The Personalized Parkinson Project - de novo cohort

Parkinson's disease (PD) is the second most prevalent degenerative brain
disease. Our understanding of the basic pathology, etiology, and progression of
PD has stagnated, partly due to the limited patient diversity captured in study
cohorts. Additionally, we lack sufficient biological insight into the
underlying etiologies and pathophysiological mechanisms to develop new
interventions that can slow down or arrest dìsease-progression. As a result,
patients do not receive the best care they deserve, leading to unnecessary
disability, and to mounting costs for society.

This PPP NOVO cohort aims to validate novel digital biomarkers for disease
progression, fostering the unique research infrastructure and data collection
protocol that are available. The PPP NOVO cohort consists of patients with de
novo (i.e., newly diagnosed and previously untreated) Parkinson*s disease who
will be followed longitudinally for two years. De novo patients create the
opportunity to study disease progression without interference of
pharmacological treatment. The observation of this natural process in the
earliest course of the disease is highly relevant for the development disease
modifying interventions, which are likely to have the biggest potential in the
earliest phases of the disease, when the loss of substantia nigra cells is
minimal. In particular, we will deploy the PPP NOVO cohort for the development
of digital biomarkers that could serve as a surrogate or, with time, possibly
as key secondary or even a primary outcome in future clinical trials of
disease-modifying interventions. Digital biomarkers hold great promise in this
regard, as they provide a means to objectively track patients and measure their
function in their own living environment, unobtrusively, and over long periods
of time. The outcomes are potentially more sensitive than currently available
clinical scales, which also be included in the protocol and perhaps also more
relevant as they provide an insight into daily life functioning over extended
periods of time.

The first objective is to validate novel digital biomarkers for disease
progression in de novo Parkinson*s disease patients. The biomarkers can
eventually serve as a primary clinical endpoint in additional future clinical
studies. As part of this present proposal, we will longitudinally collect
wearable sensor data using the Verily Study Watch from a large cohort of de
novo Parkinson patients. Our hypothesis is that digital progression biomarkers
will have greater sensitivity and greater power for detecting disease
progression than conventional scales. For the MDS-UPDRS, which is such a
conventional scale and often used as the primary endpoint in clinical trials in
PD, we recently demonstrated its inability to track individual disease
progression (Evers et al, 2019a). We will collect multi-dimensional data,
including digital data from the Verily Study Watch, to track the progression of
the earliest phase of Parkinson*s disease. Specific outcomes will focus on
tracking the progression of bradykinesia, gait impairment, postural sway,
tremor, physical activity, sleep quality, and autonomic dysfunction. Data will
consist of both the unstructured passive monitoring, as well as the
intermittent scheduled active tasks that patients will complete at home. As the
data analysis is heavily relying on a machine/deep learning approach, the
digital signatures collected in the PPP NOVO cohort will instruct the analysis
of the POC data, both as a standalone analysis (by potentially identifying
novel digital signatures and validating findings from the POC). Moreover the
PPP NOVO data will serve as a training data set to improve the yield of the
machine learning procedures applied to the POC data.

Testing the feasibility of the study protocol is defined as the second
objective of this study. The PPP NOVO cohort is considered instrumental in
optimizing planning, data acquisition, analysis and interpretation of the
digital data collected in the POC. To this aim, the entry criteria, as well as
all data collection routines, clinical protocols and the technical
infrastructure of the PPP NOVO cohort accurately mirror the planned POC study.
Thereby, we will collect critical information on potential handling and
analysis issues before actually engaging in an interventional study. This will
ultimately de-risk the overall endeavor, both in terms as investments as well
as in terms of strategic decisions. Observations on patient experience,
technical handling, support and adherence in the PPP NOVO cohort will be
critical to anticipate and counteract potential issues in the POC study and
thereby increase the chance of success.

The third objective of this study is to create an extensive longitudinal
dataset describing the clinical and functional characteristics of a
representative Parkinson*s disease de novo cohort to allow researchers to
investigate important unanswered questions in PD.

Prospective, longitudinal, single-center cohort study.

Nature and extent of the burden to patients
Participants are invited to come to the study site in Nijmegen for a full (up
to 1.0) day of data collection three times during the 2-year study duration. If
needed, they can come to Nijmegen one day ahead of the day they have their
appointment at the study site. All study assessments are routine exams done in
standard clinical practice and are generally well tolerated. The Verily Study
Watch will be worn daily for up to 23 hours. This small, unobtrusive electronic
device is easily applied and poses no significant safety issues. Data
collection does not require patient intervention, and data transfer does not
require connection to a mobile phone or computer. The Study Watch requires
minimum care (daily charge and sync, remove when near water). Furthermore,
participants will be asked to fill in a questionaire which can take up to 100
minutes. However, the questionaire can be saved during and participants get 4
weeks to complete the entire questionaire. Participants will be asked to
perform once a week two sets of eight motor tasks with the Study Watch.

Risks
There are limited risks for the patients during the data collection. The
diagnostic measurements (12-lead ECG and Holter ECG) are standard non-invasive
tests that are routinely performed in clinical practice.
Tests that may lead to discomfort / risk are the following:
. Local hematoma can occur related to the venipuncture for blood collection.
. The Verily Study Watch is a low risk non-invasive device (class lla) used as
an adjunct tool and not to guide diagnosis
or therapy, therefore it does not pose significant risks.

Benefits
Because data collection is not performed for immediate diagnostic or
therapeutic purposes, there will be no direct
benefits for the subjects enrolled in this study. As a service in return for
their efforts for research, participants will be
offered an educational program (voluntarily) on Parkinson's disease and how to
handle the disease in daily life.
Moreover, patients will indirectly benefit from the study, as their data
contribute to gain novel etiological insights for
improvement of existing treatments, development of new therapeutic approaches,
and more precise and personalized
disease management. This will provide future benefit for all patients affected
by the disease.

The Study Watch supplements and enhances the information available to the
physician, providing continuous
measurement and quantitative (rather than subjective) data. The device detects
important physiologic parameters that
are expected to change with disease conditions or behavioral patterns (e.9.,
electrodermal activity [EDA], physical
movement of the body in three dimensions [acceleration], skin temperature,
heart rhythm). As such, by wearing the
Study Watch, patients are providing unprecedented insight into the evolution of
PD and potentially allowing to identify
better ways to treat the disease. ln addition to collecting data, the device
also functions as a wristwatch.