Computational Modeling of 60 Hz Subthalamic Nucleus Deep Brain Stimulation for Gait Disorder in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Northwell Health

NCT04184791 
Computational Modeling of 60 Hz Subthalamic 
Nucleus Deep Brain Stimulation for Gait Disorder in 
Parkinson's Disease 
Protocol 
12Aug2021 

 
Computational Modeling of 60 Hz Subthalamic Nucleus Deep 
Brain Stimulation for Gait Disorder in Parkinson’s disease 
Protocol Number: 19-0217 
National Clinical Trial (NCT) Identified Number:  04184791 
Principal Investigator: Ritesh Ramdhani, MD 
Funded by: NIH National Institute of Neurological Disorders and Stroke 
Version Number:  v.1.9 
12 Aug 2021  
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
5.2 
Removal of non-English speaking exclusion 
criterion 
Study can successfully be carried out with 
proper translation in place 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 9 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ........................................................................................................................................... 11 
4.1 
Overall Design .................................................................................................................................... 11 
4.2 
Scientific Rationale for Study Design and justification for dose .................................................. 13 
4.3 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 14 
5.1 
Inclusion Criteria ................................................................................................................................ 14 
5.2 
Exclusion Criteria ............................................................................................................................... 14 
5.3 
Screen Failures .................................................................................................................................. 14 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................................ 15 
6.1 
Study Intervention(s) Administration ............................................................................................... 15 
6.1.1 
Study Intervention Description ..................................................................................... 15 
6.1.2 
Dosing and Administration ............................................................................................ 16 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 17 
6.2.1 
Acquisition and accountability ...................................................................................... 17 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 17 
6.2.3 
Product Storage and Stability ....................................................................................... 17 
6.2.4 
Preparation ...................................................................................................................... 17 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 17 
6.4 
Study Intervention Compliance ........................................................................................................ 18 
6.5 
Concomitant Therapy ........................................................................................................................ 18 
6.5.1 
Rescue Medicine ............................................................................................................ 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 19 
8.1 
Efficacy Assessments ....................................................................................................................... 19 
8.2 
Safety and Other Assessments ....................................................................................................... 21 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 22 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 

  
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8.3.3 
Classification of an Adverse Event .............................................................................. 22 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 23 
8.3.5 
Adverse Event Reporting .............................................................................................. 23 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 23 
8.3.7 
Reporting Events to Participants ................................................................................. 24 
8.3.8 
Events of Special Interest ............................................................................................. 24 
8.4 
Unanticipated Problems .................................................................................................................... 24 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 24 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 24 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
9.1 
Statistical Hypotheses ....................................................................................................................... 25 
9.2 
Sample Size Determination .............................................................................................................. 25 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 27 
9.4.1 
General Approach .......................................................................................................... 27 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 29 
9.4.4 
Safety Analyses .............................................................................................................. 29 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 29 
9.4.6 
Planned Interim Analyses ............................................................................................. 29 
9.4.7 
Sub-Group Analyses ..................................................................................................... 29 
9.4.8 
Tabulation of Individual participant Data .................................................................... 29 
9.4.9 
Exploratory Analyses ..................................................................................................... 29 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 29 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 29 
10.1.1 
Informed Consent Process ........................................................................................... 29 
10.1.2 
Study Discontinuation and Closure ............................................................................. 30 
10.1.3 
Confidentiality and Privacy ........................................................................................... 30 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.5 
Key Roles and Study Governance .............................................................................. 31 
10.1.6 
Safety Oversight ............................................................................................................. 32 
10.1.7 
Clinical Monitoring .......................................................................................................... 32 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 32 
10.1.9 
Data Handling and Record Keeping ............................................................................ 32 
10.1.10 
Protocol Deviations ........................................................................................................ 33 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 34 
10.1.12 
Conflict of Interest Policy .............................................................................................. 34 
10.2 
Additional Considerations ................................................................................................................. 34 
10.3 
Abbreviations ...................................................................................................................................... 36 
10.4 
Protocol Amendment History ........................................................................................................... 38 
11 
REFERENCES ............................................................................................................................................. 40 
 

Computational Modeling of 60Hz STN DBS for Gait Disorder in Parkinson's disease 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 

Computational Modeling of 60Hz STN DBS for Gait Disorder in Parkinson's disease 
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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Computational Modeling of 60 Hz Subthalamic Nucleus Deep Brain 
Stimulation for Gait Disorder in Parkinson’s disease 
Study Description: 
The goal of this research is to further our understanding and application of 
deep brain stimulation in Parkinson’s patients with gait disorder.  
We will assess the degree to which stimulation parameters affect gait 
parameters. We will test the hypothesis that the addition of levodopa in 
combination with stimulation produces a synergistic improvement in 
certain gait domains. In addition, we test the hypothesis that a subject’s 
gait on stimulation can be predicted with statistically significant accuracy 
using gait measurements on high frequency stimulation. Finally, we will 
test the hypothesis that the best stimulation frequency, which yields 
improvement among various gait parameters, can be predicted using 
objective sensor data collected at baseline 
 
 
Objectives: 
 
Aim 1: To determine the impact of 60Hz subthalamic deep brain 
stimulation on gait kinematics using wearable sensors  
o Aim 1.1: To determine whether 60Hz STN-DBS elicits a 
differential response in gait kinematics compared to high 
frequency  
o Aim 1.2: To determine the influence of 60Hz STN-DBS and 
levodopa on gait kinematics  
Aim 2: To develop machine learning models to predict optimal 
subthalamic deep brain stimulation frequency based on wearable 
sensor profiles of baseline Parkinson’s motor symptoms  
o Aim 2.1: To develop machine learning models to predict 
gait response to 60Hz stimulation without additional 
testing  
o Aim 2.2: To develop machine learning models to predict 
best stimulation frequency (60Hz vs. high frequency). 
Endpoints: 
Primary Endpoints:  
Gait parameters: 
 
Postural sway – root mean square (RMS) sway in antero-posterior 
(AP) and medio-lateral (ML) planes;  
 
Gait – cycle duration (seconds), speed (m/s), stance (%), swing (%), 
heel strike angle (degrees), toe off angle (degrees), stride length 
(cm), cadence (steps/min), step duration (seconds), elevation at 
midswing (cm) (foot clearance), double support (%), arm swing 
velocity (deg/s), and range of motion (degrees);  

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 
Circumduction – turn angle (degrees), turn duration (seconds), and 
turn velocity (deg/s). 
Machine learning models to: 1) predict gait kinematics on 60Hz STN-DBS; 
2) predict best stimulation frequency using wearable sensor data collected 
at baseline.  
 
Secondary Endpoints:  
Tremor (rest, kinetic, postural) 
 
Bradykinesia (finger taps, hand grasps, wrist rotation, toe taps and leg lifts) 
MDS-UPDRS III 
 
Study Population: 
We will recruit 30 patients (male and female; ages 21-80) who have 
Parkinson’s disease and who will be undergoing STN-DBS implantation or 
who have chronic bilateral STN-DBS.    
 
Description of 
Sites/Facilities Enrolling 
Participants: 
This study will take place at Northwell Health: North Shore University 
Hospital, Feinstein Institutes for Medical Research, and Physician Partner 
locations.  
Description of Study 
Intervention: 
Assess gait kinematics using wearable sensors in subjects whose STN-DBS 
is changed from low frequency (60 Hz) to high frequency (130-85 Hz) in 
both the medicated and unmedicated states.  
 
Study Duration: 
2 years  
Participant Duration: 
Chronic DBS patients: 1-4 weeks   
Preoperative DBS patients: 12-15weeks  
 
 

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1.2 
SCHEMA 
Overview of the study design: Figure 1: For subjects undergoing STN–DBS implantation, Phase I will be 
preoperative (study visit 1), and Phase II will be 12-15 weeks post initial programming (study visit 2). For chronic 
DBS patients, Phase II will commence during study visit 1. 
 
Figure 2. Overview of Aim 2 and the analysis to be performed. 

