Hyperalgesia, pain Signs and Symptoms
Conditions
Interventions
Randomization: double-blind. Randomization created by study-independent statistician using SAS 9.4 for Windows or newer (SAS Institute Inc., Cary, NC, USA), and in accordance with CHDR’s applicable st
Sponsors
Centre for Human Drug Research
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Healthy male volunteers aged 18 to 55 years, inclusive. Healthy 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
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 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Electrical Stair (pre-cold pressor): Pain Detection Threshold (PDT) (mA), Area Under the VAS pain Curve (AUC) (mA*mm), and post-test VAS (mm) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only on study day 3) 2. Electrical Stair (post-cold pressor): PDT (mA), PTT (mA), AUC (mA*mm), and post-test VAS (mm) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only on study day 3) 3. Conditioned Pain Modulation Response (change from electrical stair pre- and post-cold pressor): PDT (mA), PTT (mA), AUC (mA*mm) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only on study day 3) 4. Pressure Pain: PDT (kPa), AUC (kPa*mm), and post-test VAS (mm) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only in on study day 3) 5. Cold Pressor: PDT (°C), AUC (°C*mm), and post-test VAS (mm) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only on study day 3) 6. Thermal pain: peripheral sensitization on primary and control area - Pain Detection Threshold (PDT) (°C) at -1h, 0h, 2h, 4h, 8h, 10h and 24h* (*: only on study day 3) 7. Short Form McGill Pain Questionnaire (SF-MPQ) scores after each of the above pain tests | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Cytokines (including, but not limited to IL-1ß, IL-6, IL-8, IL-10, TNF-a and IL-1ra; IL-17), measured with ELISA on study day 2 at 0h, 2h, 4h, 10h. On study day 3 at 0h, 5min, 15min, 30min, 1h, 2h, 3h, 4h, 10h and 24h 2. LPS, CRP, LBP, PCT, sTREM-1, presepsin; measured with electrochemiluminescence on study day 3 at 0h, 5min, 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 24h and at follow-up visit 3. Antibody glycosylation patterns measured with Nano-LC-ESI-MS on study day 3 at -1h, 2h, 8h and at follow-up visit 4. Molecular inflammatory markers: Bradykinin, Kallikrein, cortisol and Prostaglandin E2, measured on study day 2 at 0h, 2h, 3h, 4h, 8h. On study day 3 at 0h, 2h, 3h, 4h, 8h, 24h 5. Activation of complement pathways: classical, alternative and lectin route, measured with WIELISA on study day 3 at 0h, 4h 6. Mitochondrial membrane potential (MMP); measured with flow cytometry on study day 2 at -1h, 3h, 6h. On study day 3 at -1h, 3h, 6h, 24h 7. Neutrophil activation markers measured with ELISA on study day 2 at 0h, 3h. On study day 3 at 0h, 3h, 24h and at follow-up visit 8. Cytokines (including, but not limited to IL-1ß, IL-6, IL-8, IL-10, TNF-a and IL-1ra; IL-17); measured with ELISA see above for timepoints 9. LPS, CRP, LBP, PCT, sTREM-1, presepsin: measured with ELISA see above for timepoints | — |
Countries
Netherlands
Outcome results
None listed