Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05008094 |
| Other study ID # |
IP-2019-04-7276 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2020 |
| Est. completion date |
February 1, 2024 |
Study information
| Verified date |
August 2021 |
| Source |
Clinical Hospital Center Rijeka |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Parkinson's disease (PD) is the second most common neurodegenerative disease, which affects
2-3% of the general population above 65 years. There are significant differences in incidence
depending on geographical location, race, and ethnicity. The exact cause of the disease is
still unknown, but the role of genetic and environmental factors has already been
established. Certain genetic forms of the disease make up for a small percentage, so it is
thought that environmental factors have a more significant impact on the development of the
disease. The incidence of PD is higher in people exposed to significant quantities of
pesticides and traumatic brain injury, while there is a smaller incidence in smokers and
people consuming more significant quantities of caffeine. The project will finish in four
years, with the first 20 months dedicated to the first phase (genetic-epidemiological
research), and the entirety of the 48 months for the second phase of the project (prospective
clinical research).
The main goal of the first phase of the project is to determine which genetic mutations are
the ones most represented in the Croatian population afflicted with the familial form of PD.
In the second phase the main goal is to determine the influence of genetic factors and
microbiological factors on the disease's progression as well as on the treatment outcomes.
Specific goals of this part of the project are to determine how many patients in the general
population of PD patients present with a genetic disorder and which genes have a role in that
disorder, as well as determine the composition of intestinal and oral microbiota both in the
patient test group and the healthy control group. Furthermore, specific goals are to evaluate
the effects of standard PD treatment on the composition of microbiota, neurodegeneration
progression and the activity of neuroinflammation in the central nervous system (CNS) and to
examine whether there is a link between the physiological and the pathophysiological function
of microbiota, using markers of disease progression and glial activity. Last specific goal is
to analyze potential pathological conformation protein forms that could be used as a
biomarker in early stages of the disease and a biomarker of disease progression.
The first phase of the study will provide the first epidemiologic data on the familial form
of PD, as well as the mutations most represented in patients with PD in Croatia.
Additionally, the prospective clinical study will contribute to enlightening the intertwined
effects of genetic and environmental factors in the emergence and progression of the disease,
as well as their effect on treatment outcome. Intestinal and oral microbiota composition
analysis will determine whether there is a difference between PD and the healthy population
while using the short-chain fatty acid profile will determine the metabolic differences
between the two groups. Analyzing the markers of CNS homeostasis, inflammation, and
neuroglial function will determine the progression of the disease and also correlate them to
genetic factors as well as the microbiota function and composition. Analyzing the
pathological conformation forms of alpha-synuclein could lead to the discovery of novel
biomarkers in the early stages of the disease, as well as to follow the progression of the
disease
Description:
Parkinson's disease (PD) is the second most common neurodegenerative disease, which affects
2-3% of the general population above 65 years. There are significant differences in incidence
depending on geographical location, race, and ethnicity. The exact cause of the disease is
still unknown, but the role of genetic and environmental factors has already been
established. Certain genetic forms of the disease make up for a small percentage, so it is
thought that environmental factors have a more significant impact on the development of the
disease. The incidence of PD is higher in people exposed to significant quantities of
pesticides and traumatic brain injury, while there is a smaller incidence in smokers and
people consuming more significant quantities of caffeine.
Moreover, intestinal and oral microbiota is regarded as a significant factor in the
pathogenesis of the disease, due to the discovered floral imbalance in people suffering from
PD. At this point, it is unknown whether the dysbiosis of the intestinal microbiota precedes
the disease or it is the result of the disturbed neuronal communication of the liver-brain
axis. Since there has not been a proper epidemiological study conducted in Croatia so far,
there is no knowledge of the number of cases of PD linked with genetic and environmental
factors, doing this project that more scientifically and socially impactful.
A specific pathophysiological event in PD is the loss of neurons in the substantia nigra,
along with the accumulation of the intracellular protein α-synuclein in the entire central
nervous system. It is important to note that PD is asymptomatic for an extended period since
the symptoms start manifesting only when there is a loss of more than 70-80% of dopaminergic
neurons. Dysfunction of glial cells, cells that are usually in charge of keeping homeostatic
conditions in the central nervous system accompanies PD. The dysfunction leads to
neuroinflammation and microglial activation, phagocytosis and the destruction of neurons. On
the other hand, there is a lack of a proper nutritive and reparative reaction from
astrocytes, glial cells involved in neuroprotection and injury repair in the CNS.
Unfortunately, there is still no specific biomarker known for PD, however alterations of
neurodegenerative, nutritive, and immunological markers in these disorders enable
experimental monitoring of disease progression. Recent research proposed a link between
intestinal microflora and glial cells in physiological conditions, but also in the
pathogenesis of various neurodegenerative disorders. It is currently thought that the first
pathophysiological changes, occur inside the intestinal nervous system, which is in direct
contact with the intestinal microflora. This way the intestinal microbiota could modulate the
pathogenesis of PD and contribute to the interindividual variability of the clinical
presentation. Even though a small number of studies did focus on this part of the
pathogenesis of the disease, the real effect of the intestinal and oral microflora dysbiosis
on the pathogenesis of PD is not established. Also, there have been no studies which explore
the relationship between genetic and environmental factors, making prospective studies with
de novo PD patients necessary in shedding light on the mean effects of the dysbiosis on the
disease progression and treatment outcome.