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Computational Modeling of 60Hz STN DBS for Gait Disorder in Parkinson's disease 
Version 1.9 
Protocol # 19-0217 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Visit 1 
Visit 21 
Informed consent 
X 
 
Demographics  (age, gender, height, and 
weight and disease duration) 
X 
 
LED2 
X 
 
MMSE 
X 
 
MDS-UPDRS III3 
X 
X 
DBS Adjustments  
 
X 
Bradykinesia Sensor assessment4 
X 
X 
Tremor Sensor assessment5 
X 
X 
Full body Opal Sensors for Gait Assessment 
X 
X 
 
1 For chronic DBS patients, phase II will commence during study visit 1. For preoperative subjects, phase 
II will be conducted on a separate visit (study visit #2) that will take place 12-15 weeks after initial 
programming of bilateral STN deep brain stimulation implantation. If fatigue develops in either cohort, 
the study will be completed at a third visit.  
2 Daily levodopa equivalent dose (LED) will be calculated based on published conversion factors for PD 
medications (41) 
3 Items 3.1, 3.3(a-e), 3.9, 3.11, 3.12, 3.13 
4The following tasks will be performed to assess bradykinesia: finger taps, hand grasps, wrist rotation, 
toe taps and leg lifts. 
5The tremor assessments will be determined from the following tasks: arms resting (resting tremor), 
arms extended (postural tremor), and finger to nose (action tremor). 
 
For chronic DBS patients, evaluation of electrode contact pairs conducted in the off medication state 
(initial step of Phase II) may be completed in conjunction with a scheduled clinical visit when the subject 
is under the clinical care of the PI. This evaluation will be considered SV1 and the remaining study 
procedures will be conducted as part of SV2 and SV3 (if needed). This may alter the SOA and extend the 
study duration, but will have no effect on the goals of the study. SV2 will commence within six months 
as the side effect threshold established during the evaluation is not expected to change during this 
timeframe. SV2 and SV3 (if needed) will be conducted within a 1-4 week period.  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
The goal of this proposal is to further our understanding and application of 60Hz subthalamic deep brain 
stimulation (STN-DBS) in Parkinson’s patients with gait disorder. It is well established that deep brain 
stimulation ameliorates the cardinal symptoms of Parkinson’s disease (PD) (e.g., tremor, bradykinesia, 
and rigidity) along with attenuating levodopa induced motor complications such as dyskinesia and motor 
fluctuations (1-3). It has been the prevailing notion that high frequency stimulation (130-185Hz) is the 
driving force of this clinical benefit; however, gait disorder, including freezing of gait, which may arise 
later in the disease course, can be recalcitrant to both STN-DBS and pharmacological therapy, resulting 

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in a decline in quality of life and increased risk for falls (2, 4-6). Indeed, frequencies <60Hz have been 
thought to worsen akinesia and increase tremor, but this supposition has been challenged, as studies 
have suggested that low frequency STN stimulation (60-80Hz) in chronic DBS patients may alleviate 
freezing and improve gait in chronic DBS patients (7-11). Furthermore, 60Hz STN-DBS has been shown to 
be beneficial in treating gait disorder in patients within the first year of implantation (12). 
 
The nature of 60Hz STN-DBS response has relied on clinical rating scales, which lack continuous, granular 
and objective measurements of gait. Therefore, by using wearable body motion sensors, we seek to 
address the following questions: 1) What specific aspects of gait and balance (e.g., gait speed, stride 
length, circumduction, postural sway) are impacted by 60hz STN-DBS? 2) Is there interplay between 
60Hz STN-DBS, dopaminergic medications, and electrode polarity with respect to changes in gait? 3) Are 
there 60Hz STN-DBS responsive PD subtype(s) and could they be elucidated from sensor based motor 
measurements? 4) Can sensor measurements of baseline motor symptoms be directly used to 
confidently estimate response of STN-DBS patient symptomatology at both high frequency and 60Hz? 
This information could reshape the manner by which Parkinson’s patients are considered for DBS as well 
as managed postoperatively, potentially improving the efficiency and time to clinical optimization. The 
following proposed studies and analyses would strive to fill the aforementioned knowledge gaps 
through two primary aims.  
 
 
Aim 1: To determine the impact of 60Hz subthalamic deep brain stimulation on gait 
kinematics using wearable sensors  
o Aim 1.1: To determine whether 60Hz STN-DBS elicits a differential response in gait 
kinematics compared to high frequency  
o Aim 1.2: To determine the influence of 60Hz STN-DBS and levodopa on gait kinematics  
 
Aim 2: To develop machine learning models to predict optimal subthalamic deep brain 
stimulation frequency based on wearable sensor profiles of baseline Parkinson’s motor 
symptoms  
o Aim 2.1: To develop machine learning models to predict gait response to 60Hz 
stimulation without additional testing  
o Aim 2.2: To develop machine learning models to predict best stimulation frequency 
(60Hz vs. high frequency). 
This study will set the stage for developing a randomized trial that would assess a new paradigm for 
selecting DBS patients for 60Hz stimulation prior to surgery, conducting initial programming and other 
elaborate programming approaches under this stimulation mode, and achieving programming 
optimization using sensors, through a data-driven approach. In addition, the results may indicate that 
certain PD phenotypic subtypes are most suitable for 60Hz DBS.  
 
2.2 
BACKGROUND  
Parkinson’s disease (PD) is characterized by four cardinal motor features, namely, bradykinesia, rigidity, 
rest tremor and postural instability/gait disorder. Some of these cardinal clinical features often 
segregate together so that clinical subtypes of PD have been described, such as “tremor predominant” 
and “postural instability gait disorder” types (13). These subtypes have clinical significance in that they 

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may provide prognostic information (e.g., tremor predominant PD often progresses more slowly over 
time) and likelihood of response to Deep Brain Stimulation (DBS). That is, DBS is an effective therapy for 
PD patients suffering from medication refractory tremor, motor complications and/or troublesome 
dyskinesia (1-3). However, gait disorder including freezing of gait, can be recalcitrant to subthalamic DBS 
(and pharmacological therapy) leading to a decline in quality of life.  
 
The subthalamic nucleus has emerged as one of the preferred anatomic substrates implanted with DBS 
electrodes for PD (14). High frequency stimulation (130-185Hz) of the STN enables reduction in 
dopaminergic medications by an average of 40-60% (15-17). Following implantation, DBS programming 
involves determining appropriate contact configuration, amplitude, pulse width (PW) and frequency in 
order to effectively alleviate the cardinal symptoms. Though there are some conventional principles to 
programming Parkinson’s patients, such as utilizing high frequencies and using shorter PW, the process 
is based largely on trial and error. As a result, programming sessions can be long and tiresome for 
patients while putting a major constraint on physician time. 
 
Gait disorder, which manifests as shuffling, reduction in speed, multistep turning, and/or freezing of gait 
(FOG), can arise later in the disease course and cause significant disability. Ultimately, patients are at 
risk for falls (18) and can become socially isolated due to their mobility limitations. These axial 
symptoms tend not to respond to high frequency STN-DBS (4-6). In fact, high frequency DBS has been 
reported in some instances to worsen gait (19, 20). Several studies have shown the efficacy of lower 
frequency stimulation (60-80Hz) of the STN in treating gait disorder and/or freezing of gait (7-12). The 
sustainability of this benefit is variable and little is known as to which patient will show a clinical 
response. Additionally, the lack of understanding of the interaction between dopaminergic medication 
and low frequency stimulation and the nature of programming the stimulator in 60Hz frequency has 
thwarted widespread use of it. 
 
There has been growing evidence that stimulation frequencies influence motor circuitry via modulation 
of neuronal oscillations. In the unmedicated PD resting state, STN neuronal oscillations in the alpha (8-
12Hz) and beta (13-30Hz) bands are present (21-23). High frequency stimulation reduces the entire beta 
band and decouples synchrony in the cortico-STN hyperdirect pathway (24, 25). These changes have 
been associated with clinical improvement of bradykinesia and rigidity (24, 26-28). Low frequency 
stimulation has been shown to improve limb bradykinesia (29, 30) while being inadequate for 
controlling tremor (31). Underscoring these clinical findings, 60Hz-DBS attenuates the high sub-band 
(19-27Hz) of the beta range while amplifying alpha and low beta sub-bands (11-15Hz) (30, 32). 
Furthermore, there is evidence that patients with FOG have lower beta power and greater beta 
unpredictability in the STN when stepping without freezing compared to non-freezers, suggesting that 
high frequency stimulation suppression of the entire band may risk worsening gait in such patients (33). 
The neurophysiological understanding of the interactions of various neuronal oscillations in the basal 
ganglia and their relationship to axial PD symptoms underscores the idea that frequency modulation 
may differentially influence various motor networks and symptoms (34-37). 
 
