Investigation of the effect of an LPS challenge on:1. Nociceptive pain thresholds (primary endpoint);2. The expression of cell surface markers related to pain responses;3. Soluble markers related to painExploration of LPS effects on state-of-the-art…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints
Pharmacodynamic endpoints (PainCart):
- Electrical Stair (pre-cold pressor): Pain Detection Threshold (PDT) (mA),
Area Under the VAS pain Curve (AUC) (mA*mm), and post-test VAS (mm).
- Electrical Stair (post-cold pressor): PDT (mA), PTT (mA), AUC (mA*mm), and
post-test VAS (mm).
- Conditioned Pain Modulation Response (change from electrical stair pre- and
post-cold pressor): PDT (mA), PTT (mA), AUC (mA*mm).
- Pressure Pain: PDT (kPa), AUC (kPa*mm), and post-test VAS (mm).
- Cold Pressor: PDT (°C), AUC (°C*mm), and post-test VAS (mm).
- Thermal pain: peripheral sensitization on primary and control area (PDT) (°C)
- Short Form McGill Pain Questionnaire (SF-MPQ) scores
Secondary outcome
Blood-based endpoints:
Circulating measures (plasma/serum), e.g.:
Cytokines (including, but not limited to IL-1β, IL-6,
IL-8, IL-10, TNF-α and IL-1ra; IL-17);
LPS, CRP, LBP, PCT, sTREM-1, presepsin;
Antibody glycosylation patterns;
Molecular inflammatory markers: Bradykinine,
Kallikreine, cortisol and Prostaglandin E2
Cellular measures:
CB2R expression;
Salt-inducible kinase;
Neutrophil activation markers.
Background summary
The human endotoxemia model allows the investigation of the pharmacological
activity of new medicinal products targeting pathways that are not present or
active in healthy volunteers. The relationship between lipopolysaccharide (LPS)
exposure and clinical signs and symptoms, circulating cytokine levels, vascular
activation, renal effects, and LPS tolerance has been investigated in earlier
CHDR studies. However, the LPS model may be relevant for many more
(patho)physiological pathways than characterized so far, such as inflammatory
pain. Other studies found in literature that assessed pain perception after LPS
administration, solely included one or two pain tests types in their design.
Therefore, in this study an in vivo LPS challenge in healthy volunteers will be
performed, investigating the effect of LPS exposure on pain-related markers
(functional assessments of nociceptive pain by using the PainCart, cell surface
markers, soluble markers) and on state-of-the-art inflammatory biomarkers
(salt-inducible kinase, neutrophil activation, antibody glycosylation).
Moreover, the correlation between in vivo LPS responses and ex vivo LPS
responses will be evaluated. Hereby, the in vivo LPS challenge together with
PainCart will be qualified as methodological tool for the clinical testing of
investigational medicinal products intended to modulate inflammatory pain
Study objective
Investigation of the effect of an LPS challenge on:
1. Nociceptive pain thresholds (primary endpoint);
2. The expression of cell surface markers related to pain responses;
3. Soluble markers related to pain
Exploration of LPS effects on state-of-the-art inflammatory biomarkers for
which clinical data are currently sparse, e.g.:
1. Cellular salt-inducible kinase;
2. Neutrophil activation markers;
3. Antibody glycosylation patterns.
Investigation of the effect of an ex vivo LPS challenge on a panel of
inflammatory markers to:
1. Compare the inflammatory responses to LPS, heat-killed E. coli, and live E.
coli;
2. Assess the relationship between in vivo and ex vivo LPS responses;
3. Build a systems biology model for LPS-driven inflammatory responses.
Study design
This is a double-blind saline-controlled, single LPS dose study in healthy male
volunteers. 2 doses of LPS will be investigated with 12 subjects per cohort: 1
ng/kg in cohort 1 and, depending on results of the first cohort, 0.5 or 2
ng/kg LPS administration in the second cohort. Within each cohort, 11 of the 12
subjects will follow the following sequence; study day 1: no administration
(baseline measurements), study day 2 saline administration, study day 3: LPS
administration. Per cohort, one subject will follow the following sequence;
study day 1: no administration (baseline measurements), study day 2: LPS
administration, study day 3 saline administration. This way, both the subject
and the researcher are blinded for treatment allocation.
Study burden and risks
No medical benefit can be expected from this study for the participating
subjects.Intravenous administration of LPS can lead to influenza-like symptoms
(e.g. chills, headache, eye sensitivity to light, nausea, myalgia and
arthralgia), increase in core temperature and pulse rate, and decline in mean
arterial pressure. Most symptoms are dose-related and resolve within 2-6 hours.
As with any study involving administration of exogenous substance, rare side
effects cannot be excluded beforehand. Reports of a decrease in cardiac
contractility have been made following administration of 4 ng/kg bodyweight,
but were temporary and were resolved after 8 to 12 hours. Noteworthy, CHDR has
extensive experience with both in vivo and ex vivo LPS challenges and will not
administer a LPS dosage of more than 2 ng/kg to subjects, thereby minimizing
the chance of stated adverse events ever happening. However, the proposed study
may be able to validate the combined application of CHDR*s in vivo LPS
challenge and PainCart, which could serve as a novel model to study an IMP's
potential to treat inflammatory hyperalgesia.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
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.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL65264.056.18 |