The project will finish in four years, with the first 20 months dedicated to the first phase
(genetic-epidemiological research), and the entirety of the 48 months for the second phase of
the project (prospective clinical research) Participants: The research group in the first
phase of the research includes patients with PD throughout the Republic of Croatia. The
population would include all the available afflicted currently residing in Croatia, which are
members or work with the Croatian PD patient's association. The estimated response is 10% of
the PD population (500-750 patients) The patients will fill the epidemiologic questionnaires
and patients with familial PD will be selected. The expected emergence of the hereditary form
of the disease in the PD population is around 10-15% (50-75). The second phase of the
research (prospective clinical trial) includes two subject groups. The first will be made up
from patients from the Clinical Hospital Centers in Rijeka, which have not been actively
treated yet (drug-naive), while the second will consist of healthy controls in the same age
range. The target number of subjects in both of these two groups is 50. Inclusion criteria
for participation of drug-naïve patients is a confirmed PD diagnosis according to the
Movement Disorder Society Clinical Diagnostic criteria. The healthy control group will
consist of participants from the same age group with the same nutritional status (body mass
index), as well as living in the same geographical area as the test group. Exclusion criteria
for participation include unique diet plans, chronic bowel disease, any autoimmune disorder,
acute infectious diseases, acute active inflammation, patient history positive for
significant gastrointestinal surgical procedures and an active antibiotic, probiotic,
nutritive supplement, corticosteroid, and immunosuppressive drugs.
The first phase - genetic-epidemiological study (20 months): In the first nine months,
throughout Croatia, participants who are members or work with the Croatian PD patient's
association will be recruited. At the end of the first year of the research, the participants
will have their whole exomes sequenced with the help of next-generation sequencing (NGS), to
find genetic variants in Croatian patients. Through the second year of research, result
analysis and dissemination are planned, as well as counseling in participants with a
confirmed familial variant of the disease. For this purpose, the participants will give blood
samples for genetic analysis. The target number of subjects in this phase of the research is
50. The participants will also be asked to fill out several structured study forms, which
should provide an estimation of the genetic background of the participant, along with
information on their biorhythm, sleep patterns, diet, life goals, and general stress.
The second phase - a prospective clinical study (48 months): Participant selection will be
conducted throughout the first year of the clinical study. The following time intervals are
selected for control visits: baseline; 6 months, 12 months, 24 months and 30 months. The
result analysis and dissemination are planned in the last two years of research. Every
participant in the study will have their exome sequenced with NGS, with the focus mostly
being on parts that have a known impact on the pathogenesis of PD. Both the patients and
healthy control population will also have their microbiota composition determined with NGS,
as well as their functional state through the analysis of the short-chain fatty acid
composition, known metabolic products of the microbiota. ELISA (Enzyme-Linked Immunosorbent
Assay) will be used to assess the inflammatory state, glial functions, and disease
progression will also be determined through specific markers in the participant's serum and
plasma samples. Fluorescent correlation spectroscopy (FCS), more specifically, Thioflavin T
(ThT) fluctuating intensity fluorescent analysis (FIFA) will be used to determine the
existence of pathological conformation protein forms and their relation to the disease's
grade and therapy. It is for these methods that the participants will be asked to give a
blood, stool, and saliva sample. The disease progression will also be monitored with
transcranial B-mod sonography and magnetic brain resonance.
The exome sequencing will be conducted at baseline, while the analysis of the composition and
function of microbiota will be performed on the first and last control visit. Biomarker
analysis, protein conformation analysis and neuro-radiological methods will be conducted at
every control examination. From the first visit, the participants will be asked to fill out
several structured study questionnaires, which will provide an estimation of the genetic
background of the participant, along with information on their biorhythm, sleep patterns,
diet, life goals, and general stress. Moreover, the cognitive state of the participants will
be evaluated through validated tests like the Mini-Mental State Examination (MMSE) and the
Montreal Cognitive Assessment (MoCA), while the general non-motoric symptoms will be
evaluated with the help of the Non-Motor Symptoms Questionnaire (NMSQ) and the Non-Motor
Symptoms Scale (NMSS). Patients will also be evaluated with the help of the UPDRS (Unified
Parkinson's disease rating scale), the most prominently scale in PD.
The main goal of the first phase of the project is to determine which genetic mutations are
the ones most represented in the Croatian population afflicted with the familial form of PD.
In the second phase the main goal is to determine the influence of genetic factors and
microbiological factors on the disease's progression as well as on the treatment outcomes.
Specific goals of this part of the project are to determine how many patients in the general
population of PD patients present with a genetic disorder and which genes have a role in that
disorder, as well as determine the composition of intestinal and oral microbiota both in the
patient test group and the healthy control group. Furthermore, specific goals are to evaluate
the effects of standard PD treatment on the composition of microbiota, neurodegeneration
progression and the activity of neuroinflammation in the CNS and to examine whether there is
a link between the physiological and the pathophysiological function of microbiota, using
markers of disease progression and glial activity. Last specific goal is to analyze potential
pathological conformation protein forms that could be used as a biomarker in early stages of
the disease and a biomarker of disease progression.
The first phase of the study will provide the first epidemiologic data on the familial form
of PD, as well as the mutations most represented in patients with PD in Croatia.
Additionally, the prospective clinical study will contribute to enlightening the intertwined
effects of genetic and environmental factors in the emergence and progression of the disease,
as well as their effect on treatment outcome. Intestinal and oral microbiota composition
analysis will determine whether there is a difference between PD and the healthy population
while using the short-chain fatty acid profile will determine the metabolic differences
between the two groups. Analyzing the markers of CNS homeostasis, inflammation, and
neuroglial function will determine the progression of the disease and also correlate them to
genetic factors as well as the microbiota function and composition. Analyzing the
pathological conformation forms of alpha-synuclein could lead to the discovery of novel
biomarkers in the early stages of the disease, as well as to follow the progression of the
disease