Therefore, it is timely to further our understanding of the impact of 60Hz subthalamic deep brain 
stimulation on gait kinematics, both with and without the presence of levodopa (Aim 1). In addition, the 
development of a computational model that implements a data-driven approach for stimulation 
parameter estimates can stand to enhance the manner by which DBS candidates and surgical targets are 
selected, as well as increase the efficiency of achieving programming optimization (Aim 2). 

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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Patients will be withdrawn from their PD medications the night before the study visit(s) in order to be 
assessed in practically defined OFF state. Subjects will experience more of their parkinsonian motor 
symptoms including possible worsening of their gait which could increase their risk of falling. 
When carbidopa/levodopa 25-100 tablet(s) are administered orally, subjects may experience 
lightheadedness, nausea, hypotension, and/or fatigue. 
During the DBS adjustments, transient stimulation induced sensory (e.g., paresthesia) or motor 
symptoms (e.g. muscle contractions or pulling sensations) may occur as amplitudes are incrementally 
raised for each electrode contact during Phase II.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Participants may not benefit from this study, but could derive a sense of well-being from having their 
gait comprehensively assessed. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Potential Benefits: 
 
Expected Outcomes: Aim 1. We would have extensively investigated the impact of 60Hz stimulation on 
several gait spatiotemporal domains (e.g., pace, turning, postural sway) and relate it to other 
stimulation features (e.g., activated electrode contacts, therapeutic amplitudes) using wearable sensors. 
We will also determine the influence that levodopa has on 60Hz stimulation in the context of kinematic 
gait changes. These results can help facilitate the application of this stimulation to certain PD-DBS 
subpopulations. Aim 2. Our results will allow for instantaneous recommendations by artificial 
intelligence on which stimulation frequency is best suitable for a subject based on a priori sensor 
measurements of motor symptoms. The ranking provided can guide clinical evaluations and potentially 
reduce the amount of time needed for programming by changing the “trial and error” paradigm to a 
sensor guided paradigm with either 60Hz or HFS initiated from the outset. 
 
Potential Risks: 
Subjects will be closely monitored following administration of carbidopa/levodopa 25/100mg tablet(s) 
to ensure any side effects are minimized and addressed immediately.  
 
Any stimulation side effect will immediately be alleviated with reduction in DBS amplitude. All 
assessments will be done at amplitudes below the side effect threshold. Furthermore, all sensor 
assessments will be conducted in a control setting with the research coordinator and Principal 
investigator present at all times to minimize risk any risk of falling during the gait assessment.  
 
3 
OBJECTIVES AND ENDPOINTS 
 

Computational Modeling of 60Hz STN DBS for Gait Disorder in Parkinson's disease 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Aim 1: To determine the impact of 60Hz 
subthalamic deep brain stimulation on 
gait kinematics using wearable sensors  
Aim 1.1: To determine whether 60Hz STN-
DBS elicits a differential response in gait 
kinematics compared to high frequency  
 
 
 
 
Aim 1.2: To determine the influence of 
60Hz STN-DBS and levodopa on gait 
kinematics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aim 2: To develop machine learning 
models to predict optimal subthalamic 
deep brain stimulation frequency based 
on wearable sensor profiles of baseline 
Parkinson’s motor symptoms  
 
Aim 2.1: To develop machine learning 
models to predict gait response to 60Hz 
stimulation without additional testing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postural sway – root mean 
square (RMS) sway in antero-
posterior (AP) and medio-lateral 
(ML) planes;  
 
Gait – cycle duration (seconds), 
speed (m/s), stance (%), swing 
(%), heel strike angle (degrees), 
toe off angle (degrees), stride 
length (cm), cadence 
(steps/min), step duration 
(seconds), elevation at midswing 
(cm) (foot clearance), double 
support (%), arm swing velocity 
(deg/s), and range of motion 
(degrees);  
 
Circumduction – turn angle 
(degrees), turn duration 
(seconds), and turn velocity 
(deg/s). 
Acquired from Opal sensors (APDM, 
Opal, and Portland, OR)  
  
 
The goal of this sub-Aim is to predict the 
gait parameters for patients on low 
frequency by using the gait sensor 
measurements obtained on high 
frequency.  
 
We will utilize the raw data collected 
during Phase II to develop regression 
models, under both ON and OFF 
medication states for all contact pairs. 
We will also build models under both ON 
and OFF medications. 
 
 
 
 
 
 
 
 
 
 
 
 
  Based on normative 
spatial-temporal gait 
analysis in healthy young 
and elderly adults (44-
46), we selected the 
following measurements 
to be assessed during this 
instrumented walk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Random Forest (RF)is 
based on an ensemble of 
decision trees, referred to 
as a ‘forest,’ where 
predictions for any new 
observation are obtained 
from averaging the 
predictions of individual 
trees (56). To develop the 
regression models, we 
use non-linear regression 
analysis based on random 
forest (RF) classifier.  
However, to assure that 
the RF based models are 
the best performing 
models, we also develop 
models based on some of 
the other machine 
learning techniques, such 
as neural networks (56), 
and use them as 
benchmarks 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This study will be conducted in two phases: Phase I. The primary goal of Phase I is to establish a baseline 
kinematic profile of subjects in terms of their tremor, bradykinesia, and gait using objective sensor 
measurements. After being consented, participant’s demographic data (age, gender, height, and weight) 
and disease duration (years) will be collected. Daily levodopa equivalent dose (LED) will be calculated 
based on published conversion factors for PD medications (41). Each subject will then be evaluated 
during an in-laboratory session under two conditions: 1) the practically defined OFF state following 
overnight withdrawal of their dopaminergic medications; and 2) levodopa ON State. Participants will be 
given 1.5 times their usual levodopa dose (up to 300mg) to ensure transition to the ON state in-
 
 
Aim 2.2: To develop machine learning 
models to predict best stimulation 
frequency (60Hz vs. high frequency). 
 
In this sub-Aim, gait parameters are 
predicted on low and high frequency in 
the context of ON and OFF medication 
conditions using baseline bradykinesia, 
tremor, and gait sensor measurements, 
plus MDS-UPDRS III rigidity and axial sub 
scores. 
 
 
 
Models will be based on 
RF classifier, where other 
modeling techniques, 
such as neural networks, 
will be used as 
benchmarks. 
Secondary 
 
 
Tremor 
Bradykinesia 
MDS-UPDRS III  
Tremor (rest, postural, kinetics) 
measurements captured from Kinesia 
inertial sensors (Great Lakes 
Technologies, OH) 
 
Bradykinesia measurements (finger taps, 
hand grasps, wrist rotation, toe taps and 
leg lifts) captured from Kinesia inertial 
sensors (Great Lakes Technologies, OH) 
 
 
 
 
 
Items 3.1, 3.3(a-e), 3.9, 3.11, 3.12, 3.13 of 
MDS-UPDRS III. 
To establish a baseline 
kinematic profile of 
subjects in terms of 
tremor, bradykinesia, 
along with gait using 
objective sensor 
measurements that will 
be used for developing 
regression models for 
Aim 2 
 
 
 
 
MDS-UPDRS assessment 
are for facial masking, 
speech, rigidity, freezing 
of gait, postural and 
postural instability  -- 
symptoms that are not 
measured by sensors in 
this study, but important 
for the machine learning 
analysis that will be  
conducted.  

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laboratory, and experimenters will repeat assessments 1 hour afterwards (or sooner based on patient 
report and visual confirmation by physician). Cognitive function in the ON state will be captured via the 
Mini Mental Status Exam (MMSE) by a study coordinator or physician.  Phase I for preoperative subjects 
will be integrated into their standard of care core assessment program for surgical interventional 
therapies in Parkinson's disease (CAPSIT-PD) (42). For those subjects with chronic DBS, their stimulators 
will be turned off for at least 50 minutes to ensure adequate “wash-out” of stimulation effects (43) prior 
to the assessment in each condition. For subjects that experience intolerable symptoms during this time, 
the assessment may take place sooner (<50 minutes after stimulators are turned off).   
 
