Non-Invasive Brainstem Modulation for the Treatment of Non-Motor Symptoms in Parkinson's Disease: An Open Label Extension (OLE) Study
Phase: NA
Conditions: Parkinson Disease, Parkinson's Disease and Parkinsonism
Sponsor: Scion NeuroStim

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SCION NEUROSTIM, INC (SNS) 
Protocol Title: Non-Invasive Brainstem Modulation for the Treatment of Non-Motor Symptoms 
in Parkinson’s Disease: A Randomized Controlled Trial (RCT) and an Open Label Extension 
(OLE) Study 
 
Protocol Short Title: STEM-PD 
 
Protocol Identifiers: 
RCT: SNS-PD-002 
OLE: SNS-PD-003 
 
Protocol Version: May 10, 2024 v6.0 
 
National Clinical Trial Identifiers: 
RCT: NCT04797611 
OLE: NCT04799418 
 
Medical Monitor: Dr. Lesco Rogers 
Scion NeuroStim, Inc 
3225 Surrey Road, Suite B 
Durham, NC 27707  USA 
Phone: (984) 286-9048 
stem-pd@scionneurostim.com 
 
 

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PROTOCOL APPROVAL FORM 
Protocol Title: Non-Invasive Brainstem Modulation for the Treatment of Non-
Motor Symptoms in Parkinson’s Disease: A Randomized Controlled Trial (RCT) 
and an Open Label Extension (OLE) Study 
Short Title: STEM-PD 
Version: 6.0 
Date: May 10, 2024 
 
This study protocol was subjected to critical review. The information it contains is 
consistent with Scion NeuroStim, Inc. Current knowledge of the risks and benefits 
of the investigational technology, as well as with the moral, ethical, and scientific 
principles governing clinical research as set forth in the Declaration of Helsinki, as 
amended in 2000 and clarified in 2004i, and the guidelines on Good Clinical Practice. 
 
 
This study protocol has been reviewed and approved by the following: 
 
 
 
__________________________________________ 
 
______________________________ 
Robert Black, PhD  
 
 
                     Date  
Chief Operating Officer 
 
 
 

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Principal Investigator Signature Page 
 
Protocol Title 
Non-Invasive Brainstem Modulation for the Treatment of Non-Motor 
Symptoms in Parkinson’s Disease: A Randomized Controlled Trial 
(RCT) and an Open Label Extension (OLE) Study 
Protocol Short Title 
STEM-PD 
Protocol Identifiers 
SNS-PD-002  
SNS-PD-003 
Version Date 
May 10, 2024 
Revision 
6.0 
 
I, the undersigned, have read and understood the protocol specified above and agree on its content. 
I agree to perform and conduct the study as described in the protocol and in accordance with the 
relevant laws/regulations and standards outlined in the Clinical Trial Agreement. I agree to 1) 
protect the rights, safety, and welfare of subjects under my care 2) control the devices under 
investigation 3) supervise all testing of the device involving human subjects 4) ensure that 
informed consent is obtained from each subject in accordance with 21 CFR Part 50 and that the 
study is not commenced until FDA and IRB approvals have been obtained. 
 
 
______________________________ 
_________________________ 
_________ 
Name  
 
 
 
 
Signature 
 
 
 
Date

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Table of Contents 
1. 
Protocol Summary ................................................................................................................ 7 
1.1. 
Synopsis................................................................................................................... 7 
1.1.1 Study Description ........................................................................................... 7 
1.1.2 Objectives ....................................................................................................... 7 
1.1.3 Endpoints ....................................................................................................... 8 
1.1.4 Study Population ............................................................................................ 9 
1.1.5 Description of Sites/Facilities Enrolling Participants ................................... 9 
1.1.6 Description of Study Intervention .................................................................. 9 
1.2 
Schema .................................................................................................................. 12 
1.3 
Abbreviations ........................................................................................................ 14 
2 
Introduction ......................................................................................................................... 17 
2.1 
Study Rationale:   .................................................................................................. 17 
2.2 Background: ................................................................................................................ 18 
2.2.1 Vestibular System ......................................................................................... 18 
2.2.2 Pre-Clinical and Clinical Study Background .............................................. 19 
2.3 
Risk Benefit Assessment ........................................................................................ 21 
3 
Objectives and Endpoints .................................................................................................. 22 
3.1 Primary endpoint ........................................................................................................ 22 
3.1.1 Objectives: ................................................................................................... 22 
3.1.2 Endpoint:...................................................................................................... 22 
3.2 Secondary endpoints ................................................................................................... 22 
3.2.1 Objectives: ................................................................................................... 22 
3.2.2 Endpoints: .................................................................................................... 22 
3.3 Safety endpoints: ......................................................................................................... 23 
3.3.1 Objectives: ................................................................................................... 23 
3.3.2 Endpoints: .................................................................................................... 23 
3.4 Exploratory Endpoints ................................................................................................ 23 
3.4.1 Objectives: ................................................................................................... 23 
3.4.2 Endpoints: .................................................................................................... 23 
4 
Study design: ....................................................................................................................... 24 

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4.1 
Study Schedule and Activities ............................................................................... 24 
4.1.1 STEM-PD RCT............................................................................................. 25 
4.1.2 Open Label Extension (Day 113 – 365) ....................................................... 29 
4.1.3 Covid-19 Related Schedule Deviations ........................................................ 33 
4.1.4 Snowbird Policy in OLE .............................................................................. 33 
4.2 
Overall Design: ..................................................................................................... 33 
4.3 Justification for Treatment Protocol: ......................................................................... 33 
4.4 End of Study Definition for RCT:................................................................................ 34 
4.5 End of Study Definition for OLE: ............................................................................... 34 
5 
Study population ................................................................................................................. 35 
5.1 
Inclusion Criteria .................................................................................................. 35 
5.2 
Exclusion Criteria ................................................................................................. 36 
5.3 
Concomitant Therapy............................................................................................ 37 
5.3.1 Approved Concomitant Medications............................................................ 37 
5.3.2 Excluded concomitant medications and drugs ............................................ 38 
5.3.3 Contraception .............................................................................................. 39 
5.4 
Screen Failures ..................................................................................................... 39 
5.5 Strategies for Recruitment and Retention ................................................................... 39 
6 
Study Intervention .............................................................................................................. 40 
6.1 
Study Intervention Administration ........................................................................ 40 
6.2 
Preparation/Handling/Storage/Accountability ..................................................... 41 
6.3 
Device Randomization, Blinding, and Unblinding ............................................... 41 
6.4 
Study Intervention Adherence ............................................................................... 42 
7 
Study Intervention Discontinuation and Participant Discontinuation/Withdrawal .... 43 
7.1 
Discontinuation of Study Intervention .................................................................. 43 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................... 43 
7.2.1 Withdrawal Criteria ..................................................................................... 43 
 
7.2.2 Lost to Follow-Up ........................................................................................ 44 
8 
Safety Oversight .................................................................................................................. 44 
8.1 Device Deficiency ....................................................................................................... 44 
8.2 Adverse Events (AEs), Adverse Device Effects (ADEs), Serious AEs (SAEs), Serious 
Adverse Device Effects (SADEs), Unanticipated Adverse Device Effects (UADE) and 

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Unanticipated Problem Reporting .................................................................................... 44 
8.2.1 AEs, ADEs, SAEs, SADEs and UADEs will be defined per ISO14155:2020 
and/or 21 CFR Part 812, as described below.8.2.1 Adverse Event (AE): ............ 44 
8.2.2 Adverse Device Effect (ADE): ..................................................................... 44 
8.2.3 Serious Adverse Event (SAE): ...................................................................... 45 
8.2.4 Serious Adverse Device Effect (SADE): ...................................................... 45 
8.2.5 Unanticipated Adverse Device Effect (UADE): ........................................... 45 
8.2.6 Procedures for AEs: ..................................................................................... 46 
8.3 Protocol Deviations .................................................................................................... 47 
8.4 Clinical Monitoring .................................................................................................... 47 
9 Statistical Considerations ........................................................................................................ 48 
9.1 Sample Size Determination ......................................................................................... 48 
9.2 Statistical design ......................................................................................................... 48 
10 Confidentiality and Privacy ............................................................................................... 48 
11 Record Retention ................................................................................................................ 49 
12 References ............................................................................................................................ 50 
Appendix: .................................................................................................................................... 54 
1.0 Schedule of Events ...................................................................................................... 54 
2.0 Protocol Version History ............................................................................................ 61 
 
 

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1. Protocol Summary 
1.1. 
Synopsis 
Title: Non-Invasive Brainstem Modulation for the Treatment of Non-motor symptoms in 
Parkinson’s Disease: A Randomized Controlled Trial (RCT) and an Open Label Extension (OLE) 
Study 
 
1.1.1 Study Description 
This paired set of studies seeks to establish the safety and efficacy of twice daily time-varying 
caloric vestibular stimulation (tvCVS) treatments using a solid-state Device developed by Scion 
NeuroStim, Inc (SNS), also known as ThermoNeuroModulation (TNM™), for treating symptoms 
associated with PD.  The studies will be conducted at 15 centers, at minimum, in the United States 
and the United Kingdom. The majority of centers will be in the United States. Up to 290 
participants will screen for the double-blinded, controlled, randomized clinical trial (RCT) and 
will self-administer tvCVS treatments twice daily in the home setting over a period of 12 weeks 
(84 days). Participants will continue to be enrolled in to the RCT until at least 184 participants 
have randomized prior to competitive enrollment closing. The RCT will be immediately followed 
by an open label extension (OLE) study during which all study participants will receive treatment 
for 12 weeks (84 days). Study participants will be followed for 16 weeks (112 days) post treatment-
cessation and then the twice daily treatments will be re-introduced for the final 8 weeks (56 days). 
The RCT and OLE have been separated into two distinct studies with separate informed consent 
to enable the closeout and analysis of the RCT portion which will support regulatory submissions 
during the conduct of the OLE.  However, participation in the OLE study will be a selection 
criterion for participating in the RCT, and thus, the two studies are defined within the context of a 
single protocol. 
Please note that the terms treatment and therapy are used interchangeably within this protocol, as 
the TNMTM Device treatment is therapeutic. 
 
