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…
ID
Source
Brief title
Condition
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
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
Background summary
Excessive activation of the central nervous system (CNS) inflammatory response
has been implicated in a wide range of neurological diseases, including
multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer*s disease (AD) and
amyotrophic lateral sclerosis (ALS). In these diseases, dysregulation of
peripheral, systemic and central inflammatory cytokine signalling leads to
vascular dysfunction and chronic activation of microglial cells with subsequent
neuroinflammation and loss of neuronal function. The increasing evidence for
the involvement of neuroinflammation in CNS diseases has resulted in the
development of a broad range of investigational products targeting
neuroinflammation. A well characterized, in vivo microglial
activation/neuroinflammation model would be beneficial for the early clinical
evaluation of pharmacological activity of these novel compounds, but currently
isn*t readily available.
Lipopolysaccharide (LPS) is a large molecule found on the outer membrane of
Gram-negative bacteria. It activates the transmembrane receptor toll-like
receptor 4 (TLR4), leading to the activation of the central transcription
factor nuclear factor-kB and secretion of pro-inflammatory cytokines such as
Tumor necrosis factor (TNF), interferon gamma (IFN)-*, IFN-α, interleukin
(IL)-6, IL-1b, IL-8, IL-17, and IL-23. Systemic administration of LPS has also
been associated with activation of the complement system, which when
hyperactivated, may also contribute to the pathophysiology of CNS diseases. At
CHDR, administering intravenous (IV) LPS as a challenge agent is an established
model to induce a systemic inflammatory response in a controlled manner.
However, IV LPS has also been used by other researchers to induce microglia
activation, which was assessed by positron emission tomography (PET) 18 kDa
translocator protein (TSPO) brain imaging. Consequently, IV LPS could be
potential challenge agent for establishing a neuroinflammation model.
While PET-TSPO imaging has been used to assess microglial activation following
IV LPS administration, the use of blood and cerebrospinal fluid (CSF) biomarker
measurements could offer complementary and potentially more detailed insights
into the inflammatory process. However, no studies have systematically examined
neuroinflammatory biomarkers in CSF following IV LPS administration, resulting
in a knowledge gap regarding the optimal timing of CSF sampling and which
biomarkers to measure. Addressing this gap is essential for advancing our
understanding of neuroinflammation and refining this potential in vivo
neuroinflammation model for future phase 1 studies, particularly those
evaluating novel compounds targeting neuroinflammation.
In this study, we aim to explore the potential of IV LPS as a model for
neuroinflammation, by characterizing both the central and peripheral
inflammatory response by analysis of inflammatory markers in CSF and in blood.
Furthermore, we aim to evaluate complement protein activation. Additionally, an
exploratory objective of this study is to assess the blood-brain-barrier
permeability following LPS administration, with the goal of elucidating the
intricate relationship between BBB disruption, systemic inflammation and
neuroinflammation.
Study objective
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
Secondary objectives:
• To evaluate complement activation after IV LPS administration.
• To evaluate if lumbar punctures cause an inflammatory response
Study design
This will be a double-blind, randomized, saline-controlled, exploratory study.
It is a single-center, inflammatory challenge study, to evaluate
neuroinflammation measured in blood and CSF after IV LPS administration in 27
healthy male volunteers. In this study healthy male volunteers (in 3 subgroups)
will receive 1.0 ng/kg IV LPS as a challenge agent or saline (6:3) and CSF
sampling (1 baseline and 2 post-LPS administration) and blood collection will
be performed for the detection of central as well as systemic inflammation.
Study burden and risks
Burden
The burden of the participants is described in the Study Assessments
• Safety and tolerability assessments, including vital signs, weight and
height, physical examination, electrocardiography, collection of blood samples
• Pharmacodynamic assessments, including blood (328.9 mL via an i.v. catheter
placed in an antecubital vein in the arm, the indwelling catheter will be kept
patent by saline flush after each blood sampling), and CSF (22.5 mL) via lumbar
puncture.
Benefit
No medical benefit can be expected from this study for the participating
subjects.
Risk assessment
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 in vivo LPS challenges and in this study, we will not
administer a LPS dosage of more than 1 ng/kg to subjects, thereby minimizing
the chance of stated adverse events ever happening.
For this study, it was concluded that a spinal catheter would be too burdensome
for the participants. Previous experience at CHDR has shown significantly more
AEs compared to lumbar punctures. The maximum amount of lumbar punctures per
participant was set at three per participant to get enough data to answer the
research questions, but to limit the burden as much as possible.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
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
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 abuse.
20. Participation in an investigational drug, device or biomarker study, more
than four times per year, and last dosing of previous study was within 30 days,
or 5 half-lives (whichever is longest) prior to first LPS dosing of this study.
21. Loss or donation of blood over 500 mL within three months (males) prior to
screening or intention to donate blood or blood products during the study.
22. Plasma donation within 14 days prior to screening.
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 |
|---|---|
| CCMO | NL87910.056.24 |