During each condition, a movement disorder’s specialist will conduct an assessment of items 3.1, 3.3(a-
e), 3.9, 3.11, 3.12, 3.13 of MDS-UPDRS III. Afterwards, each participant will be outfitted with full body 
Opal sensors (APDM, Opal, and Portland, OR) affixed to the wrists, feet, sternum and lumbar spine (L5 
level). A trained research coordinator will instruct each participant to conduct the Stand and Walk (SAW) 
test. During this test, subjects will stand for 30 seconds quietly, then walk 7 meters at their comfortable 
speed, turn 180 degrees, and walk back. Walking aides will be permissible, if needed. Unless the 
participant is unable to do so, the SAW test will be conducted twice for each trial in order to capture a 
sufficient number of gait cycles. Based on normative spatial-temporal gait analysis in healthy young and 
elderly adults (44-46), we selected the following measurements to be assessed during this instrumented 
walk: 1) Postural sway – root mean square (RMS) sway in antero-posterior (AP) and medio-lateral (ML) 
planes; 2) Gait – cycle duration (seconds), speed (m/s), stance (%), swing (%), heel strike angle (degrees), 
toe off angle (degrees), stride length (cm), cadence (steps/min), step duration (seconds), elevation at 
midswing (cm) (foot clearance), double support (%), arm swing velocity (deg/s), and range of motion 
(degrees); 3) Circumduction – turn angle (degrees), turn duration (seconds), and turn velocity (deg/s). 
 
Following the gait testing, participants will undergo tremor and bradykinesia analysis with the Kinesia 
inertial sensors (Great Lakes Technologies, OH) that will be affixed to their finger and ankle. While 
seated, subjects will be guided through a series of movement tasks by interacting with the ONE tablet 
from Kinesia. Each motor test will appear on the touch screen interface that will instruct the participant 
on the motor task. The following tasks will be performed to assess bradykinesia: finger taps, hand 
grasps, wrist rotation, toe taps and leg lifts. The tremor assessments will be determined from the 
following tasks: arms resting (resting tremor), arms extended (postural tremor), and finger to nose 
(action tremor). Each motor task will last 15 seconds.  
 
Phase II. The primary goal of Phase II is to investigate the impact of stimulation frequencies (low and 
high), stimulation spatial characteristics and levodopa on gait kinematic domains. Participants will be 
evaluated in two conditions: 1) OFF medication/ON stimulation; 2) ON medication/ON stimulation. 
Patient’s weight will be collected prior to this assessment. For chronic DBS patients, phase II will 
commence during study visit 1. For preoperative subjects, phase II will be conducted on a separate visit 
(study visit #2) that will take place 12-15 weeks after initial programming of bilateral STN deep brain 
stimulation implantation. This visit will also be conducted in a laboratory setting. The impact of the 
lesion effect from the surgery would also be avoided with this timeframe.  
 
During condition (1), patients will be evaluated following overnight withdrawal of dopaminergic 
medications. Afterwards, each electrode contact will be reprogrammed by the Lead Principal 
Investigator in both low frequency and HFS. For each of the 4 contacts on both electrodes, the 
amplitude will be slowly increased by 0.1-V increment until sustained sensory or motor side effects are 
produced in HFS. The amplitude below the side effect threshold will be used along with a standard pulse 
width of 60μs. For low frequency stimulation (LFS) programming, milliamps will be adjusted to keep the 

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total electrical energy delivered (TEED) between both LFS and HFS conditions equivalent for each 
respective contact. The TEED is calculated as milliamp2 x frequency x pulse width/impedance (47). 
 
The opal body sensors (APDM, Opal, Portland, OR) will be fixed to each subject’s wrists, ankles, sternum 
and lumbar spine and the SAW task will be carried out by the research coordinator for each combination 
of low and high frequency stimulation for the four contact pairs (total of 8 trials with each contact pair 
being either LFS or HFS, exclusively; refer to Figure 1). The gait measurements will be the same as in 
Phase I. Bradykinesia and tremor assessments will be conducted for each combination of stimulation 
and contact pairs using the Kinesia inertial sensors (Great Lakes Technologies, OH) as well. Ratings of 
items 3.1, 3.3 (a-e), 3.9, 3.11, 3.12, 3.13 of MDS-UPDRS III will also be conducted for each stimulation-
contact pairing. Following each stimulation parameter change, there will be a 10-minute latency before 
the gait task is conducted. The participants will be blinded to each stimulation change.  
 
During condition (2), the stimulators will be turned off and subjects will be given 1.5 times their usual 
levodopa dose (up to 300mg) to ensure transition to the medication ON state. Retesting will be done 1 
hour after the levodopa challenge (or sooner based on patient report and visual confirmation by 
physician). Gait, bradykinesia and tremor sensor assessments as well as MDS-UPDRS III rigidity and axial 
subscore ratings will be conducted in the same manner as condition (1). The participants will be blinded 
to stimulation changes. At the completion of Visit 2, participants will return to their initial programming 
settings and resume their medication regimen as per their standard of care. If participant fatigue 
develops, he/she will have the option to complete condition (2) on another visit within a 4 week time 
period. 
 
Beginning September 2020, and until the COVID-19 pandemic has passed, all subjects who are not fully 
vaccinated against COVID-19 will be tested for COVID-19 prior to participation (as outlined in Section 
10.2). As a result, remote consent will be employed during the COVID-19 pandemic (see Section 8.2). 
COVID-19 tests will be performed by nasopharyngeal swab at a Northwell facility, the cost of which will 
be billed to the study fund. 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN AND JUSTIFICATION FOR DOSE 
 
Several studies have shown the efficacy of lower frequency stimulation, defined anywhere from 60-80Hz 
of the STN, in treating gait dysfunction and freezing that develop years later among chronic DBS patients 
(7-12). We reported that 60Hz stimulation could be utilized and beneficial within the first year of 
implantation for a small number of patients with significant gait disorder (12). We also showed that 
stimulation through the ventral contacts was utilized in all patients with relatively modest changes 
achieved in levodopa equivalent daily dose. Building upon this result, we performed a systemic analysis 
to determine whether a clinical pattern exists among subjects that benefited most from certain 
stimulation frequencies (38). The team analyzed preoperative MDS-UPDRS III scores (32 indicators) 
collected from 20 PD patients implanted with STN-DBS on either 60 Hz stimulation (ten patients) or HFS 
(130–185 Hz) (ten patients) for an average of 12 months. The goal was to apply machine learning to 
accurately “classify” patients into their corresponding optimal stimulation frequency group using a 
subset or all of the patient-specific indicators collected preoperatively. Machine learning algorithms are 
of two main types, namely, supervised and unsupervised algorithms. Supervised learning algorithms 
require ground truth (e.g., direct measurements or observations) for the data used in training and 
testing, whereas unsupervised learning algorithms do not require ground truth and are typically used to 

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group the data into clusters with respect to their similarities. In supervised learning, the task of 
estimating the ground truth for a new observation is generally referred to as making a “prediction.” 
Predicting ground truths of categorical type is typically referred to as “classification,” and predicting 
ground truths of continuous type is generally referred to as “regression.” In our prior work, we 
developed a novel supervised machine learning model based on random forest method that was able to 
classify patients into subgroups with 95% accuracy and determined that gait and rest tremor of the right 
hand were consistently the most important factors to the classification. 
 
4.3 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 21-80 
4. Patients diagnosed with Parkinson’s disease (PD) (Hughes 1992) 
5. PD subjects who have bilateral STN-DBS (greater than 3 months) or in the preoperative stage of 
being implanted with bilateral STN-DBS  
6. Have underlying gait disorder defined as a score of 2 or more on the gait sub-score of the MDS-
UPDRS III in the levodopa-OFF state 
7. Currently treated with oral levodopa therapy 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Cognitive deficits based on historical record that limit participant compliance with study 
protocol 
2. Vestibular disorder or musculoskeletal problems affecting gait or balance 
 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 

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Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
decompensation of their Parkinson’s disease due to other medical issues or acute musculoskeletal 
problems may be rescreened after they have returned to their baseline physical state. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Subjects will be recruited from the Neurology Parkinson’s and Movement Disorders Division at Northwell 
Health and from local physicians within and outside of Northwell Health. Outreach will include 
recruitment databases such as [but not limited to] Fox Trial Finder, CenterWatch, The Parkinson 
Alliance, Northwell E-news bulletin and the Northwell Health Clinical Trials webpage. For participants 
recruited outside of Northwell Health, medical records will be required to confirm eligibility. Participant 
screening and recruitment will then be conducted by the Lead Principal Investigator and research 
coordinator. Retention of participants will be maintained through thoroughness by the lead principal 
investigator and research coordinator. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Deep Brain Stimulation Programming 
Parkinson’s patients who will be undergoing STN-DBS implantation or who have chronic bilateral STN-
DBS will be eligible to participate. Each electrode contact will be reprogrammed by the Lead Principal 
Investigator in both low frequency and HFS. For each of the 4 contacts on both electrodes, the 
amplitude will be slowly increased by 0.1-V increment until sustained sensory or motor side effects are 
produced in HFS. The amplitude below the side effect threshold will be used along with a standard pulse 
width of 60μs.  
 