1.1.2 Objectives 
Randomized Clinical Trial (RCT): STEM-PD (SNS-PD-002) 
Primary Objectives: The primary objective of the RCT will be to test the hypothesis that   TNM™ 
treatments provide safe and effective therapy for the reduction of non-motor symptom burden in 
participants with PD.  
Secondary Objectives:  This study will seek to establish whether TNM™ treatments provide 
adjuvant therapeutic effectiveness beyond that observed with dopamine replacement therapies 
(DRTs) to (1) provide global benefits, (2) improve activities of daily living related to motor 
function, (3) provide clinically meaningful change (4) improve motor symptoms and (5) improve 
quality of life (QoL) for participants with PD.  
Safety Objectives: This study will seek to establish the safety of TNM™ by monitoring adverse 
events by evaluating whether TNM™ is associated with a worsening of balance, functional 

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mobility and gait in participants with PD. 
Exploratory Objectives: This study will seek to establish the effectiveness of TNM™ therapy 
for treating specific non-motor symptoms (NMS) and in treating motor complications from oral 
dopamine replacement therapies.  Outcomes will evaluate the clinical meaningfulness of 
symptomatic improvements, explore the temporal kinetics of motor symptom response to 
treatment, evaluate the potential of Device therapy to improve gait and to establish the health 
economics for TNM™ therapy.   
 
Open Label Extension OLE: STEM-PD-OLE (SNS-PD-003) 
The purpose of the OLE study is to gather the additional data needed to support reimbursement.  
Objectives: The OLE has been designed to address the following objectives: (1) demonstrate 
reproducibility of the results from the RCT in a second cohort (i.e. all participants, including 
recipients of active treatment and recipients of passive treatment in the RCT will receive active 
treatment in OLE), (2) evaluate effectiveness of the Device treatments over an extended treatment 
interval, (3) collect additional data to support health economic benefits, (4) confirm clinical 
meaningfulness of RCT results and (5) evaluate the potential for the device to slow disease 
progression. 
 
1.1.3 Endpoints   
All endpoints in the RCT will compare differences in change scores between the end of treatment 
visit and the baseline across the two treatment groups unless otherwise noted. In the OLE, the end 
of the 12-week (84 day) treatment period will be considered the primary timepoint for evaluating 
effectiveness of treatment.  The measures outlined below will be used for both the RCT and the 
OLE (except where noted). 
The primary endpoint will be the change in The International Parkinson and Movement Disorder 
Society Nonmotor Rating Scale (MDS-NMS) 1 total score.  
Secondary endpoints will include changes to the following scores:  
 The International Parkinson and Movement Disorder Society Unified Parkinson’s 
Disease Rating Scale Part II: Motor Aspects of Experiences of Daily Living (MDS-
UPDRS II) 2 
 The combined measure of The International Parkinson and Movement Disorder Society 
Unified Parkinson’s Disease Rating Scale: Parts I, II and III3  
 the Clinical Global Impressions Scale- Improvement (CGI-I) 
 The International Parkinson and Movement Disorder Society Unified Parkinson’s 
Disease Rating Scale Part III: Motor Exam (MDS-UPDRS III) 2 
 the Parkinson’s Disease Questionnaire 39 summary index score (PDQ-39SI) 4 
Adverse events (AEs) will be monitored. A safety endpoint will assess whether device therapy 
negatively impacts balance, functional mobility or gait for participants with PD and will be 
measured via the mini-BESTest 5. 

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Exploratory endpoints will include the following:  
 The Montreal Cognitive Assessment (MoCA)  
 The Oral Symbol Digit Modality Test (oSDMT) 
 The Modified Schwab and England Activities of Daily Living Scale (S&E) 
 The Parkinson’s Sleep Scale-2 (PDSS-2) 
 The Epworth Sleepiness Scale (ESS) 
 The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) 
 The Geriatric Depression Scale (GDS) 
 The Parkinson’s Anxiety Scale (PAS) 
 The Patient Reported Outcome – Parkinson’s Disease (PRO-PD) 
 The MDS-NMS Non-Motor Fluctuations (NMF) Total Score 
 The Hoehn & Yahr score 
 Zarit Burden Interview 
 The Unified Parkinson’s Disease Rating Scale Part I (UPDRS I) 
 EncephaLogTM Finger Tapping Test 
 EncephaLogTM Timed Up and Go Test (TUG) - 3-meter TUG at home and 10-meter TUG in 
the clinic 
 Patient Global Impression of Improvement (PGI-I)– OLE only 
 International Parkinson and Movement Disorder Society Sponsored Unified Parkinson’s 
Disease Rating Scale Part I: Non-Motor Aspects of Experiences of Daily Living (MDS-
UPDRS I) 
 
Treatment adherence, TNM™ Device usability/satisfaction and itemized answers from UPDRS 
IV will also be evaluated. A Non-Motor Symptom focused Clinical Global Impression of 
Improvement (NMS-CGI-I) and a transition question evaluating impression of change for NMS 
will also be used to help establish the clinical significance for the primary endpoint. 
1.1.4 Study Population 
This study seeks to evaluate the safety and effectiveness of TNM™ for non-demented adult 
patients diagnosed with PD who report limitations in activities of daily living, experience at least 
a moderate burden of NMS (i.e., score ≥ 9 on the MDS-UPDRS Part I at study screen) and are 
currently taking stable doses of oral DRTs. 
1.1.5 Description of Sites/Facilities Enrolling Participants 
This study will be carried out at a minimum of 15 centers. A majority of the sites are in the United 
States. There will also be some sites in the United Kingdom. The sites will include movement 
disorder specialty clinics, community-based neurology clinics, and academic centers. All sites will 
have the expertise in the conduct of clinical trials for Parkinson’s disease therapeutics and 
documentation of staff training for all clinical assessments. 
1.1.6 Description of Study Intervention 
This study will investigate the safety and efficacy of tvCVS treatments for the management of 
symptoms related to PD. The tvCVS treatments will be delivered by means of the solid-state 
TNM™ device, developed by SNS. The Device delivers software-driven, time-varying thermal 

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waveforms to modulate neural areas, including the brainstem, by means of caloric vestibular 
stimulation. The Device is fashioned like a set of over-the-ear music earphones, with two 
independently controlled thermoelectric devices attached to aluminum earpieces that fit inside the 
ear canals and abut, but do not enter, the bony portion of the ear canals (see Figure 1A).  Specific 
details regarding the Device design have been previously published 6. 
Study participants will be randomized to receive one of two treatment types. In the active treatment 
condition, participants will receive tvCVS by means of saw-tooth waveforms where a warm 
sawtooth is delivered to one ear and a cold sawtooth is delivered to the other ear (see Figure 1C 
for an example). The warm sawtooth will go from body temperature to 42 °C, and the cold 
sawtooth will go from body temperature to 17 °C. The two waveforms will be delivered 
simultaneously but will have different oscillation frequencies. After each 2-day period, the warm 
and cold waveforms will be switched so that the opposite ears will receive the different caloric 
stimulation. Thus, every 2 days, the ear receiving the cold stimulus will be switched to the warm 
stimulus and vice versa.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
In the passive treatment condition, no power will be delivered to the heating and cooling elements 
within the headset. However, a small amount of caloric vestibular stimulation will be transmitted 
Figure 1. TNM device and treatment. (A) Schematic showing device design of the 
Generation 4.0 TNM Device. (B) Patient undergoing treatment while wearing the 
TNM headset and lying on an incline wedge pillow. (C) Example of target and actual 
thermal profiles of the saw-tooth, time-varying thermal waveform used for the active 
treatment condition. (D) Example of the thermal profile of the passive treatment 
condition 

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upon placement of the aluminum earpieces, which will be initially cool (i.e., at room temperature) 
at the start of the treatment and will gradually warm to body temperature upon insertion into the 
participants external ear canals. This passive treatment provides the minimal amount of passive 
stimulation that the device feasibly allows, to maintain consistency with the active treatment 
device.  All other sensory experiences associated with device treatment will be the same and 
include the following: auditory tones indicating the start and stop of the treatment, a faint whirring 
noise elicited by the cooling fans within the headset, pressure sensations felt when wearing the 
headset, and the visual displays on the LED screen. Additionally, the choreography of starting, 
running and stopping a treatment will be identical for both active and passive stimulation 
conditions. 
In both conditions, nineteen-minute treatments will be delivered twice-daily in the supine position, 
and ideally, treatments will be separated by at least one hour. This protocol will be followed for 
84 days.  Additional window days will be available to accommodate for potential scheduling 
conflicts (+/- one day for phone calls, +/- 3 days for virtual and clinic visits, and + 10 days for 
Covid-19 related scheduling conflicts). 
The same time-varying saw-tooth waveform and BID treatment schedule was used in a pivotal 
trial investigating the safety and efficacy of TNM™ therapy for the prevention of episodic 
migraine and the pilot study in PD7, 8. Both studies demonstrated high tolerability of tvCVS 
treatments. 
 
