Extended characterization of human endotoxemia: LPS-induced hyperalgesia and inflammatory responses

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 24

Inclusion Criteria

1. Healthy male volunteers aged 18 to 55 years, inclusive. Health status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;
2. Body Mass Index (BMI) in the range of 18 to 28 kg/m2, and a minimum body weight of 50 kg;
3. Be able to abstain from smoking between the screening visit and the study discharge visit;
4. No history of alcohol or drug abuse;
5. No history of trauma with likely damage to the spleen or surgery to spleen;
6. Free from any clinically significant febrile illness 30 days preceding study day 1;
7. Non-atopic constitution, including non-asthmatic;
8. No use of any prescription drugs, including aspirin or other non-steroid anti-inflammatory drugs;
9. Able to give written informed consent and willing to comply with all study-related procedures.

Exclusion Criteria

1. History of sepsis, cardiovascular disease, previous syncope or malignancy;
2. Reported unintended weight loss or gain of at least 5 kg in four weeks at screening;
3. Haemorrhagic diathesis (easy bruising, epistaxis, gastro-intestinal bleeding);
4. First degree family history of premature cardiovascular disease event (if diagnosed before 50 years of age);
5. Previous participation in a LPS challenge trial or prior exposure to endotoxin;
6. Recent antibiotic use, operation or intervention by surgeon/dentist;
7. Any active inflammatory or infectious disease (e.g. periodontitis);
8. Hypertension (defined as systolic blood pressure RR > 160 mmHg or diastolic blood pressure RR > 90 mmHg, repeatedly measured after 5 minutes in resting supine position);
9. Hypotension (defined as systolic blood pressure RR < 100 mmHg or diastolic blood pressure RR < 50 mmHg);
10. Clinically significant abnormalities on the 12-lead ECG (QRS complex > 120 ms, PR interval > 240 ms, QTcF interval > 470 ms);
11. Positive test results for Hepatitis B, Hepatitis C, HIV or any other obvious disease associated with immune deficiency;
12. Renal insufficiency as defined by plasma creatinine >= 120 µmol/L;
13. Biochemical diagnosis of diabetes mellitus;
14. Biochemical diagnosis of hypo- or hyperthyroidism (TSH <0.3 or >4.8 mU/L)
15. Any medical condition or abnormal laboratory value that is judged clinically significant by the investigator;
16. Other medical or psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol;
17. Donation of blood within 3 months prior to screening or donation of plasma within 14 days prior to screening;
18. Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times in the past year;
19. Not having a general practitioner;
20. Not willing to accept information transfer which concerns participation in the study, or information regarding health, like laboratory results, findings at anamnesis or physical examination and eventual adverse events to and from his general practitioner;
21. Not willing to give permission to have the general practitioner to be notified upon participation in this study.
22. Any current, clinically significant, known medical condition in particular any existing conditions that would affect sensitivity to cold (such as atherosclerosis, Raynaud*s disease, urticaria, hypothyroidism) or pain (i.e., disease that causes pain, hypesthesia, hyperalgesia, allodynia, paraesthesia, neuropathy)
23. Subjects indicating pain tests intolerable at screening or achieving tolerance at >80% of maximum input intensity for any pain test for cold, pressure and electrical tests.

Study & Design

Study Type: Observational invasive

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Safety endpoints<br /><br><br /><br>Pharmacodynamic endpoints (PainCart):<br /><br>- Electrical Stair (pre-cold pressor): Pain Detection Threshold (PDT) (mA),<br /><br>Area Under the VAS pain Curve (AUC) (mAmm), and post-test VAS (mm).<br /><br>- Electrical Stair (post-cold pressor): PDT (mA), PTT (mA), AUC (mAmm), and<br /><br>post-test VAS (mm).<br /><br>- Conditioned Pain Modulation Response (change from electrical stair pre- and<br /><br>post-cold pressor): PDT (mA), PTT (mA), AUC (mAmm).<br /><br>- Pressure Pain: PDT (kPa), AUC (kPamm), and post-test VAS (mm).<br /><br>- Cold Pressor: PDT (°C), AUC (°C*mm), and post-test VAS (mm).<br /><br>- Thermal pain: peripheral sensitization on primary and control area (PDT) (°C)<br /><br>- Short Form McGill Pain Questionnaire (SF-MPQ) scores</p><br>

Secondary Outcome Measures

Name	Time	Method
<p> Blood-based endpoints:<br /><br>Circulating measures (plasma/serum), e.g.:<br /><br>Cytokines (including, but not limited to IL-1β, IL-6,<br /><br>IL-8, IL-10, TNF-a and IL-1ra; IL-17);<br /><br>LPS, CRP, LBP, PCT, sTREM-1, presepsin;<br /><br>Antibody glycosylation patterns;<br /><br>Molecular inflammatory markers: Bradykinine,<br /><br>Kallikreine, cortisol and Prostaglandin E2<br /><br>Cellular measures:<br /><br>CB2R expression;<br /><br>Salt-inducible kinase;<br /><br>Neutrophil activation markers.</p><br>