Inertial Sensors:  
Participants will also be outfitted with the full body Opal sensors (APDM, Opal, and Portland, OR) affixed 
to the wrists, feet, sternum and lumbar spine (L5 level) and the Kinesia inertial sensors 
(Great Lakes Technologies, OH) that will be affixed to their finger and ankle. For the gait analysis, the 
Mobility Lab System (APDM, Portland, OR) will be used. It includes both ambulatory PD monitoring as 
well as expansive analytical software that measures outcomes from watch size sensors that are tethered 
to various body regions by Velcro bands. Each sensor acquires 3-D linear acceleration, angular velocity 
and magnetic field information for directional orientation from accelerometers, gyroscopes, and 
magnetometers, respectively (48). The sensor data is wirelessly streamed to a laptop where Mobility Lab 
software will generate the gait and balance metrics. iSway and iTUG are two of the modules within the 
software system. iTUG’s gait calculations, including stride length, velocity, cadence, trunk movements, 
turning, and turn to sit, were deemed to be most reliable and correlated well to the UPDRS III (49). 
iSWAY has also been validated to measure dynamics of postural control (50).  
 
The Kinesia One (Great Lake Neurotechnologies, Cleveland, OH) sensor incorporates both triaxial 
accelerometers and gyroscopes in a small compact sensor device worn on a finger and ankle and will be 
used for the tremor and bradykinesia analysis. Subjects will follow motor tasks displayed on Kinesia’s 

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touch screen tablet as the sensor data is captured and accessed from Kinesia’s web application, which is 
a HIPAA-compliant online interface.  
  
The Kinesia and Mobility Lab devices are FDA approved medical devices and are both commercially 
available.  
 
During both study phases, participants will be assessed in the OFF medication state following overnight 
withdrawal of dopaminergic medications.  They will be given 1.5 times their usual levodopa dose (up to 
300mg) using Carbidopa/levodopa 25/100 tablet to ensure transition to the ON medication state. 
Carbidopa/levodopa 25/100 is widely used in treating PD and virtually all PD patients have taken it at 
some point in their treatment course. In addition, it is the drug of choice for the CAPSIT-PD, used for the 
preoperative assessment for deep brain stimulation.  
 
Patients will return to the original DBS settings and medication regimen at the conclusion of each study 
visit.  
6.1.2 DOSING AND ADMINISTRATION 
 
During Phase I, participants will receive no stimulation. For those subjects with chronic DBS, their 
stimulators will be turned off for at least 50 minutes to ensure adequate “wash-out” of stimulation 
effects prior to the assessment in each condition. If symptoms become intolerable, the wash out period 
may be shortened. This will be determined by the PI on a case by case basis. During Phase II, the Lead 
Principal Investigator will reprogram each electrode contract pair in both 60Hz frequency and high 
frequency stimulation (HFS). For each of the 4 contacts on both electrodes, the amplitude will be slowly 
increased by 0.1-V/mA increment until sustained sensory or motor side effects are produced in HFS. The 
amplitude below the side effect threshold will be used along with a standard pulse width of 60μs.  
 
In both Phases, participants will assessed in the practically defined levodopa OFF condition--whereby 
they will have their overnight dopaminergic medications withdrawn--and the Levodopa ON condition, in 
which participants will be given 1.5 times their usual levodopa dose (up to 300mg) using 
carbidopa/levodopa 25/100 tablets with water.  
SINEMET tablets are available in a 1:4 ratio of carbidopa to levodopa (SINEMET 25-100) as well as 1:10 
ratio (SINEMET 25-250 and SINEMET 10-100). Tablets of the two ratios may be given separately or 
combined as needed to provide the optimum dosage. Studies show that peripheral dopa decarboxylase 
is saturated by carbidopa at approximately 70 to 100mg a day. Patients receiving less than this amount 
of carbidopa are more likely to experience nausea and vomiting. The optimum daily dosage of Sinemet must 
be determined by careful titration in each patient. 
         This dosage schedule provides 75 mg of carbidopa per day.  
         The patient should be informed that Sinemet is an immediate-release formulation of carbidopa 
levodopa that is designed to begin release of ingredients within 30 minutes. 
 
All study participants will be on a levodopa regimen. They will be given 1.5 times their usual 
dopaminergic dose in the form of the study drug with 3 tabs being the maximum dosage. This is 
in line with the standard of care in assessing the transition of a Parkinson’s patient from the OFF 
levodopa state to the ON state in a controlled setting. 
 
Study drug will be taken at the research site by mouth with water.  

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 
Participants will be instructed to discontinue dopaminergic medications the night before each study visit, 
but they will remain on all other prescription medications. A drug-drug interaction is not anticipated 
during study participation with carbidopa/levodopa, as PD subjects, especially those with gait disorder, 
remain on some formulation of levodopa. 
 
Additional tablets will be administered (up to 1.5 times their usual dopaminergic dose) if wearing off is 
observed prior to the completion of study assessments. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The devices and drug identified as study interventions in this protocol will not be implanted or 
administered as investigational. Chronic DBS patients or patients planning to undergo DBS implantation 
are eligible for this study. Similarly, patients eligible for this study will already be taking levodopa as a 
part of their standard care for their Parkinson’s disease. While this protocol does not intend to 
investigate the effects of Sinemet, this drug will be provided from an investigational supply. 
Carbidopa/levodopa (brand name: Sinemet) 25/100 oral tablets will be acquired in bulk (100 count 
single dose blister packs) from the North Shore University Hospital Pharmacy via email order to 
Elizabeth Mathew, Rph or another NSUH pharmacist in Dr. Mathew’s absence; the cost of which will be 
paid by study funds. Patient-specific prescriptions will not be utilized. Study drug will be acquired by a 
study coordinator and administered by Dr. Ramdhani. The Northwell Drug Accountability Record Form 
template will be utilized to document lot#, expiration, administrations, disposal, etc. Unused drug will 
be disposed of via the North Shore University Hospital Pharmacy at the end of the study.     
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Carbidopa/levodopa (brand name: Sinemet) 25/100 oral tablets. Tablets are yellow, oval, uncoated, that 
are scored and coded “650” on one side and “Sinemet” on the other side. Supplied in single dose blister 
packs, total count of 100. Sinemet is an FDA approved drug. No special preparation, randomization, 
packing, or other requests are required for this protocol. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
The kinesia and APDM mobility lab sensors will be stored in the Principal Investigators office in a locked 
cabinet. Carbidopa/levodopa (brand name: Sinemet) oral tablets will be stored at room temperature, 
protected from light, in the Principal Investigator’s office in a locked cabinet and will be maintained in 
accordance with applicable investigational drug guidance. 
 
 
6.2.4 PREPARATION 
 
Not applicable 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 

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Participants will be blinded to the stimulation changes in Phase II, conditions (1) & (2) as described in the 
study design. Any blinded ratings of the MDS-UPDRS Part III will be done at the discretion of the PI. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Adherence to the protocol will be assessed via completed study tasks during each of the study phases 
and conditions.  
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. If a subject is not taking carbidopa/levodopa 25/100 as part of their 
routine treatment, the principal investigator will prescribe the number of tablets needed for Phase I and II. 
Subject’s dopaminergic medications will be withdrawn the night before each study visit, but they will 
remain on all other prescription medications. A drug-drug interaction is not anticipated during the study 
visit with carbidopa/levodopa, as PD subjects, especially those with gait disorder, remain on some 
formulation of levodopa.  
 
6.5.1 RESCUE MEDICINE 
Not Applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
This study does not require continuous follow-up. All assessments and interventions will be conducted 
during the study visits and subjects will return to their default DBS settings and medication regimen 
after each visit. There will be no change to their standard of care PD management.  
 
If a subject is unable to complete the study visit due to occurrence of any of the aforementioned 
potential risks, they will offered the opportunity to complete the remainder of the study at another 
study visit within 4 weeks.  
 