 

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1.2 Schema  
Figure 2. Visit Schedule - RCT 
 
 
 
 
 

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Figure 3. Visit Schedule - OLE 
 
 
 
 

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1.3 Abbreviations 
ADL: activity of daily living  
AEs: adverse events  
ANCOVA: analysis of covariance  
BLave: average score from a given assessment from the two baseline assessments 
BID: twice daily  
CFR: Code of Federal Regulations 
CGI-I: Clinical Global Impressions of Improvement Scale  
CRA: Clinical Research Associate  
C-SSRS: Columbia Suicide Severity Rating Scale 
CVS: caloric vestibular stimulation   
DRN: dorsal raphe nucleus 
DRT: dopamine replacement therapy 
ePROs: electronic patient reported outcomes 
ESS: Epworth Sleepiness Scale  
FDA: United States Food and Drug Administration  
FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue Scale  
GCP: Good Clinical Practice  
GDS: Geriatric Depression Scale  
ICF: Informed Consent Form 
ICH: International Conference on Harmonisation of Technical Requirements  
ID: identification  
IJLI: intrajejunal levodopa infusion  
IRB: Institutional Review Board  
ITT: intention-to-treat  
LED: light emitting diode  
MCID: minimal clinically important difference  
MDS-NMS: International Parkinson and Movement Disorder Society Nonmotor Rating Scale   
MDS-UPDRS I: International Parkinson and Movement Disorder Society Sponsored Unified 
Parkinson’s Disease Rating Scale Part I: Non-Motor Aspects of Experiences of Daily Living  
MDS-UPDRS II: International Parkinson and Movement Disorder Society Sponsored Unified 

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Parkinson’s Disease Rating Scale Part II: Motor Aspects of Experiences of Daily Living  
MDS-UPDRS III: International Parkinson and Movement Disorder Society Sponsored Unified 
Parkinson’s Disease Rating Scale Part III: Motor Exam  
MDS-UPDRS: the International Parkinson and Movement Disorder Society Sponsored Unified 
Parkinson’s Disease Rating Scale  
MHRA: Medicines and Healthcare products Regulatory Agency  
Mini-BESTest: mini-Balance Evaluation Systems test  
MoCA: Montreal Cognitive Assessment  
NMF: non-motor fluctuations 
NMS: non-motor symptom  
NMS-CGI-I: Non-Motor Symptom focused Clinical Global Impression of Improvement  
NMSS: Non-Motor Symptom Scale  
NSR: non-significant risk  
OLE: open label extension  
OLE SAP: the statistical analysis plan for analysis planned for the open label extension  
oSDMT: oral Symbol Digit Modality Test  
PAS: Parkinson’s Anxiety Scale  
PD: Parkinson’s disease  
PDQ-39SI: Parkinson’s Disease Questionnaire 39 summary index score  
PDSS-2: Parkinson’s Disease Sleep Scale-2  
PI: Pulsatility Index  
PP: per-protocol  
PPN: pedunculopontine nucleus  
PRO-PD: Patient Reported Outcome – Parkinson’s Disease   
QoL: quality of life  
RCT: randomized clinical trial  
RCT SAP: the statistical analysis plan for analysis planned for the randomized controlled trial 
REC: Research Ethics Committee  
SAE: serious adverse event  
SADE: serious adverse device effect 
SAPs: statistical analysis plans 
S&E: Modified Schwab and England Activities of Daily Living Scale  

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SNpc: Substantia Nigra pars compacta  
SNS: Scion Neurostim, Inc  
TNM™: ThermoNeuroModulation  
tvCVS: timed-varying caloric vestibular stimulation  
TUG: Timed Up and Go  
UADE: unexpected adverse device effect  
UK: United Kingdom 
UPDRS: Unified Parkinson’s Disease Rating Scale 
VN: vestibular nuclei   
ZBI: Zarit Burden Interview 
 
 

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2 Introduction 
2.1 Study Rationale:   
Parkinson’s disease (PD) is a progressive neurodegenerative disorder afflicting approximately 10 
million people world-wide. PD affects multiple neurotransmitter systems in the central and 
autonomic nervous systems and is characterized by a wide range of both motor and non-motor 
symptoms.  The cardinal motor features of PD (i.e., bradykinesia, rigidity and resting tremor) can 
typically be treated effectively with DRTs, at least during the early stages of the disease. However, 
a number of complications arise with prolonged use of DRTs including reduced efficacy, 
development of motor dysfunction including periods of wearing off and/or involuntary dyskinesias 
and the development of nonmotor complications such as hallucinations, compulsive behaviors and 
drowsiness.  Late-stage interventions, such as deep brain stimulation (DBS) or intrajejunal 
levodopa infusion (IJLI), are sometimes used to address motor symptoms once patients begin to 
experience significant reduction in DRT efficacy and/or the emergence of motor complications. 
However, these interventions are costly, pose significant surgical and post-surgical risks and are 
associated with additional side effects that make them unsuitable for certain patients. Thus, a 
noninvasive therapy with low side-effects would provide a significant advancement in the standard 
of care for PD.  
An even greater need for the PD community are therapies that adequately address the non-motor 
symptoms (NMS) related to PD. NMS are core features of PD and cross a broad spectrum of 
domains including cognitive impairments/dementia, sleep disorders, daytime sleepiness/fatigue, 
mood dysfunction, autonomic dysfunction, urinary dysfunction, gastrointestinal dysfunction, 
perceptual impairments and sexual dysfunction.  NMS often present early in the disease and, in 
many cases, prior to the onset of motor symptoms. They tend to increase in both occurrence and 
severity as the disease progresses, and significantly impact quality of life 9, 10, often more so than 
the classic motor symptoms associated with the disease11, 12. Additionally, NMS greatly increase 
caregiver burden13, and are major determinants for placing patients in nursing homes. Even with 
awareness of the substantial impact on quality of life, NMS symptoms often go untreated for 
several reasons. First, patients often do not declare these symptoms in the clinic, as many are 
unaware that NMS they may be experiencing are associated with PD14.  Second, NMS often are 
not given significant attention in the clinic, due to the complexity of treating each individual NMS 
with an individualized therapy, as is the standard approach15.   PD patients typically present with 
an average of four to ten NMS and therefore, adequate treatment for NMS typically results in 
patients taking many medications to treat their symptoms.  This multi-drug approach substantially 
increases the treatment administration burden for the patient- a major complaint from patient 
groups17 and significantly impacts the health economics of treating patients with PD.  Furthermore, 
each individual therapy is associated with its own side-effect profile, and therefore, each therapy 
must be weighed carefully to determine whether the therapy is likely to provide an overall benefit 
to the patient. A noninvasive therapy that could effectively address even one non-motor symptom 
with low side-effect profile would benefit patients. However, a single, noninvasive and low side-
effect therapy that might successfully address multiple symptoms could have an even greater 
impact in that it may provide clinicians a simple approach to address NMS and have positive 
effects on both treatment adherence and health economics15.   
 

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2.2 Background: 
2.2.1 Vestibular System 
The vestibular system has an expansive reach throughout the brainstem and higher brain regions. 
Three semi-circular canals in each ear are oriented at right angles to each other.  This allows these 
components of the vestibular system to detect rotational movement in any plane.  Fluid within 
these canals will move relative to the canals during head movements.  This fluid pushes on a 
structure called a cupola, which contains hair cells that translate mechanical movement to electrical 
signals.  The vestibular system utilizes endogenous sensory pathways for signal propagation, 
making it an ideal conduit to safely provide brain-wide neurostimulation. 
Caloric vestibular stimulation (CVS) is a technique developed more than a century ago and is 
commonly used to diagnose balance disorders or to confirm absence or existence of brainstem 
function. Historically, water or air irrigators have been used to warm or cool the external auditory 
canal of patients. Both warming and cooling temperature changes lead to density changes in the 
endolymphatic fluid in the semicircular canals and create convection currents, which result in 
cupular deflection, change in the tonic firing rate of the vestibular nerves and elicit the vestibulo-
ocular reflex or horizontal nystagmus6. Warming temperatures increase while cooling 
temperatures decrease the tonic firing rate of the vestibulocochlear nerves (see Figure 3). 
Vestibular stimulation has been associated with release of a number of neurotransmitters including 
serotonin18, histamine19, acetylcholine20, 21 and GABA22.  It has also been shown to modulate 
various networks and nuclei in the brain including the basal ganglia23 cerebellum, brainstem, 
hippocampus, insula24, thalamus25, locus coeruleus26 and prefrontal cortex27, suggesting 
significant potential for CVS to modulate both motor and non-motor functions 6.  Furthermore, 
tracing studies28-31, 32 have demonstrated monosynaptic or polysynaptic connectivity of the 
vestibular nuclei (VN) to several regions involved in the PD motor pathology including: 
1. the dorsolateral striatum (caudate/putamen) via the thalamus and cortex33 where an 
imbalance in striatonigral and striatopallidal output due to loss of dopamine 
transmission is thought to underlie the bradykinesia symptoms in PD34, 
2. the pedunculopontine nucleus (PPN) located within mesencephalic locomotor region 
of the reticular formation 35, thought to be involved in gait and postural stability (as 
well as several non-motor functions) and which has recently become a target for DBS 
in PD36-38, and 
3. the cerebellum which has been implicated in the expression of levodopa-induced 
dyskinesia39, is believed to play a modulatory roll in resting tremor, and is 
interconnected with several basal ganglia nuclei including the striatum via the thalamus 
as well as the globus pallidus external and subthalamic nucleus via the pontine nuclei40.   
 
The VN also provides direct and/or indirect inputs to many regions implicated in non-motor PD 
symptoms, including: 
1. the corticolimbic network (anterior cingulate cortex, dorsolateral prefrontal cortex, 
amygdala and hippocampus), the dorsal raphe nucleus (DRN) and the parabrachial 
nucleus which have all been implicated in depression and anxiety24, 28, 32 

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2. the sensory association cortices, temporal-parietal regions, peri-sylvia, PPN and 
hippocampal structures implicated in memory and cognition36, 41,  
3. the pariaquaductal gray implicated in blood pressure/ orthostatic hypotension42 and 
bladder control (the latter of which is also regulated by other regions that receive direct 
or indirect VN inputs including the hypothalamus, cerebellum, basal ganglia and frontal 
cortex43), and  
4. the PPN and DRN implicated in sleep and arousal36, 37, 44-46.  A role for the PPN and 
thalamus in visual hallucinations in PD has been established47.  Furthermore, galvanic 
vestibular stimulation, a related approach, has been shown to increase deficient 
functional connectivity of the PPN in PD48. 
 
Finally, while much is unknown about the neuropathology underlying the complications arising 
from DRTs, abnormal synchrony between basal ganglia and cerebellar circuits39 and alterations in 
striatal and prefrontal cortical function49 are thought to underlie levodopa induced dyskinesias and 
dopamine dysregulation syndrome, respectively.  The VN connectivity with these regions, 
depicted in Figure 3, suggests potential for CVS-mediated relief from the complications of such 
therapies. 
 
2.2.2 Pre-Clinical and Clinical Study Background 
Several preclinical studies support the potential effectiveness of vestibular stimulation in the 
treatment of PD symptoms including a hemi-parkinsonian rat study showing that galvanic 
vestibular nerve stimulation (a related technique that applies electrical rather than thermal currents 
but which is less suitable for home administration), is associated with improved locomotor ability 
and increased GABA concentration in substantia nigra pars reticulata22.  Additionally, human 
studies in laboratory settings have demonstrated that galvanic vestibular stimulation reduces 
postural sway, postural response time 50 and bradykinetic rest-to-active transitions in the wrist and 
trunk51. Vestibular stimulation has also recently been shown to help normalize functional 
connectivity between the pedunculopontine nucleus – a structure of emerging functional 
significance for motor and non-motor features of PD - and the pallidum and inferior parietal and 
cerebellar cortices48.  Although these results demonstrate the potential therapeutic value of 
vestibular stimulation to address PD symptoms, they were acquired under highly prescribed and 
controlled laboratory conditions, utilized a narrow range of mostly experimental rather than 
clinical outcomes, and perhaps most importantly, only evaluated the acute effects of treatment (i.e., 
within a few hours of stimulation).   

