Assess amyloid beta clearance from CSF to serum in response to HFCWO in healthy volunteers:- Change from baseline in amyloid beta 40 (ng/ml) in CSFAssess endogenous protein biomarker clearance from CSF to serum in response to HFCWO in healthy…
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Brief title
Condition
- Other condition
Synonym
Health condition
Method Development
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Change in neurofilament light chain
• Change in amyloid beta
• Change in tau
• Change in total amount of neural derived exosomes.
Secondary outcome
n.a.
Background summary
Cerebrospinal fluid (CSF) outflow from the central nervous system (CNS)
compartment has been a topic of interest for a long time due to its critical
role in CNS homeostasis. Pathways of CSF clearance to the peripheral
circulation have been studied extensively but have not yet been fully
elucidated. Currently, the strongest evidence points to clearance via
perineural outflow pathways along nerve sheaths, across arachnoid villi,
through dural lymphatics and possibly by re-entry into the CNS parenchyma via
the glymphatic system . The majority of work on perineural outflow pathways
have found that both the olfactory nerve and the optic nerve may be large sites
of CSF clearance. However, few studies have focused on peripheral CSF outflow
pathways (PCOPs) along the brain stem and spinal cord, where perineural
pathways are also thought to exist along multiple cranial and spinal nerves.
Differential outflow pathways mediate clearance of distinct CSF molecular
classes as in vivo evidence found that there were size-dependent differences in
the rate of molecular outflow from CSF.
CSF functions in part to remove several toxic metabolites and proteins from the
CNS parenchyma. Accumulation of such toxic metabolites is believed to play a
role in various neurodegenerative diseases. CSF measurement of various toxic
molecules as disease biomarkers is in fact commonplace in clinical diagnosis. A
recently resurgent hypothesis suggests that Aβ accumulation seen in Alzheimer*s
Disease (AD) may not only be due to increased production of Aβ but that reduced
clearance of CSF from the CNS may also be an important factor. The rate of
clearance of Aβ has indeed been shown to be significantly lower in AD patients
compared to the healthy population. Similarly, previous research also found
altered CSF dynamics in amyotrophic lateral sclerosis patients. Furthermore,
aging was also found to be associated with reduced clearance rates of CSF in
humans and this may significantly contribute to the age-related reduction of
CNS Aβ clearance rates. Surprisingly, it was recently demonstrated that
clearance of CSF proteins, like Aβ, could be increased through exercise in
mouse models of AD. These studies also showed that exercise improved overall
cognition in these mouse models. This supports observations of improved
cognitive function in AD patients following intervention with exercise
programs. Physical exercise is known to have a significant protective role in
neurodegeneration, but the exact mechanism underlying this is unclear. Physical
exercise markedly stimulates cardiac and ventilatory function, both of which
are known to promote oscillatory movements of the CSF given the proximity of
the heart and lungs to the spinal column. This may enhance CSF clearance and
thus provide one mechanism underlying the benefit of exercise in
neurodegeneration. Together these findings hint at an important role for CSF
clearance rates in the pathology of various neurodegenerative diseases and call
for additional research in understanding the impact of exercise on this process.
Understanding mechanisms affecting perineural outflow of CSF constituents is
also critical for optimizing intrathecal (IT) drug administration. Previous
research has found significant inter-individual variability in CSF
concentrations after IT drug administration. Moreover, only a small amount of
IT administered drug may reach CNS parts most distant from site of
administration. Several factors may impact the variability in CSF drug
concentrations between individuals following IT dosing, including dosing
procedures as well as the size and molecular nature of the drug compound
administered. This is supported by rodent studies, where CSF half-lives of
various IT dosed compounds differed greatly. Neuraxial spread from the
administration site is required for IT dosed drugs to reach their CNS targets.
Peripheral perineural outflow may be a significant factor in clearing drugs
from CSF and could thus reduce neuraxial spread and IT drug delivery to CNS
target sites. Therefore, a better understanding of CSF molecular clearance via
perineural outflow paths may improve IT modelling and help to optimize IT
dosing.
This study attempts to contribute to the understanding of CSF clearance through
the PCOP by employing high-frequency chest wall oscillation (HFCWO) to mimic
the effects of exercise on CSF clearance. HFCWO is commonly used to enhance
ventilation and airway clearance in many diseases. A recent study has shown
that CSF molecular clearance can be modulated by HFCWO. This study aims to
investigate this by direct quantification of endogenous CSF proteins before and
after HFCWO.
Study objective
Assess amyloid beta clearance from CSF to serum in response to HFCWO in healthy
volunteers:
- Change from baseline in amyloid beta 40 (ng/ml) in CSF
Assess endogenous protein biomarker clearance from CSF to serum in response to
HFCWO in healthy volunteers
- Change from baseline in neurofilament light chain (pg/ml) in serum
- Change from baseline in neurofilament light chain (pg/ml) in CSF
- Change from baseline in amyloid beta 40 (ng/ml) in serum
- Change from baseline in amyloid beta 42/40 (ng/ml) in serum
- Change from baseline in amyloid beta 42/40 (ng/ml) in CSF
- Change from baseline in total-tau (pg/ml) in serum
- Change from baseline in total-tau (pg/ml) in CSF
- Change from baseline in total neuronal derived exosomes in CSF
- Change from baseline in total neuronal derived exosomes in serum
Study design
This study will investigate the impact of HFCWO on CSF protein biomarker
clearance. The participant population will consist of 34 healthy volunteers.
