neuroinflammation
Conditions
Interventions
None listed
Sponsors
Centre for Human Drug Research
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Healthy male volunteers aged 18 to 45 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. BMI in the range of 18 to 30 kg/m2, a minimum body weight of 50 kg. 3. Able to give written informed consent and willing to comply with all study-related procedures. 4.Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions.
Exclusion criteria
Exclusion criteria: 1. Previous participation in a systemic (IV or inhaled) LPS challenge trial within a year before the first study day. 2. Antibiotic use, operation, or intervention by surgeon/dentist within one month before the first study day. 3. Any clinically significant febrile illness 30 days prior to the start of the study. 4. Any active inflammatory or infectious disease (e.g., periodontitis), excluding onychomycosis. 5. Any disease associated with immune system impairment, including auto-immune diseases. HIV, transplantation patients and active allergies when treated with medication.(non-active hay fever is acceptable) 6. History of trauma with likely damage to the spleen or surgery to the spleen. 7. History of sepsis, cardiovascular disease or malignancy. 8. History or presence of an abnormal ECG, including, but not limited to, complete left bundle branch block, second- or third-degree heart block, evidence of prior myocardial infarction, or any other abnormality that is clinically significant in the investigator*s opinion or precludes accurate interpretation and calculations of cardiac intervals (e.g., QT, QRS). 9. (A history of) any clinically significant medical condition or abnormalities, as judged by the investigator. 10. 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. 11. Evidence of clinically significant hepatic or renal impairment in the opinion of the investigator, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 the upper limit of normal (ULN) or bilirubin > 1.5 ULN. Patients with Gilbert syndrome without evidence of hepatic impairment may be enrolled. 12. Positive test results for Hepatitis B, Hepatitis C, HIV antibody or any other obvious disease associated with immune deficiency. 13. Use of immunosuppressive or immunomodulatory medication that affects the LPS response as judged by the investigator within 30 days of LPS administration, or less than 5 half-lives (whichever is longer) or planned to use during the study. 14. Use of any vitamin (including vitamin D), mineral, herbal, and dietary supplements within 7 days prior to dosing and/or LPS administration or within less than 5 half -lives (whichever is longer), until the EOS. Given the extensive half-life of vitamin D, incidental use is permitted between 5 half-lives (+/- 250 days) and 3 months prior to LPS administration if judged to be clinically irrelevant by the investigator. 15. Subjects who smoke more than 6 cigarettes or the equivalent in tobacco per day and are unwilling to abstain from smoking during the study period (from screening until end of study). 16. Any vaccination within the last 4 weeks before day 1 or intention to receive any vaccination(s) before the end of study. 17. Serious adverse reaction or serious hypersensitivity to any drug. 18. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at screening. 19. Subjects with a positive urine drug screen (Cocaine, amphetamines, opiates (morphine), benzodiazepines and cannabinoids) or alcohol test result at screening or first admission or a history of substance ab
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary objectives: • To characterize the central inflammatory response to IV LPS by measuring biomarkers in CSF • To characterize the systemic inflammatory response to IV LPS by measuring biomarkers in blood • Characterize CSF/Blood ratios for each biomarker over time Primary endpoints: • CSF inflammatory biomarkers including, but not limited to IL-1β, IL-18, IL-6, IL-8, TNF, CXCL10 • Systemic inflammatory biomarkers including, but not limited to IL-1β, IL-18, IL-6, IL-8, TNF, CXCL10 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives: • To evaluate complement activation after IV LPS administration. • To evaluate if lumbar punctures cause an inflammatory response Secondary endpoints: • Complement activation products (e.g. C3a, sC5b) in plasma • CSF inflammatory biomarkers including, but not limited to IL-1β, IL-18, IL-6, IL-8, TNF, CXCL10 | — |
Countries
Netherlands
Outcome results
None listed