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Figure 3. The effects of CVS on the vestibulocochlear nerves and the connectivity of 
the vestibular nuclei to brain regions implicated in Parkinson’s disease.  The 
schematic illustrates the induction of CVS where warming temperatures (red ear insert) 
increase, and cooling temperatures (blue ear insert) decrease the tonic firing rate of the 
vestibulocochlear nerve (8th cranial nerve).  The vestibulocochlear nerve conveys signals 
from the sensory organs to the VN located within the brainstem. The vestibular signal is 
then propagated throughout widespread regions of the brain via synaptic and polysynaptic 
relays. 

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Despite the evidence for widespread activation of neural circuits by means of CVS52 and a long 
history to support its clinical safety, investigation into the therapeutic potential of CVS has been 
limited by the lack of device design suited for prolonged treatments, appropriate control of dosing, 
avoidance of adaptation, and home use.  To address these deficits, SNS developed a novel, solid-
state device for delivering CVS6. The TNM™ Device provides controlled, time-varying thermal 
waveforms (tvCVS) that enable prolonged vestibular stimulation in absence of semicircular canal 
adaptation which is observed after a few minutes of constant temperature CVS53.   
In previous SNS sponsored clinical trials, including both a pivotal RCT investigating the safety 
and efficacy of Device treatment for the prevention of episodic migraine54 as well as a single-site 
RCT investigating the feasibility and efficacy of TNM™ for the management of symptoms 
associated with PD, a previous version of the Device (Generation 3.1) was found to be easy to use 
and treatment adherence was excellent. Additionally, participants in both studies found Device 
treatments to be highly tolerable with no reported significant or unexpected adverse events related 
to device use. Furthermore, no negative actions on balance mood or cognition have been reported 
thus far 7, 8, 54. Rather, evidence from the PD RCT suggested that tvCVS may improve these 
domains7, 8, 54.  The next generation device (4.0) which has been adapted to improve usability for 
patients with PD will be utilized in this study.   
Notably, previous studies have demonstrated that twice-daily tvCVS treatments with the TNM™ 
Device for 8 weeks (56 days) is associated with clinically-relevant and persistent reductions in 
both motor symptoms and NMS in PD 7, 8, 55.  Robust reductions in NMS total burden were 
demonstrated using two independent validated measures, the Non-Motor Symptom Scale 
(NMSS)56 and the MDS-UPDRS Part I 2. Improvement in NMS were evident across a broad 
spectrum of domains including attention/memory, mood/cognition, sleep/fatigue, sexual function, 
gastrointestinal function and urinary function. Evidence for reduced global NMS burden was 
further supported by substantive improvements in independent measures of specific NMS 
including the MoCA and the Hospital Anxiety and Depression Scale. 
Participants receiving active treatment also demonstrated significant improvements in motor 
function according to the MDS-UPDRS II, MDS-UPDRS III and the TUG. All participants in the 
single-site RCT study were taking stable doses of DRTs.  MDS-UPDRS motor exams were 
conducted by a single rater who was blind to treatment allocation, and all assessments were 
performed at a consistent interval from the last DRT dose in the case of oral DRTs.  
For both motor and non-motor symptoms, additional benefits were demonstrated in the second 4 
weeks (28 days) of treatment relative to the first, and the clinical effects in the PD study were 
durable (i.e., stable one-month post-treatment).  Allocation guess data from this study indicated 
that participants remained blind to treatment allocation.  
 
2.3 Risk Benefit Assessment 
There is a long-standing history to support the safety of CVS as a technique, as the approach has 
been used diagnostically for more than a century in patients from infancy through late adulthood. 
The low incidence of AEs potentially related to Device use in PD or other conditions, and absence 
of serious adverse events (SAEs), unexpected adverse device effects UADEs or negative sequela 
on measures of mood, cognition or balance in the previous randomized clinical trials7, 8, 54 supports 

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the safety of longitudinal tvCVS treatments. As with earlier models, the TNM™ Device is intended 
for home-use.   
An earlier version of the TNM™ Device (3.2) was granted De Novo market entry by the U.S. Food 
and Drug Administration (US FDA) as a Class II device for the prevention of episodic migraine 
(12 years of age and older).  The Device is also CE marked in the E.U. as a Class IIa device for 
the prevention of episodic migraine in adults.  Furthermore, the US FDA has designated the Device 
to be of non-significant risk for studies of Parkinson’s disease. 
3 Objectives and Endpoints 
For the RCT, endpoints will evaluate differences in change scores at the end of the treatment period 
relative to the average baseline between active treatment-arm and passive treatment-arm 
participants, unless otherwise noted. The purpose of the OLE study is to gather the additional data 
needed to support reimbursement.  Refer to the OLE SAP for information regarding endpoint 
evaluation in the OLE. 
3.1 Primary endpoint 
3.1.1 Objectives:  
The primary objective of this study will be to evaluate the effectiveness of tvCVS for 
reducing non-motor symptom burden in participants with PD. 
3.1.2 Endpoint:  
MDS-NMS – a rater completed assessment evaluating burden of NMS in PD: 
The reduction in the MDS-NMS total score at the end of the treatment period relative to 
the average baseline score will be evaluated to determine whether changes in the active 
group are significantly greater to those in the passive treatment group. The MDS-NMS 
Non-Motor Fluctuations Subscale will NOT be included as part of the primary endpoint. 
3.2 Secondary endpoints 
3.2.1 Objectives:  
This study will seek to establish whether TNM™ treatments provide adjuvant therapeutic 
effectiveness beyond that observed with dopamine replacement therapies (DRTs) to (1) 
provide global benefits, (2) improve activities of daily living related to motor function, (3) 
provide clinically meaningful change (4) improve motor symptoms and (5) improve quality 
of life (QoL) for participants with PD. 
3.2.2 Endpoints:  
 The combined measure of MDS-UPDRS Parts I, II, and III– a measure of the global 
impact of PD across diverse domains (i.e., summed score from the MDS-UPDRS Parts 
I, II and III) 
 MDS-UPDRS II – patient reported evaluation of activities of daily living relating to 
motor function 
 CGI-I - clinician assessment in how much the patient's illness has improved or 

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worsened relative to a baseline state at the beginning of the intervention; may also be 
referred to as the overall CGI-I 
 MDS-UPDRS III - clinician-scored motor exam  
 the Parkinson’s Disease Questionnaire 39 summary index score (PDQ-39SI) – quality 
of life measure that assesses how often people living with PD are affected across 8 
dimensions of daily living 
3.3 Safety endpoints:  
3.3.1 Objectives:  
This study will seek to establish the safety of TNM™ by monitoring adverse events and 
by evaluating whether TNM™ is associated with a worsening of balance, functional 
mobility and gait in participants with Parkinson’s disease. 
3.3.2 Endpoints:  
 AE frequency 
 mini-BESTest – a performance-based measure of dynamic balance, functional mobility 
and gait 
3.4 Exploratory Endpoints 
3.4.1 Objectives:  
The exploratory endpoints of this trial have been selected to provide further support the 
primary and secondary endpoints of the study and to reveal the temporal kinetics of 
response to TNM™ therapy.   
3.4.2 Endpoints:  
 the Montreal Cognitive Assessment (MoCA) - rapid screening instrument for mild 
cognitive dysfunction in patients with neurologic disorders including PD (3 different 
versions [8.1, 8.2, and 8.3] will be used to avoid learning effects) 
 the Oral Symbol Digit Modality Test (oSDMT) – quickly screens for organic cerebral 
dysfunction by measuring processing speed 
 the Modified Schwab and England Activities of Daily Living Scale (S & E) 57 58 58 58 58 
58 58 58 58 58  -clinical outcome assessment of an individual’s ability to function in 
activities of daily living  
 the Parkinson’s Sleep Scale-2 (PDSS-2)- assessment to quantify nocturnal sleep issue 
in PD 
 the Epworth Sleepiness Scale (ESS) – a brief measure that is commonly used to assess 
daytime sleepiness in PD and other disorders  
 the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) - a 
measure of an individual's level of fatigue during their usual daily activities over the 
past week  
 the Geriatric Depression Scale-15 (GDS-15) – a short questionnaire for assessing 
depression in older adults 
 the Parkinson Anxiety Scale (PAS) – a brief questionnaire to detect anxiety severity in 
PD 

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 the Patient Reported Outcome – Parkinson’s Disease (PRO-PD) – a self-rating tool to 
assess PD symptom severity  
 the MDS-NMS Non-Motor Fluctuations (NMF) Total Score - a rater completed 
assessment evaluating fluctuations of NMS in PD 
 the Hoehn & Yahr score – staging tool describing the level of disability in PD 
(subcomponent of the MDS-UPDRS III) 
 Zarit Burden Interview - measure of caregiving burden completed by caregivers  
 Unified Parkinson’s Disease Rating Scale Part I (UPDRS I): a measure of mentation, 
behavior and mood in PD 
 Finger tapping test – smart phone application (EncephaLogTM) providing a quantitative 
measure of bradykinesia 
 Timed Up and Go Tests – smart phone application tests that measures gait and the 
probability of falls in adults (EncephaLogTM) 
• 3-meter TUG (time to complete)  
• 10-meter TUG (stride length, cadence, rotation time, time to complete) 
 Patient Global Impression of Improvement – a patient determined scale to assess how 
much their illness has improved or worsened relative to a baseline state at the beginning 
of the intervention (OLE measure only) 
 International Parkinson and Movement Disorder Society Sponsored Unified 
Parkinson’s Disease Rating Scale Part I: Non-Motor Aspects of Experiences of Daily 
Living (MDS-UPDRS I) 
Descriptive statistics will be provided for treatment adherence and for itemized answers 
from the Device Usability Questionnaire and UPDRS IV (a measure of complications of 
therapy in PD). An NMS-focused Clinical Global Impression of Improvement (NMS-CGI-
I) (a clinician determined scale to assess how much NMS have clinically improved or 
worsened relative to a baseline state at the beginning of the intervention) and a transition 
rating question (a patient reported outcome assessing how much their NMS have improved 
or worsened relative to a baseline state at the beginning of the intervention) will be utilized 
to verify the clinical significance of the primary endpoint.  For additional information, see 
the RCT SAP. 
4 Study design: 
4.1 Study Schedule and Activities 
The STEM-PD RCT will last 113 days (plus additional visit window days), beginning with a pre-
treatment baseline period of four weeks (28 days).  The baseline period will be followed by the 
treatment period of 12 weeks (84 days).  During the RCT, clinical assessments will occur every 4 
weeks (28 days) and efficacy will be determined by evaluating therapeutic gains at the end of 12-
week (84 day) treatment period relative to the average of the baseline.   
Upon completion of the STEM-PD RCT, participants will be offered the opportunity to participate 
in the open label extension (OLE) phase (to commence immediately upon completion of STEM-
PD RCT) which will last 36 weeks (252 days).  In the OLE, all study participants will receive 
active treatment for 12 weeks (84 days) followed by a 16-week (112 day) post treatment 
observation period and then an additional 8-week (56 day) treatment period.  See Schema for 