The data to be collected at the time of study intervention discontinuation will include the following: 
 
Any demographic and clinical data 
 
Sensor based data   
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
 
Significant study intervention non-compliance  
 
If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 

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 
Disease progression which requires discontinuation of the study intervention 
 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (eCRF). Subjects who sign the informed consent form, and receive the study intervention, 
and subsequently withdraw, or are withdrawn or discontinued from the study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits if they 
are undergoing DBS implantation or at most 2 study visits if they are considered chronic DBS subjects 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit within 4 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.] 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Description of the Study Phases. This study will be conducted in two phases: Phase I. Each subject will 
then be evaluated during an in-laboratory session under two conditions: 1) the practically defined OFF 
state following overnight withdrawal of their dopaminergic medications; and 2) levodopa ON State. 
Participants will be given 1.5 times their usual levodopa dose (up to 300mg) to ensure transition to the 
ON state in-laboratory, and experimenters will repeat assessments 1 hour afterwards (or sooner based 
on patient report and visual confirmation by physician). Cognitive function in the ON state will be 
captured via the Mini Mental Status Exam (MMSE) by a study coordinator or physician. Phase I for 
preoperative subjects will be integrated into their standard of care core assessment program for surgical 
interventional therapies in Parkinson's disease (CAPSIT-PD) (42). For those subjects with chronic DBS, 
their stimulators will be turned off for at least 50 minutes to ensure adequate “wash-out” of stimulation 
effects (43) prior to the assessment in each condition. If symptoms become intolerable, the wash out 
period may be shortened. This will be determined by the PI on a case by case basis. 
 
During each condition, a movement disorder’s specialist will conduct an assessment of items 3.1, 3.3(a-
e), 3.9, 3.11, 3.12, 3.13 of MDS-UPDRS III. Afterwards, each participant will be outfitted with full body 
Opal sensors (APDM, Opal, and Portland, OR) affixed to the wrists, feet, sternum and lumbar spine (L5 
level). A trained research coordinator will instruct each participant to conduct the Stand and Walk (SAW) 

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test. During this test, subjects will stand for 30 seconds quietly, then walk 7 meters at their comfortable 
speed, turn 180 degrees, and walk back. Walking aides will be permissible, if needed. Unless the 
participant is unable to do so, the SAW test will be conducted twice for each trial in order to capture a 
sufficient number of gait cycles. Based on normative spatial-temporal gait analysis in healthy young and 
elderly adults (44-46), we selected the following measurements to be assessed during this instrumented 
walk: 1) Postural sway – root mean square (RMS) sway in antero-posterior (AP) and medio-lateral (ML) 
planes; 2) Gait – cycle duration (seconds), speed (m/s), stance (%), swing (%), heel strike angle (degrees), 
toe off angle (degrees), stride length (cm), cadence (steps/min), step duration (seconds), elevation at 
midswing (cm) (foot clearance), double support (%), arm swing velocity (deg/s), and range of motion 
(degrees); 3) Circumduction – turn angle (degrees), turn duration (seconds), and turn velocity (deg/s). 
 
Following the gait testing, participants will undergo tremor and bradykinesia analysis with the Kinesia 
inertial sensors (Great Lakes Technologies, OH) that will be affixed to their finger and ankle. While 
seated, subjects will be guided through a series of movement tasks by interacting with the ONE tablet 
from Kinesia. Each motor test will appear on the touch screen interface that will instruct the participant 
on the motor task. The following tasks will be performed to assess bradykinesia: finger taps, hand 
grasps, wrist rotation, toe taps and leg lifts. The tremor assessments will be determined from the 
following tasks: arms resting (resting tremor), arms extended (postural tremor), and finger to nose 
(action tremor). Each motor task will last 15 seconds. 
 
Phase II. Participants will be evaluated in two conditions: 1) OFF medication/ON stimulation; 2) ON 
medication/ON stimulation.  
 
During condition (1), patients will be evaluated following overnight withdrawal of dopaminergic 
medications. Afterwards, each electrode contact will be reprogrammed by the Lead Principal 
Investigator in both low frequency and HFS. For each of the 4 contacts on both electrodes, the 
amplitude will be slowly increased by 0.1-V increment until sustained sensory or motor side effects are 
produced in HFS. The amplitude below the side effect threshold will be used along with a standard pulse 
width of 60μs. For low frequency stimulation (LFS) programming, milliamps will be adjusted to keep the 
total electrical energy delivered (TEED) between both LFS and HFS conditions equivalent for each 
respective contact. The TEED is calculated as milliamp2 x frequency x pulse width/impedance (47). 
 
The opal body sensors (APDM, Opal, Portland, OR) will be fixed to each subject’s wrists, ankles, sternum 
and lumbar spine and the SAW task will be carried out by the research coordinator for each combination 
of low and high frequency stimulation for the four contact pairs (total of 8 trials with each contact pair 
being either LFS or HFS, exclusively; refer to Figure 1). The gait measurements will be the same as in 
Phase I. Bradykinesia and tremor assessments will be conducted for each combination of stimulation 
and contact pairs using the Kinesia inertial sensors (Great Lakes Technologies, OH) as well. To minimize 
participant fatigue, the following bradykinesia and tremor assessments will be conducted during this 
phase: Hand grasps, leg lifts, rest tremor and postural tremor. Ratings of items 3.1, 3.3 (a-e), 3.9, 3.11, 
3.12, 3.13 of MDS-UPDRS III will also be conducted for each stimulation contact pairing. Following each 
stimulation parameter change, there will be a 10-minute latency before the gait task is conducted. The 
participants will be blinded to each stimulation change. 
 
During condition (2), the stimulators will be turned off and subjects will be given 1.5 times their usual 
levodopa dose (up to 300mg) to ensure transition to the medication ON state. Retesting will be done 1 
hour after the levodopa challenge (or sooner based on patient report and visual confirmation by 
physician). Gait, bradykinesia and tremor sensor assessments as well as MDS-UPDRS III rigidity and axial 

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subscore ratings will be conducted in the same manner as condition (1). The participants will be blinded 
to stimulation changes. At the completion of Visit 2, participants will return to their initial programming 
settings and resume their medication regimen as per their standard of care. If participant fatigue 
develops, he/she will have the option to complete condition (2) on another visit within a 4 week time 
period. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
  
Description of Consent and Procedure for Obtaining Informed Consent  
Participants will be consented by the Lead Principal Investigator in person at the Parkinson’s and 
Movement Disorders Center. All potential participants will be asked to review a copy of the informed 
consent form, regardless of diagnosis, unless there is evidence of serious mental disability that would 
impair judgment or reasoning. Patients will not be approached regarding study participation by anyone 
not directly involved in their treatment, unless the patient has given permission for this interaction or 
has self-referred. The patient will then be contacted by the Principal Investigator and will be offered 
written information about the study. Informed written consent will be obtained prior to any study 
assessment.  Subsequent clinical evaluation may result in an exclusion from the study. The PI and 
research coordinator will review the informed consent form with potential participants and address any 
questions or concerns prior to obtaining written informed consent for participation. The research 
members will also address any future questions or concerns of participants. A copy of the consent will 
be provided to the participant after it has been signed and witnessed.    
Remote consent will be employed during the COVID-19 pandemic through a combination of telephone 
and email contact by the investigator and coordinator per Northwell HRPP Policies and Procedures. 
Initial and/or interim discussions with the PI may also take place in-person during clinical visits. The 
coordinator will provide potential participants with a brief summary of the study and a copy of the 
consent document for review. If the subject is interested in participation, the PI will discuss the study 
and answer any questions. If the subject agrees to participate in research, he/she will be directed by the 
PI to sign the consent form and return it by mail or email (scanned consent form as a PDF) to the study 
coordinator. Alternative methods such as facsimile will be utilized depending on the subject’s access. An 
enrollment note will be generated for each subject to document this process. Once the signed consent 
document is received by the coordinator, it will be forwarded to the PI for signature. The study team will 
note the date discrepancies of the signatures on both the consent document and enrollment note. The 
study coordinator will send a copy of the fully signed consent document to the subject for his/her files. 
When in-person consent is possible (e.g., during a clinical visit), traditional consent methods will be 
employed.  
 
Study Visit 1 will be scheduled within 30 days of subject consent.    
 
