoxemia (also referred to as treatment). All
subjects will undergo experimental endotoxemia twice, on day 7 and on day 14.
For accurate resemblance of the clinical situation, we will conduct a
continuous LPS administration model which is more similar to an ongoing
inflammation as seen in patients. To this end, subjects will receive LPS in an
initial bolus of 1ng/kg, followed by continuous infusion at 1ng/kg/hr during 3
hours, analogous to a previous study of our group.
Intervention
The subjects will be randomized in three groups (each n=10):
PA (placebo-ASA, treatment group): first course placebo, second course ASA
AA (ASA-ASA, prophylaxis group): first course ASA, second course ASA
PP (placebo-placebo, control group): first course placebo, second course
placebo
In the ASA course, subjects receive low-dose ASA of 80 mg/day for the course of
7 days, they start with a loading dose of 160 mg.
Study burden and risks
Subjects will visit the research unit a total of six times; for screening,
medication instruction, the first endotoxemia day, urine deposit, the second
endotoxemia day and for follow-up. Volunteers will be recruited and are
subjected to a medical examination (including interview, medical history and
physical examination).
The use of ASA in this (low) dose is registered for patients and the risk on
adverse events is low. The main potential side effects of ASA are
gastrointestinal complaints and a prolonged bleeding time. Many adverse effects
of ASA are dose related, and are extremely rare at low dosages.
The administration of a lipopolysaccharide induces flu-like symptoms. This
model of systemic inflammation has been applied for more than 10 years in our
department and thousands of subjects worldwide have participated in endotoxemia
trials. During the endotoxemia experiment day, subjects will be under constant
supervision of an physician with continuous monitoring of blood pressure and
heart rate. The endotoxemia protocol and associated risks are identical to
earlier endotoxemia studies performed in our institute.
In total, a maximum of 450 ml blood will be drawn during the study, which is
comparable to previous studies and never resulted in adverse events. Subjects
will not benefit directly from participation to the study. The total risks to
the subjects in this study is classified as a *negligible risk* (low risk on
minor harms). A subject fee is provided.
Geert Grooteplein 10
Nijmegen 6500HB
NL
Geert Grooteplein 10
Nijmegen 6500HB
NL
Listed location countries
Age
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-phospate 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 *mol/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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001971-61-NL |
| CCMO | NL57410.091.16 |