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details.  
The phases and activities of the study are listed below: 
4.1.1 STEM-PD RCT 
Pre-screening procedures: Sites will recruit potential participants from their 
practice/service or the general public as long as inclusion/exclusion criteria can be verified.  
The use of advertisements may be used at the site's discretion. During the pre-screening 
period, the study should be described, preliminary questions answered, and review of 
potential participant’s medical records can occur, however, no protocol-specific activities 
should occur until after informed consent is obtained and documented.   
 
Study screening procedures (Day –14 to –1):  
Informed Consent 
Participants will be shown an example of the Study Device as part of the informed consent 
process.  Potential participants should be given a private space to review the ICF and an 
ample opportunity to have all questions answered. Capacity to provide consent must be 
assessed by a clinician with experience working with Parkinson’s Disease patients, and 
should be documented, as no Legally Authorized Representative is allowed. Informed 
consent should be signed and dated by both the study participant and authorized study staff 
performing the informed consent process, and a signed and dated copy provided to the 
participant, prior to any study related activities being conducted.  Although participants 
will only consent at the screen for involvement in the 16-week (112 days) STEM-PD RCT 
portion of the study, screening applicants who do not anticipate participating in the 36-
week (252 days) OLE will be excluded from the study.  
 
Additionally, the protocol-required study partner will also be provided with an informed 
consent to review and discuss. The purpose of the informed consent for the study partner 
is to ensure that they understand and agree that they are required to assist, if necessary, the 
participant in the execution of certain at home assessments, such as the TUG, as well as 
answer specific questions by the study staff related to the participant’s overall health and 
activities of daily living. The study partner should be afforded the same informed consent 
process stipulations as the participant, including that the informed consent be signed and 
dated by both the study partner and the authorized research study staff performing the 
informed consent process, and provided a sign and dated copy.  
 
Screening steps: The screening activities should be performed per the schedule of events 
(SOE) noted in the appendix. If at any time study staff recognizes that the recruit does not 
meet the inclusion and exclusion criteria for the study, they will inform the individual being 
screened and will note the reason for screen failure in the study documentation.  
 
 Intake of medical history and concomitant medications 
 MoCA v8.1 
 MDS-UPDRS Part I - screening tool for non-motor symptom burden 
 Ear exam   
 C-SSRS- questionnaire regarding suicidal thoughts 

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 PRO-PD 
 Conduct Height/Weight measurements 
Additionally, the study staff will: 
 Activate EncephaLogTM account and train the participant on study procedures using 
the application.  
 Assist participant with setup of the MediData application on their phone 
 Provide and review instructions for virtual visits. 
 Review general study schedule and timeline. 
 Review of inclusion/exclusion criteria 
Baseline 1 (telemedicine visit)- day 0:  The baseline activities should be performed per 
the SOE in the appendix. **Of note, the collection of MDS-UPDRS Part III data should 
begin 30-90 minutes after time of the last DRT dose, with participant confirmation of on-
state. The timing of the administration of the MDS-UPDRS Part III from dose should be 
recorded and kept consistent at each administration of the assessment for that participant.  
 Confirmation of timing of last DRT 
 Viewing of the educational video related to PD with opportunity to ask follow-up 
questions 
 Modified MDS-UPDRS Part III (excluding items related to rigidity and postural 
reflexes)  
 Concomitant medication and adverse event review 
 MDS-NMS (does not include the NMF subscale) 
 MDS-UPDRS Part II 
 PDQ-39 
Virtual visits will be performed using the site’s standard of care telemedicine platform. 
 EncephaLogTM testing: Participants will complete the finger tapping tests and 3m TUG 
test once weekly at home, at a time convenient for them. The application will provide the 
participant with notifications at the regularly scheduled interval timing to remind them to 
complete the assessment.  Participants who received a smart phone strap and utilized it for 
the first administration of the TUG should continue to complete the TUG using the strap 
for all timepoints. Assessments should be performed in the on-state. 
Phone contact – day 15 (+/- 1 day): The study coordinator will call the participant at the 
scheduled time, to ask if the participant has experienced any adverse events or changed any 
medications since the start of the study. Study sites are encouraged to have continuous 
communication with the study participant and study partner outside of the defined protocol 
visits, in the manner most accommodating to them, to assist with rapport, retention, and 
the identification of medication changes or adverse events in real-time. 
Baseline Patient reported outcomes – day 28 (+/- 1 day): The study coordinator will call 
the participant at the scheduled time to ask if the participant has experienced any adverse 
events or changed any medications since the start of the study.  They will then ask 
participants to complete the ePROs at a time when they are in an on-state: 
 PDQ-39 
 MDS-UPDRS Part II 

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 FACIT-F  
 GDS 
 PAS 
 PDSS-2  
 ESS  
Baseline 2 (in clinic) – day 29 (+/- 3 days): 
The randomization activities should be performed per the SOE in the appendix. The 
collection of MDS-UPDRS Part III data should begin 30-90 minutes after time of the last 
DRT dose, with participant confirmation of on-state. The timing of the administration of 
the MDS-UPDRS Part III from dose should be recorded and kept consistent at each 
administration of the assessment for that participant. 
 Concomitant medication and adverse event review 
 MDS-UPDRS Part III with video (captured using the Machine Medicine Kelvin 
software)  
 mini-BESTest  
 10m TUG (EncephaLogTM) 
 MDS-UPDRS I 
 Ear exam  
 Weight 
 Pregnancy test, as required  
 MDS-NMS (including the Non-Motor Fluctuations Subscale) 
 MoCA v8.2 
 CGI baseline interview (overall and focused) 
 oSDMT  
 Modified Schwab & England 
 UPDRS I 
 UPDRS IV 
 PRO-PD  
 Zarit Burden Interview 
 Review of inclusion/exclusion criteria 
The participant should be fitted, and the device adjusted as necessary with the ear pad 
selection documented.  Participants should confirm that they find wearing the unpowered 
device to be comfortable enough to proceed with the study treatment prior to 
randomization. If they do not, the reason for screen failure should be noted in the study 
documentation.  
Randomization will occur only after all scheduled assessments and activities have been 
completed and normal findings on the ear exam is verified and will occur by selecting an 
envelope from the randomization package, scanning the bar code to the Device and 
ensuring that the treatments are loaded. The participant and study partner will be trained 
on how to use and care for the Device, take it home and commence with twice daily 
treatments. 
 

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Treatment Period: The 12 weeks (84 days +/- 3 days) following the pre-treatment baseline 
period constitute the treatment period.  Participants will self-administer treatments twice 
daily for the full treatment period up until the scheduled end of treatment visit.  Treatment 
adherence will be recorded by the device.   
 
Study staff will confirm and document that they remain blinded to treatment allocation at 
the beginning of every study visit after randomization. If a study staff member directly 
responsible for assessment or safety evaluation becomes unblinded, they will no longer be 
eligible to complete the delegated study assessments per the protocol for that participant.  
Phone contacts: (days 43, 56, 71, 84, 99, 112: +/- 1 day) 
Participants will complete interim assessments at weeks 8 (day 56) and 12 (day 84).  During 
phone calls scheduled every 2 weeks, study staff will review concomitant medications, 
potentials adverse events and device treatment adherence and issues with the study 
participant.  Study sites are encouraged to have continuous communication with the study 
participant and study partner outside of the defined protocol visits, in the manner 
most accommodating to them, to assist with rapport, retention, and the identification 
of medication changes or adverse events in real-time. 
 Interim assessments (week 8/days 56, 57 and week 12/days 84, 85) 
i. ePROs (days 56 and 84 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
• Transition Questionnaire (day 56 only) 
ii. Treatment Virtual visits 1 and 2 (days 57 and 85 +/- 3 days) 
• Concomitant medication and adverse event review  
• MDS-NMS (does not include the NMF subscale) 
• Modified MDS-UPDRS Part III (excluding items related to rigidity 
and postural reflexes)  
Virtual visits will be performed using the site’s standard of care 
telemedicine platform. 
 End of treatment visit (week 16/days 112, 113 or early termination)  
i. ePROs (day 112 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
• GDS 
• PAS 
• PDSS-2  
• ESS  
• FACIT-F  
ii. In clinic visit (day 113 +/- 3 days) 
• Concomitant medication and adverse event review 
• MDS-UPDRS Part III with video (captured using the Machine 
Medicine Kelvin software).  The timing of the administration of the 
MDS-UPDRS Part III from last DRT dose should be recorded and 