All study visits will be conducted by the PI and research coordinator in a controlled setting. Each subject 
will be closely monitored during each motor assessment to reduce risk of falls and will be queried 
regularly during the visit to assess for fatigue.  
 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 

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• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Study staff will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
AEs will be reported to the study sponsor and the IRB within X 7 days of the study staff learning of the 
event.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to IRB any serious adverse event, whether or not considered 
study intervention related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 

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in accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the IRB. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Not applicable  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 

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To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within <1 week > of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within <2 weeks> of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within <2 weeks > of the IRB’s receipt of the report of the 
problem from the investigator.] 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Aim 1. Our preliminary study established that gait and rest tremor are important factors to determine 
whether patients benefit from 60Hz stimulation or high frequency stimulation (38). However, the degree 
to which stimulation parameters affect gait parameters is not well established. In Aim 1, we will test the 
hypothesis that certain gait parameters are differentially affected between 60Hz and high frequency 
STN-DBS at various electrode contact configurations. In addition, in our preliminary analysis, we 
observed a modest reduction in dopaminergic medications in patients on 60Hz stimulation (12). Hence, 
we will also test the hypothesis that for some patients, the addition of levodopa in combination with 
60Hz stimulation produces a synergistic improvement in certain gait domains.  
 
Aim 2. Our preliminary data suggested that there is a link between the patient’s baseline motor 
symptomatology measured by the MDS-UPDRS III ratings and the best stimulation frequency (60 Hz or 
HFS) chosen for the patient based on intensive clinical evaluations, which remained unchanged for an 
average of 12 months. In Aim 2, we test the hypothesis that a subject’s gait kinematics on 60Hz 
stimulation can be predicted with statistically significant accuracy using gait measurements on high 
frequency stimulation. In addition, we will test the hypothesis that the best stimulation frequency (60Hz 
or HFS stimulation), which yields improvement among various gait parameters, can be predicted using 
objective sensor data collected at baseline. We define baseline motor performance as the severity of 
motor symptoms in the levodopa OFF and ON state without stimulation. In the remainder of this 
proposal, for simplicity we refer to 60 Hz stimulation and high frequency stimulation (130-180Hz) as low 
frequency (LFS) and high frequency (HFS), respectively. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
To determine the sample size, we averaged the gait parameters (across all age groups) along with 
pooled variance captured on the APDM inertial sensors for healthy subjects (53) and PD patients with 
gait disorder (54) and computed a reasonable sample size of 24 (which equates to a Cohen’s d= 0.8) with 
a power of 0.80 and level of significance of 0.05. Assuming a 20% attrition rate, we will attempt to 
recruit 30 patients. 
 
Sample Size estimation 

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 (α) = 0.05, Zα = 1.96 
 (β) = 0.80 
 
Reference Gait values for healthy individuals using APDM sensors 
Age Groups                                          n                             mean  
                   normalized speed                        STD               Variance 
 
20-29 
41 
1.14 
  0.12 
0.0144 
30-39 
41 
1.16 
0.14 
0.0196 
40-49 
42 
1.14 
0.16 
0.0256 
50-59 
45 
1.21 
0.14 
0.0196 
60-69 
51 
1.13 
0.12 
0.0144 
70-89 
72 
0.86 
0.23 
0.0529 
 
Ages 50-89: Mean Velocity - 1.06  
Calculated Pooled Variance for Ages 50-89- 0.03  
Calculated Pooled Variance for All ages – 0.03 
Fang X, Liu C, Jiang Z. Reference values of gait using APDM movement monitoring inertial sensor system. R Soc 
Open Sci. 2018;5(1):170818 
 
Gait Parameters for PD patients with gait disorder (FOG- & FOG +) using APDM sensors 
 

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Average age 68 STD 8.4 (FOG -) 
Average Age 69  STD 7.9 ( FOG+) 
Mean Velocity – 0.925 (FOG- & FOG+) 
de Souza Fortaleza AC, Mancini M, Carlson-Kuhta P, King LA, Nutt JG, Chagas EF, Freitas IFJ, Horak FB. Dual task 
interference on postural sway, postural transitions and gait in people with Parkinson's disease and freezing of gait. 
Gait Posture. 2017;56:76-81. 
 
Effect Size 1.06-0.925  = .14 
N = 15.79 (.03)/ (.14)2   = 24 + 20% attrition = total study recruitment 29 subjects.  
Final Study N= 30 subjects 
 
9.3 
POPULATIONS FOR ANALYSES 
Not applicable 
 
9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
We will perform descriptive statistics—i.e., mean (standard deviation) on all demographic, LED, MDS-
UPDRS III (Total score), baseline DBS parameters and gait kinematic parameters. In order to eliminate 
body height as a confounder, we will normalize (N), according to gender, the following parameters: 
speed (S), stride length (L), cadence (C) according to Schwesig et al.(55). 
D = sqrt (body height/mean body height)      
SN = S / D2  
LN = L / D2  
CN = C x D2 
 

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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Aim 1.1.  
Using the analytical software of APDM, the SWAY and TUG algorithms included in the SAW test will 
calculate asymmetry and variability for: postural sway (RMS AP & ML planes), cadence (CN), gait cycle 
duration, gait speed (SN), swing, double support, elevation at midswing, foot strike angle, toe off angle, 
stance, step duration, stride length (LN), arm swing velocity, arm range of motion, turn angle, turn 
duration, and turn velocity. All data will be tested for normality with Shapiro-Wilk test. Linear mixed 
models with repeated measures (LMMRM) will be used to compare high and low frequency over all 
contact pairs in the levodopa-OFF state. Parameter estimation will be based on restricted maximum 
likelihood and the form of the covariance matrix will be chosen based on Akaike’s Information Criteria 
and Schwarz’ Bayesian Criterion. The Holm-Bonferroni method will be used to adjust for multiple 
comparisons for the 20 outcome measures.  
 
Aim 1.2. To investigate levodopa’s effects on the gait domains, we will include the data for levodopa-ON 
and add a binary variable for levodopa (on or off) to the LMMRM from Aim1.1. 
 
Aim 2.1. We will utilize the raw data collected during Phase II to develop regression models, under both 
ON and OFF medication states for all contact pairs. The top panel in Figure 2 presents the overview of 
Aim 2.1; the goal of this sub-Aim is to predict the gait parameters for patients on low frequency by using 
the gait sensor measurements obtained on high frequency. Additional independent variables/regressors 
include general patient/disease characteristics such as age, gender, and disease duration. We will also 
build models under both ON and OFF medications. To develop the regression models, we use non-linear 
regression analysis based on random forest (RF) classifier. RF is based on an ensemble of decision trees, 
referred to as a ‘forest,’ where predictions for any new observation are obtained from averaging the 
predictions of individual trees (56). Generally, RF models are not prone to overfitting and are robust 
against noisy or high-dimensional datasets (57). In addition, they are generally interpretable, allowing 
for further examination of results and easier subject subtyping with respect to symptomology. However, 
to assure that the RF based models are the best performing models, we also develop models based on 
some of the other machine learning techniques, such as neural networks (56), and use them as 
benchmarks. If needed, to improve model performance we will perform model building in RF models to 
identify and include the most important parameters (38). We will use techniques such as cross-
validation (e.g., leave-one-out) and bootstrapping to examine the generalizability of the models and 
acquire confidence intervals for the predicted values. Lastly, we will compare the best performing 
models obtained for both ON and OFF medications and their most important contributing parameters to 
further investigate the interaction of medications and stimulation frequency.  
 
Aim 2.2. Similar to Aim 2.1, in this sub-Aim we conduct regression analysis to predict gait parameters. 
However, in this sub-Aim, gait parameters are predicted on low and high frequency in the context of ON 
and OFF medication conditions using baseline bradykinesia, tremor, and gait sensor measurements, plus 
MDS-UPDRS III rigidity and axial sub scores. Patient and disease characteristics will be used as 
regressors. Again, models will be based on RF classifier, where other modeling techniques, such as neura 
networks, will be used as benchmarks. The best performing parameters identified in Aim 2.1 will be 
used to guide the model building in this sub-Aim. Also, aforementioned performance enhancing 
techniques will be used, if possible, and confidence intervals will be generated using bootstrapping. 
These models will be able to predict the best stimulation frequency and contact pairs for the patient 
immediately after baseline evaluations and provide a confidence level. Similar to Aim 2.1, we will 

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develop these models with and without accounting for PD medications to further quantify their impact 
and provide additional options for patients. 
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints will be factored into the regression modeling for AIM 2.  
 