Participants will be randomized to receive the HFCWO intervention or no
intervention in a 1:1 ratio (HFCWO to no HFCWO). They will be admitted on day
-1 to the study clinic for safety measurements, blood draws and lumbar puncture
for baseline CSF measurement. On Day 1, HFCWO will be applied for 30 minutes at
0, 60, 120, 210, 300 and 420 minutes with blood drawing performed directly
after this application. After the final HFCWO session (at 420 minutes) a second
lumbar puncture and safety assessments will be performed. Physical examinations
and vital signs will be collected regularly during Day 1. A final follow-up
safety visit is planned on Day 8.
This design allows us to determine CSF clearance from the CNS and the
identification of the effect of biomechanical modulation on the peripheral
cerebrospinal fluid outflow pathway in healthy subjects. This will enable us to
better interpret results from future trials with intrathecally administered
study medication.
Intervention
Participants will be randomized to receive the intervention to no intervention
in a 1:1 ratio (HFCWO to no HFCWO).
Study burden and risks
The risks of venepuncture and lumbar puncture are well known, and will be done
by experienced medical personnel following current safety and hygiene
guidelines, thereby minimizing risk of the aforementioned possible adverse
effects. The risks of HFCWO are minimal.
The frequency of lumbar punctures being performed in the current study is
limited to the minimum amount necessary, which further minimizes risks.
Additionally, all possible adverse effects are well monitorable and well
manageable.
Taking the risk, the minimization thereof and the scientific benefits of the
study in consideration, it is deemed acceptable to perform the procedures as
described in the protocol.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure
2. Healthy male or female subjects, 18 to 50 years of age, inclusive at
screening.
3. Body mass index (BMI) between 18 and 30 kg/m2, inclusive at screening, and
with a minimum weight of 50 kg.
4. All women of childbearing potential must practice effective contraception
during the study.
5. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis). In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects.
3. History of malignancy not deemed cured by their treating physician.
4. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab),
or human immunodeficiency virus antibody (HIV Ab) at screening.
5. 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.
6. Abnormal findings in the resting ECG at screening defined as:
a. QTcF> 450 or < 300 msec for men and QTcF> 470 or < 300 msec for women
b. Notable resting bradycardia (HR < 40 bpm ) or tachycardia (HR > 100 bpm)
c. Personal or family history of congenital long QT syndrome or sudden death;
d. ECG with QRS and/or T wave judged to be unfavourable for a consistently
accurate QT measurement (e.g., neuromuscular artefact that cannot be readily
eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T-
and U-waves, prominent U waves);
e. Evidence of atrial fibrillation, atrial flutter, complete branch block,
Wolf-Parkinson-White Syndrome, or cardiac pacemaker
7. Participation in an investigational drug or device study (last dosing of
previous study was within 90 days prior to first dosing of this study)
8. History of abuse of addictive substances (alcohol, illegal substances) or
current use of more than 21 units alcohol per week, drug abuse, or regular user
of sedatives, hypnotics, tranquillisers, or any other addictive agent
9. Positive test for drugs of abuse at screening. A retest may be performed at
the discretion of the investigator.
10. Alcohol will not be allowed from at least 24 hours before each visit,
including screening and follow-up
11. Smoker of more than 10 cigarettes per day prior to screening or who use
tobacco products equivalent to more than 10 cigarettes per day and unable to
abstain from smoking whilst in the unit.
12. Is demonstrating excess in caffeine consumption (more than eight cups of
coffee or equivalent per day)
13. Loss or donation of blood over 500 mL within three months (males) or four
months (females) prior to screening or intention to donate blood or blood
products during the study.
14. If a woman, pregnant, or breast-feeding, or planning to become pregnant
during the study.
15. For CSF sampling, any of the criteria below:
a. History of clinically significant hypersensitivity to local anesthetics that
may be used for LP (e.g., lidocaine).
b. Criteria that would preclude an LP, such as a local infection at the site of
the LP, <100 × 103/µl platelet count at screening or clinically significant
coagulation abnormality or significant active bleeding, or treatment with an
anticoagulant or treatment with more than two antiplatelet agents.
c. History of clinically significant back pathology and/or back injury (e.g.,
degenerative disease, spinal deformity, or spinal surgery) that may predispose
to complications or technical difficulty with LP.
16. Allergic to iodine.
17. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or psychiatric disease.
18. Positive screening cultures for Multidrug resistant bacteria (BRMO) and/or
Methicillin resistant staphylococcus aureus (MRSA) or no consent to perform
BRMO and MRSA culture in case of increased risk for colonization with these
bacteria.
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 | NL82938.056.22 |