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kept consistent with the timing from last dose to administration as 
noted in the BL2 visit. Administration must occur within 30 – 90 
minutes after last dose.  
• Mini-BESTest 
• 10m TUG (EncephaLogTM) 
• MDS-UPDRS Part I 
• MDS-NMS (includes the NMF subscale) 
• CGI-I (overall and focused) 
• S&E 
• Ear exam 
• MoCA v8.3 
• UPDRS I 
• UPDRS IV 
• PRO-PD 
• Zarit Burden Interview 
• Device Usability Questionnaire  
• Conduct weight measurement 
• Device return and supply return 
After the completion of study assessments, participants will be offered the opportunity to 
consent to the OLE of the study.  Participants will not be made aware of their allocation 
during the RCT portion of the study at any point. Used Devices will be promptly shipped 
back to the distributer using the Device Return form.   
4.1.2 Open Label Extension (Day 113 – 365) 
Baseline OLE Visit: Day 113 (+ 3 days): After signing the informed consent form (again capacity 
to provide consent should be determined and documented in the same manner as the RCT, as no 
Legally Authorized Representative is allowed) for the OLE, participants will complete their initial 
OLE treatment visit in the clinic per the SOE. This treatment visit can be completed either 
immediately following the completion of the end of treatment visit for the RCT or can be scheduled 
within 3 days.  Once normal findings are verified from the RCT Day 113 ear exam, participants 
will be allocated a new Device for treatment period one, and allocation information should be 
logged in the Device Inventory Control log. 
OLE first treatment period: Participants will self-administer treatments twice daily for the full 
treatment period up until the scheduled end of treatment visit (week 28/day 197).  Treatment 
adherence will be recorded by the device.  Participants will complete interim assessments at weeks 
20 (days 140, 141) and 24 (days 168, 169).   
 EncephaLogTM testing: Participants will complete the finger tapping assessment and 3m TUG 
test once weekly at home, at a time convenient for them through the end of the first treatment 
period (through day 197). The application will provide the participant with notifications at the 
regularly scheduled interval timing to remind them to complete the assessment.  Participants who 
received a smart phone strap and utilized it for the first administration of the TUG should continue 
to complete the TUG using the strap for all timepoints.  Assessments should be completed in the 
on-state. 
Phone Calls: (days 127, 140, 155, 168, 183, 196: +/- 1 day) 

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During phone calls scheduled every 2 weeks, study staff will review concomitant medications and 
potentials adverse events. Participants will return study Devices at their end of treatment visit. 
Study sites are encouraged to have continuous communication with the study participant and study 
partner outside of the defined protocol visits, in the manner most accommodating to them, to assist 
with rapport, retention, and the identification of medication changes or adverse events in real-time. 
 Interim assessments (week 20/days 140, 141 and week 24/days 168, 169) 
i. 
ePROs (day 140 and day 168 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
ii. 
Treatment Virtual visits 1 and 2 (day 141 and day 169 +/- 3 days) 
• Concomitant medication and adverse event review 
• MDS-NMS (does not include the NMF subscale) 
• Modified MDS-UPDRS Part III (excluding items related to rigidity and postural 
reflexes)  
Virtual visits will be performed using the site’s standard of care telemedicine 
platform. 
 End of treatment visit 1(week 28/days 196, 197 or early termination)  
i. 
ePROs (day 196 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
• GDS 
• PAS 
• PDSS-2  
• ESS  
• FACIT-F  
ii. 
In clinic visit (day 197 +/- 3 days) 
• Concomitant medication and adverse event review 
• MDS-UPDRS Part III with video (captured using the Machine Medicine Kelvin 
software).  The timing of the administration of the MDS-UPDRS Part III from 
last DRT dose should be recorded and kept consistent with the timing from last 
dose to administration as noted in the BL2 visit. Administration must occur 
within 30 – 90 minutes after last dose. 
• Mini-BESTest 
• 10m TUG (EncephaLogTM) 
• MDS-UPDRS Part I 
• MDS-NMS (includes the NMF subscale) 
• CGI-I (overall and focused) 
• S&E 
• PGI-I 
• Device Usability Questionnaire 
• Ear exam 
• MoCA v8.1 

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• UPDRS I 
• UPDRS IV 
• PRO-PD 
• Zarit Burden Interview 
• Conduct weight measurement 
• Device return and supply return 
 
Post-treatment observation: Participants will complete post-treatment follow up assessments at 
weeks 32 (days 224, 225), 38 (days 266, 267) and 44 (days 308, 309).   
 
Phone Calls: (days 211, 224, 239, 253, 266, 281, 295, 308: +/- 1 day)  
During phone calls scheduled every 2 weeks, study staff will review concomitant medications and 
potentials adverse events. 
 Follow-up Interim assessments 1 and 2 (week 32/days 224, 225 and week 38/days 266, 
267) 
i. 
ePROs (day 224 and day 266 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
ii. 
Virtual visits (day 225 and day 267 +/- 3 days) 
• Concomitant medication and adverse event review 
• MDS-NMS (does not include the NMF subscale) 
• Modified MDS-UPDRS Part III (excluding items related to rigidity and postural 
reflexes)  
Virtual visits will be performed using the site’s standard of care telemedicine 
platform. 
 Follow up visit 3 (week 44/days 308, 309)  
i. 
ePROs (day 308 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
• GDS 
• PAS 
• PDSS-2  
• ESS  
• FACIT-F  
ii. 
In clinic visit (day 309 +/- 3 days) 
• Concomitant medication and adverse event review 
• MDS-UPDRS Part III with video (captured using the Machine Medicine Kelvin 
software).  The timing of the administration of the MDS-UPDRS Part III from 
last DRT dose should be recorded and kept consistent with the timing from last 
dose to administration as noted in the BL2 visit. Administration must occur 
within 30 – 90 minutes after last dose. 
• MDS-NMS (includes the NMF subscale) 

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• S&E 
• Ear exam 
• MoCA v8.2 
• Mini-BESTest 
• PRO-PD 
• UPDRS IV 
• Zarit Burden Interview 
• Conduct weight measurement 
• Device allocation for treatment period two (requires that normal findings on ear 
exam be verified first) 
 
OLE second treatment period (days 309-365): Participants will self-administer treatments twice 
daily for the full treatment period up until the scheduled end of treatment visit (week 52/day 365 
+ window days).  Treatment adherence will be recorded by the device.     
 
Phone calls: (days 323, 337, 351 and 364 +/- 1 day) 
During phone calls scheduled every 2 weeks, study staff will review concomitant medications and 
potentials adverse events. Participants will return study Devices and at their end of treatment visit. 
 End of treatment visit 2 (week 52/days 364, 365 or early termination)  
i. 
ePROs (day 364 +/- 1 day) – to be completed in the on-state 
• PDQ-39 
• MDS-UPDRS Part II 
• GDS 
• PAS 
• PDSS-2  
• ESS  
• FACIT-F 
ii. 
In clinic visit (day 365 +/- 3 days) 
• Concomitant medication and adverse event review  
• MDS-UPDRS Part III with video (captured using the Machine Medicine Kelvin 
software).  The timing of the administration of the MDS-UPDRS Part III from 
last DRT dose should be recorded and kept consistent with the timing from last 
dose to administration as noted in the BL2 visit. Administration must occur 
within 30 – 90 minutes after last dose. 
• MDS-NMS (includes the NMF subscale) 
• CGI-I (overall and focused) 
• S&E 
• Ear exam 
• MoCA v8.3 
• PRO-PD 
• UPDRS IV 
• Zarit Burden Interview 
• Mini-BESTest 

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• Conduct weight measurement 
 
4.1.3 Covid-19 Related Schedule Deviations 
Additional protocol approved timing deviation can be considered for enrolled participants who are 
diagnosed with Covid-19 or are required to quarantine per local or national guidelines. Participants 
meeting these requirements may be afforded additional time windows for in person study visits of 
up to 10 days.  If guidelines prohibit the participant from coming to the clinic during the 10-day 
window, but the participant is able to complete a virtual assessment, data should be collected using 
this format with a note to file detailing the reasons for the virtual data collection. 
4.1.4 Snowbird Policy in OLE 
“Snowbirds” are study participants who live in warmer clients during the winter months and in 
cooler climates during the summer months. Snowbirds may be approved to change sites if they 
move to another location after completion of the RCT and can continue study activities at an IRB 
approved site in their new location. Any changes to sites must be pre-approved by the Sponsor 
prior to transition and the participant must be in the OLE portion of the study. The participant will 
be required to consent at the new site on the new site’s IRB-approved informed consent document 
and will be withdrawn from the original site. Source documents will be transferred from the 
original site to the new site, as coordinated by the Sponsor.  
4.2 Overall Design:  
This multicenter, double-blinded, controlled, randomized safety and effectiveness trial will be 
conducted to determine the superiority of TNM™ active treatment over passive treatment for 
reducing NMS burden in PD.  Participants will be randomized in a 1:1 ratio by site location.  
Intention-to-treat (ITT), modified intention-to-treat (mITT) and per-protocol (PP) data will be 
analyzed.  The study will be conducted across at least 15 clinical centers in the United States and 
the United Kingdom. All site personnel will be trained on and confirmed understanding of local, 
federal, and international regulations, as required. Participants will self-administer ~19-minute 
tvCVS treatments (BID) over a period of 12 weeks (84 days) using the TNM™ Device.  The 
primary and secondary endpoints for the RCT will compare treatment effect sizes (calculated as 
the change scores from the end of treatment to the BLave) between the active and passive treatment 
groups, unless otherwise noted in the RCT SAP.  Exploratory endpoints will evaluate supporting 
but independent measures. Analysis of safety and effectiveness will occur after the RCT is 
complete. This will allow for analysis of the RCT data while the OLE is being conducted. In the 
OLE, the potential for additional gains with longer treatment intervals and the durability of gains 
will also be evaluated. See the RCT SAP and the OLE SAP for additional details. 
4.3 Justification for Treatment Protocol:   
The results from the single-site RCT study provide strong evidence to support the safety and 
effectiveness of TNM™ Device treatments for managing the symptoms associated with PD.  
TNM™ Device treatments in this study utilized the same time-varying waveform and BID 
schedule as was used in a pivotal study that demonstrated TNM™ is a safe and effective 

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prophylactic for episodic migraine.  The study described herein will utilize the same active 
treatment waveform and BID treatment regimen as were used in these previous studies.  
In this study, participants will treat for 12 weeks (84 days) rather than 8 weeks (56 days), as was 
the case for the single-site RCT study.  The selection of a longer treatment interval was based on 
the finding that the treatment response, including measures of NMS burden, did not reach an 
asymptote during the 8 weeks of treatment.  These results suggest that additional gains may be 
obtained with longer treatment intervals.  Notably, 12-week treatment intervals were shown to be 
safe for the indication of episodic migraine, and there has been no evidence from a small crossover 
study in PD that treatment intervals of 12-16 weeks of treatments increases the risk of device-
related AEs relative to 8 weeks.  The treatment interval in this study will be limited to 12 weeks 
to minimize confounding variables that may arise with participants changing concomitant 
medications. 
The primary goal of this study is to replicate the results obtained from the PD single-site RCT in 
a multicenter RCT. As such, this study will focus on comparing an active treatment to a passive 
treatment. 
4.4 End of Study Definition for RCT:   
Participants will continue to be enrolled in the RCT until at least 184 participants have randomized.  
All other study participants that have been randomized into the RCT at this point will be allowed 
to continue in the RCT and enroll in and complete the OLE.  The RCT will end when the final 
participant has completed the end of treatment assessment, at which point, the RCT will be closed 
out and analysis will occur.  
4.5 End of Study Definition for OLE:   
The end of study for the OLE will be considered complete when participants who have enrolled in 
the OLE are no longer being examined or the last participant’s last study visit has occurred at week 
52 (day 365 +/- 3 days) and or early termination has occurred.   
 