9.4.4 SAFETY ANALYSES 
Not applicable 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Refer to section 9.4.1 
  
9.4.6 PLANNED INTERIM ANALYSES  
Not applicable 
 
9.4.7 SUB-GROUP ANALYSES 
The subgroup analyses will be analyzed based on age, gender, and disease duration for both primary 
and secondary endpoints.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and time point.  
9.4.9 EXPLORATORY ANALYSES 
Not applicable 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
A consent form describing in detail the study intervention, study procedures, and risks is given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 

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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
In the event that consent is obtained during Study Visit 1, we request a waiver of written documentation 
of consent for the dopaminergic medication withdrawal to take place 12 hrs prior to this visit. This 
waiver will not affect data validity, subject safety, or one’s willingness to participate. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and/or IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 

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confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor.  
 
All research activities will be conducted in a private and controlled setting.  
 
The collected data will include self-reported demographic information as well as clinical and sensor based 
measurements. A REDCap (Research Electronic Data Capture) database will be created for the purposes of this 
project at Northwell Health. This is a secure web based research data management application in which 
demographic data, baseline DBS parameters, and daily levodopa equivalent dose will be stored. Data will be de-
identified and stored securely in a HIPAA compliant manner. A unique study identification number will 
identify individual participants and their research data. The clinical research coordinator will input data into 
this database within 24 hours of acquiring clinical data for each subject.  
All sensor based data will be stored on secured research laptop and backed up to an encrypted external hard-drive 
regularly. Paper copies of all research materials as well as backup copies of sensor data and the database will be 
stored on encrypted portal storage devices that will be kept securely in the PI’s office.  All research and data 
storage equipment will be stored in the PI’s office in a locked cabinet.  
Each subject will have a unique identification number that will be used for all assessments. The PI and Research 
coordinator will conduct routine monitoring and cleaning of the data to ensure accuracy. The dataset will be de-
identified and shared with the research team at the University of Tennessee Knoxville in adherence to the 
resource-sharing plan.    
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored in a REDCap Database at Northwell and an 
encrypted external hard-drive. De-identified, archived data will be transmitted securely to the 
University of Tennessee for use by other researchers on this project to conduct Aim 2. Permission to 
transmit data to the UTK will be included in the informed consent. This transference of data will occur in 
parallel following completion of each subject’s study visits for Aim 1.  
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Ritesh Ramdhani, MD 
Director, Deep Brain Stimulation Program 
N/A 

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Associate Director, Parkinson's and Movement Disorders 
Northwell Health  
Institution Name  
611 Northern Boulevard 
Great Neck, NY 11021 
Address 
516-325-7000 
Phone Number 
rramdhani@northwell.edu 
Email 
 
 
10.1.6 SAFETY OVERSIGHT 
The PI will review aggregate safety data every six months and provide the outcomes of these reviews to 
the IRB for acknowledgement.  
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring for this study will be performed by Study PI with each study visit. Random review of 
study data will be done by PT to ensure accuracy of data input and cataloging.  
• 
Independent audits will be conducted by Northwell IRB to ensure monitoring practices are 
performed consistently across all participating sites if needed 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study site will perform internal quality management of study conduct, data collection, 
documentation and completion. An individualized quality management plan will be developed to 
describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the study PI will verify that the clinical trial is 
conducted and data are generated are collected, documented (recorded), and reported in compliance 
with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 

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10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  
 
Data (including demographics, medical history, DBS surgical history, results of sensor and clinical rating 
scale assessments, adverse events (AEs), and any clinical observations) will be entered into <Redcap 
Database at Northwell Health>, a 21 CFR Part 11-compliant data capture system provided by the 
<Northwell Health>. Clinical data will be entered directly from the source documents. Sensor based data 
will be stored on an encrypted research laptop that will be backed up to an encrypted external HD.  
The clinical and sensor dataset will be de-identified and shared with the research team at the University 
of Tennessee Knoxville in adherence to the resource-sharing plan.  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within no more than 7 working days of identification of the protocol deviation.  All deviations 
must be addressed in study source documents, reported to National Institute of Neurological Disorders 
and Stroke (NINDS) Program Official and <Northwell Health’s IRB>.  Protocol deviations must be sent to 
the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 

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knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol 
deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Data from this study may be requested from other researchers 5 years after the 
completion of the primary endpoint by contacting Dr. Ritesh Ramdhani. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the National Institute of Neurological Disorders and Stroke (NINDS) has 
established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Study visits were suspended in March 2020 due to the COVID-19 pandemic. We plan to resume study 
visits in the fall of 2020 according to institutional and state guidelines. This timeline is subject to change 
based on the status of COVID-19 in New York; future suspensions may be required if there is a spike in 
the number of infections. Due to current facility restrictions and limited space availability, SVs will be 
conducted between our offices at the Neuroscience Institute (Great Neck, NY) and the Feinstein 
Institutes for Medical Research (Manhasset, NY).  
 
The following safety measures will be taken.  
 
1. All study subjects will undergo a telephone preappointment COVID Screen  
a. Those without symptoms will get a COVID test 48-72hrs prior to their first study visit 
(SV).  
b. If the COVID test is positive, they will have their SV postponed for 2 weeks and will 
be retested prior to SV1. 

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c. Those with reported symptoms on telephone prescreening will have their SV 
postponed for 14 days followed by a COVID test 48-72 hrs prior to their first SV. 
2. Fully vaccinated subjects will be exempt from COVID-19 testing prior to SV1. Testing may be 
warranted at any time if the subject reports symptoms of COVID-19 during telephone 
preappointment screening. 
3. Any subject with an initial positive COVID test must have a negative result upon retest, prior 
to participation. 
4. Preappointment screening will be repeated prior to each SV. Postponement of SV or repeat 
COVID-19 testing may be warranted.  
5. Prior to each study visit, subjects will be instructed when to enter the building, don a mask, 
and have their temperature checked. If a fever is present, their SV will be postponed for 14 
days or more and they will be (re)tested for COVID-19. 
6. Attempt will be made to conduct all SVs on consecutive research days (within 2 weeks). 
COVID-19 testing may be repeated if participation exceeds 14 days.   
7. All research staff will follow site specific COVID-19 safety and hygiene policies including 
wearing an N95 mask 
8. When possible, a plexiglass barrier will be placed on the table between research 
coordinator/PI and subject for additional safety. 
9. Social distancing will be practiced whenever possible. 
 
 

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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 

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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
4/15/19 
Original 
N/A 
1.1 
10/29/19 
Updated eligibility criteria, editorial 
clarification, LD dose maximum 
300mg, shortened off period for 
chronic DBS subject experiencing 
intolerable symptoms, additional of 
external referral sources and on-line 
outreach 
Clarity, patient comfort, to 
meet recruitment goals 
1.2 
1/8/20 
Addition of second SAW test for 
every trial, change source of LD 
tablets from patient to NSUH 
pharmacy. 
Ensure enough gait cycles are 
captured, remove drug 
supply/cost burden on 
participants. 
1.3 
1/22/20 
IP supply changed from bottle to 
single dose blister packs; Removal of 
finger taps, touch nose, wrist 
rotation, and toe taps sensor 
assessments from Phase II 
Availability through NSUH 
pharmacy; participant fatigue 
1.4 
3/2/20 
Completion of one SAW test if 
participant is unable to do both; 
chronic DBS eligibility revised from 
one year to 6 months; 
administration of additional 
levodopa in event of wearing off   
Subject safety and comfort, 
facilitate recruitment, maintain 
levodopa ON state during 
assessments 
1.5 
8/4/20 
Add Visit 3 to Schedule of Activities; 
Addition of COVID-19 safety 
measures including preappointment 
screening, COVID-19 testing and 
remote consent. 
Clarity; COVID-19 pandemic 
1.6 
12/22/20 
Chronic DBS patient eligibility 
revised from 6 months to 3 months 
Facilitate recruitment 
1.7 
3/11/21 
Fully vaccinated subjects exempt 
from COVID-19 testing prior to SV1; 
updated remote consent 
procedures; modified SOA to include 
optional use of clinical visit to 
complete electrode contact pair 
evaluation. 
CDC guidance, subject 
convenience 
1.8 
4/15/21 
Removal of blinding requirement for 
MDS-UPDRS Part III assessments 
Blinded assessments are not 
factored into primary study 
analysis; not shown to be 

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significant features on interim 
computational modeling (n=10) 
1.9 
8/12/21 
Removal of non-English speaking 
criterion 
Translation is sufficient to 
carryout study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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