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5 Study population 
5.1 Inclusion Criteria 
Inclusion Criteria: Each participant must have a pre-treatment history that, when initially 
screened by a principal investigator or designee, documents that she/he meets all elements of the 
following:   
1. Adult participants (aged 18 – 85 years inclusive).  
2. Have been diagnosed with PD according to the UK Brain Bank Criteria (allowing for an 
exclusion in Step 2 for "more than one affected relative").    
3. Participants must have demonstrated a sustained positive response to DRTs (e.g., levodopa, 
dopamine agonists or monoamine oxidase inhibitors) defined as either good or excellent 
responses (50-100%) for at least one year or moderate responses (30-49)% for at least three 
years prior to Screen. 
4. Participant reports limitation or clinician-investigator determined limitation, based on 
knowledge of medical history, to one or more activities of daily living (e.g., writing, 
walking, bathing, dressing, eating, toileting, etc.). 
5. Participants must be able and willing to consent to participate in the study for the RCT and 
OLE. 
6. Participants must be willing and able to comply with study requirements.  
7. Participants and investigators must expect that the participant will be able to remain on a 
stable regimen of concomitant therapies used for the management of PD motor and non-
motor symptoms and not to introduce new medications used to treat motor or non-motor 
symptoms associated with PD during the RCT or the first three months of the OLE 
(Day197). Details are specified in the Concomitant Medication section below. 
8. Participants must have at minimum a moderate burden of NMS (i.e., MDS-UPDRS part Ia 
and part Ib summed total score ≥ 9)58 at study screen to avoid floor effects for the primary 
endpoint (MDS-NMS).  
9. The principal investigator or designee must have confidence in the participant’s ability to 
reliably use the TNM™ device, understand the assessments (provided in English only) and 
to complete the assessment battery within a given on-state period.   
10. Must have a study partner (defined as someone who sees the participant for more than one 
hour a day, 3x per week) that is willing to consent and participate in the trial. 
11. Participants must have capabilities to use and access smartphones for the collection of some 
study data and/or tablets or computers for access to telemedicine platforms. 
**Study participants may be mechanically aided in data entry by study partners who have 
consented to take part in the study.  
 
12. Must be willing to answer questions related to sexual interest, arousal and performance in 
an interview with study staff. 

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5.2 Exclusion Criteria 
Exclusion Criteria: Each participant who meets any of the below will be excluded from study 
participation:  
1. Participant anticipates being unable to attend all visits and complete all study activities in 
both the RCT and OLE. 
2. Women of child-bearing potential who are pregnant or plan to become pregnant during the 
course of the RCT or OLE. 
• Women of child-bearing potential (i.e., are not yet either 3 years removed from 
their first menopausal symptom or 12 months removed from last menses), who are 
not abstinent or exclusively in same sex relationships must: 
o test negative for pregnancy as indicated by a negative urine pregnancy test; 
o agree to use an approved contraception method listed in section 5.3.3 for 
the entirety of the RCT and OLE; 
3. Have a history or prior diagnosis of dementia or adjusted score ≤ 20 on the Montreal 
Cognitive Assessment (MoCA) at the screening visit. 
**This exclusion criterion has been set specifically to improve the validity of scores assessed 
from the scaled questionnaires rather than reflecting a particular concern about safety for this 
population. 
4. Have experienced a myocardial infarction, angina or stroke within the past 12 months or a 
transient ischemic attack (TIA) within 6 months. 
5. Are receiving deep brain stimulation therapy. 
6. Are treated with a pump for continuous delivery of dopamine replacement therapy. 
7. Have received MRI guided high intensity focused ultrasound within the past 12 months. 
8. Experience frequent falls (defined as 2 or more falls in the past month related to 
Parkinson’s disease). Parkinson's falls are defined as falls associated with bradykinesia, 
freezing, turning, change in posture and postural dizziness and do not include accidental 
falls. 
9. Work night shifts. 
10. Has any significant co-morbidity or illness which in the opinion of the investigator would 
prevent safe participation in the study, compliance with protocol requirements or which 
presents with symptoms that are also common in PD. 
11. Demonstrate 
suicidality 
at 
screening 
(scores 
≥ 
4 
on 
the 
C-SSRS 
Baseline in section “Suicidal Ideation” (In the past Month)).  Participants that respond 
affirmatively to question 4 or 5 (In the past Month) should receive a referral for mental 
health counseling   according to local site regulations and standards. 
12. Use a hearing aid that is implanted or that cannot be easily removed and replaced. 
13. Have a cochlear implant or myringotomy tubes. 

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14. Have chronic tinnitus that has been ongoing for at least 3 months and causes significant 
impairment of communication and/or impairment of activities of daily living. 
15. Have previously been diagnosed with traumatic brain injury with ongoing sequela. 
16. Have been diagnosed with a co-morbid neurological disorder that may present with 
symptoms overlapping with PD (e.g., stroke, brain tumor, epilepsy, Alzheimer’s disease, 
multiple sclerosis, amyotrophic lateral sclerosis, atypical Parkinsonism or aneurysm). 
17. Have been previously diagnosed with either clinically meaningful central vestibular 
dysfunction (lifetime) or have experienced clinically meaningful peripheral vestibular 
dysfunction within the last 12 months.  For this purpose, clinically meaningful is defined 
as vestibular dysfunction which causes at least a minimal impairment in the individual 
activities of daily living (e.g., dressing, bathing, preparing food, conducting household 
chores, work or recreational activities). 
18. In the Investigator’s opinion, currently abuse alcohol, abuse drugs (including legal, illegal 
or prescribed drugs) or have a history of alcohol or drug dependency within the past 5 years 
or use any drugs excluded as noted in the Excluded Medications List in section 5.3.2. 
19. Have unresolved complications from a previous surgical procedure at the baseline visits, 
such as swelling or persistent pain, that requires medical intervention. 
20. Have active ear infections, perforated tympanic membrane or labyrinthitis, as identified by 
a general ear examination performed by medically qualified Investigators. 
21. Have a recent history of frequent ear infections (≥ 1 per year over the past two years). 
22. Are currently enrolled or have participated in another interventional clinical trial within the 
last 30 days. 
23. Has a planned surgery scheduled to occur during the RCT or the first 90 days of the OLE 
that would typically be followed with a prescription for pain management. 
24. Have had eye surgery within the previous three months or ear surgery within the previous 
six months. 
5.3 Concomitant Therapy 
5.3.1 Approved Concomitant Medications 
• The use of the following medications used to treat motor and non-motor symptoms 
associated with PD will be permitted during the study as long as the type or dose does not 
change during the course of the study or the 4 weeks immediately preceding the study: oral 
DRTs (e.g., levodopa/carbidopa or dopamine agonist based therapies), transdermal DRTs 
(e.g., rotigotine transdermal system), anti-cholinergics, MAO-B inhibitors, COMT 
inhibitors, amantadine, therapies to promote sleep including melatonin or benzodiazepines 
such as Klonopin, drugs to treat urinary frequency such as oxybutynin, tolterodine, 
trospium, solifenacin succinate, darifenacin, mirabegron, and fesoterodine fumarate.   
• The use of selective serotonin reuptake inhibitors or other anti-depression/anti-anxiety 
medications will also be permitted during the study so long as the type or dose does not 
change during the study or the 12 weeks immediately preceding the study. 

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• Medications prescribed for other concomitant illnesses are allowed as long as they are not 
listed in the Excluded Medications list in section 5.3.2. Vaccines, supplements, and over 
the counter medications, including those taken occasionally (for example: seasonal allergy 
medications), should be documented if a dose occurred during the protocol timeframe. 
• When medications are prescribed for indications other than symptoms associated with PD, 
physicians will be encouraged to utilize the one that is least likely to impact motor and non-
motor symptoms associated with PD. 
• Changes to medications for motor symptoms and NMS of PD are not permitted. 
Participants will be advised that during the RCT and first 3 months of the OLE, they should 
maintain patterns of usage of approved therapeutic medications that they normally use and 
that they should not initiate new medication (type, dosage or route of administration), 
medicating patterns or other interventions unless their provider deems the change to be 
medically necessary, as changes in concomitant treatments will interfere with the ability to 
attribute clinical change during the study to use of the Device. Any medically necessary 
changes to medications for motor symptoms and NMS of PD that do occur during the study 
will be recorded as concomitant medications and participants will continue in the study. 
Reasons for changes in medications used to treat motor symptoms or NMS of PD will be 
recorded, and participants who make changes in PD medications or add new medications 
likely to modulate symptoms associated with PD during the study will be included in the 
ITT analysis but excluded from the PP and mITT analysis.   
5.3.2 Excluded concomitant medications, drugs and supplements 
• Antipsychotic Medications (i.e., either neuroleptics or atypical antipsychotics) 
• Anti-emetics (e.g., 5-HT3 receptor antagonists, D2 receptor antagonists, first-generation 
H1 Receptor antagonists, muscarinic antagonists, SP/NK1 receptors antagonists or 
corticosteroids that may be prescribed for anti-emetic purposes) prescribed chronically 
(taken more than 2 times per week, consistently) 
• Inhaled or ingested cannabinoids (e.g., marijuana, cannabidiol (CBD), tetrahydrocannbinol 
(THC) or nabilone) within 4 weeks of screening. 
• Any drug that has not been legalized on a United States Federal level 
• Controlled substances that have not been prescribed under the care of a licensed-
professional. 
• Off-state rescue medications (e.g., apomorphine injections or levodopa-based inhalers) not 
prescribed with a stable dosing regimen (i.e. taken as needed/PRN). 
•  Mucuna pruriens supplements 
• Medications producing side effects that mimic any of the motor or nonmotor symptoms of 
PD.  For example, narcotic medications prescribed for pain management are known to 
produce several NMS evaluated as part of the primary outcome measure (e.g., cognitive 
impairments, constipation, etc.). Potential participants who are taking narcotics should 
have a 4-week washout from narcotic use prior to study screen. Questions regarding 
medication changes should be referred to the Medical Monitor 
 

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5.3.3 Contraception 
Females of child-bearing potential who engage in heterosexual intercourse during the trial must 
utilize one of these approved methods for contraception: 
• Oral Hormonal Contraception 
• Patch Contraception 
• Hormonal Ring 
• Intrauterine Device (IUD) 
• Contraceptive Implantation 
• Contraceptive Shot 
• Barrier Method, including: 
 Male Condom 
 Female Condom 
 Diaphragm 
 Cervical Cap with spermicide 
 Contraceptive Sponge 
 Spermicide 
5.4 Screen Failures 
Participants who fail the initial screening process will be notified as soon as the screen failure is 
recognized. Participants that failed the screening process due to failing to meet the inclusion 
criteria or meeting exclusion criteria may be rescreened at a later date if the reason for their original 
exclusion no longer applies, or if a protocol amendment changes the eligibility criteria that caused 
the original screen failure. A minimum of 30 days should occur between re-assessing eligibility. 
Participants that were excluded because they demonstrated evidence of suicidality on the C-SSRS 
at the original screening will not be permitted to rescreen. 
Participants that were excluded due to an insufficient NMS burden threshold under a previous 
protocol version will be permitted to rescreen once, if the original screening MDS-UPDRS Part I 
score was ≥ 9, regardless of the source of their original score (i.e., “Patient Alone” or “Patient + 
Informant”).  Additionally, participants that were excluded at the original screening due to an 
insufficient NMS burden under a previous protocol version and had an MDS-UPDRS Part I score 
of 7 or 8 will be permitted to rescreen once if the source of their original MDS-UPDRS Part I score 
was “Patient Alone”, and they now have the ability to have “Patient + Informant” source of data. 
Participants that were excluded due to an insufficient NMS burden with MDS-UPDRS Part I 
scores ≤ 6 will not be permitted to rescreen. 
5.5 Strategies for Recruitment and Retention 
The majority of participants for the study are expected to be drawn from existing patient 
populations at the clinical sites/services after medical record review. However, sites may choose 
to utilize recruitment aids such as IRB-approved advertisements. 
The Sponsor will assign a Clinical Research Associate (CRA), also known as a study monitor, to 
each site. Enrollment for each site will be closely monitored by the CRA via Pre-screening logs 
that will be reviewed on a regular basis.  If needed, the CRA will work closely with the site to 
identify recruitment barriers and find solutions to overcome these hurdles.   

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A variety of strategies are being utilized to promote participant retention. The study design 
facilitates retention as most study activities can be performed in the participant’s home, thereby 
reducing participant and caregiver burden. Additionally, participants will receive stipends to 
compensate for the travel and time burden associated with participation in the study. Study sites 
are encouraged to have continuous communication with the study participant and study partner 
outside of the defined protocol visits, in the manner most accommodating to them, to assist with 
rapport and retention. Participant retention will also be closely monitored and the CRA will work 
with the site to identify solutions should retention issues arise. 
6 Study Intervention 
Intended Use: The TNM™ Device is intended to stimulate the vestibular system via external ear 
canals using software-controlled thermal waveforms.  
6.1 Study Intervention Administration 
The generation 3.2 TNM™ device was granted market entry by the FDA as a Class II medical 
device indicated for the home-use prevention of episodic migraine in adolescent and adult 
patients 12 and older.   
The generation 4.0 Device will be utilized in this study. See Scion TNM™ 4.0 Information for 
Use brochure for more details. The device has been designated as non-significant risk (NSR) by 
the FDA for studies in PD.   
For treatment, all participants will recline on a wedge pillow (provided by SNS) to position the 
horizontal semicircular canal in the optimal orientation for maximal caloric effect.  Participants 
will start and stop the device with a single push button to activate a run. Starting and stopping the 
device requires an extended push (2 seconds) to avoid false activations due to short button pushes. 
The LED display provides a “countdown” icon to provide the participant with feedback on how 
the treatment session is proceeding.  The display also tells the participant how many treatments 
are left within the prescription period.  The device provides an audio alert that denotes the start 
and completion of a treatment run.  The same visual and auditory information will be presented to 
the two treatment arms.   
Device treatment does not require active engagement of the participant.  Therefore, participants 
will be told that they should feel free to read, watch television or rest so long as they remain in the 
supine position for the duration of treatment. Participants may be provided items to make the 
treatment time more conducive to reclining leisure activities such as reading, watching tv, etc.  An 
example of such an item would be prism glasses to enable reading, if desired, while lying supine 
during a treatment.    
Participants will be asked to treat twice daily.  Each treatment duration is roughly 19 minutes. 
Participants will only wear the device when administering a treatment. Participants will be 
instructed to self-administer treatments in the on-state and at a time when they do not anticipate 
interruptions that would require them to pause a treatment. 
No reference to caloric vestibular stimulation or “CVS” will be made with study participants. The 
device will be referred to as a brainstem neuromodulation Device, and the specific mechanism of 
action will not be disclosed to participants. Additional details regarding device description can be 

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found in site provided guidance documents. 
All participants will be told that they may or may not benefit from device therapy in terms of 
reduction in PD-related symptoms. All participants will be told that participants in both treatment 
arms may or may not sense slight pressure from the earpieces, a warming or cooling sensation, 
slight nausea or dizziness or noises from the Device.  To mitigate risk of falls that may result from 
orthostatic hypotension, participants will be instructed to take their time getting up after a treatment 
and to avoid going directly from a supine position to standing up and moving around.  
As part of the Informed Consent, participants will be told that they will receive up to 20 weeks 
total of the treatment that has been shown to be most effective for treating symptoms in PD should 
they agree to participate in the open label extension (OLE).  
Study Partners and site personnel should encourage participant adherence to device usage 
throughout duration of the trial but maintain a neutral position regarding efficacy to promote 
scientific integrity of the study. 
 
6.2 Preparation/Handling/Storage/Accountability 
Study devices must be stored in a secure area with limited access. Storage rooms used for this 
purpose must have continuous locked access and only delegated research staff should be allowed 
to enter.  
Upon receipt, the shipment of study devices will be inventoried. Any discrepancies or damaged 
shipments will be brought to the attention of the sponsor. Copies of the packing slips will be 
retained, and inventory will be documented on the Investigator Inventory Control Form located in 
the Investigator Site File for the study. The Sponsor and the Investigator are required to closely 
monitor the shipping, use, and final disposal of devices.  
Investigators must also maintain complete, current, and accurate records of the receipt, use, or 
disposition of investigational devices. Delegated research staff should complete the Investigator 
Inventory Control Form whenever one of the following occurs: 1) devices are received from the 
Sponsor, 2) devices are dispensed to participants, 3) devices are returned from participants and 4) 
devices are shipped back to the Sponsor.  In the case of a damaged or failed device, an 
Investigational Device Return Form should be completed, and the Sponsor immediately notified. 
Upon completion or termination of the study (or the Investigator's part of the study), or at the 
sponsor's request, the Investigator is required to return to the Sponsor any remaining supply of the 
device, unless otherwise directed. 
6.3 Device Randomization, Blinding, and Unblinding 
The Generation 4.0 TNM™ device uses a bar code reader to import a prescription waveform.  The 
use of the bar code aids blinding during randomization since the QR code is not readable by staff 
members.  Bar codes will be printed and placed in sealed envelopes and the treatment allocation 
will not be available to the site staff.   Unblinding will only occur in response to a Serious 
Unexpected/Unanticipated Device Event and requires written permission by the study sponsor [see 
below]. 
Packets containing 4 sealed envelopes with the printed bar codes for randomization assignments 

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will be provided.  Each batch will contain two active treatment and two passive treatment 
assignments.  The envelopes will be randomly shuffled by an agent not involved with the study. A 
given packet must be completed before the next packet is opened. 
For randomization, after eligibility is confirmed and documented, delegated study staff will select 
an envelope from the packets, scan the bar code in the envelope and then store the barcode on the 
randomization source log.  Study staff will load the treatment onto the device, record the device 
number allocated to the participant and will train the participant according to the training script 
provided.  The first treatment will be performed at the participant’s home to maintain blinding of 
the study staff.  
All study staff will be blind to treatment allocation and participants will be told at informed 
consent, and all subsequent visits, that they should not discuss their treatment experience with the 
study staff. Confirmation that the study staff remain blinded to treatment allocation will be 
documented at each visit. If a study staff member directly responsible for assessment or safety 
evaluation becomes unblinded, they will no longer be eligible to complete the delegated study 
assessments per the protocol for that participant. Participants will be told that pain should not be 
associated with treatment, and if they do experience pain, that they should stop treatment and 
contact the study staff immediately and/or seek medical attention if necessary.     
Study staff will not have access to the allocation treatment on site, as treatment allocation is not 
required to treat any potential adverse events. Unblinding at the study sites will only occur in the 
case of a SADE (serious adverse event at least possibly related to the device) or UADE (serious 
and unanticipated/unexpected adverse events at least possibly related to the device) that also 
require cessation of device treatment.  If this situation seems likely, the Unblinding Investigator, 
noted in the Delegation of Authority Log, should contact SNS at the contact information below to 
request approval to unblind and obtain the assigned treatment allocation.  The unblinded 
Investigator will not be allowed to complete assessments for that participant if they become 
unblinded. The safety event will be reported as required by this protocol. Should treatment 
allocation information be required for handling of an AE, a CRF providing the details of the 
incident will be completed. 
 
 
Unblinding Sponsor Contact: 
Dr. Kristen Ade 
kade@scionneurostim.com 
24-hour number: 202-213-4793 
 
6.4 Study Intervention Adherence  
The actual, measured temperature profile for each run will be automatically saved to Device 
memory, as will the time and date of each treatment run.  These data will be accessible via a USB 
port that is covered by a hatch on the device body and will be downloaded by SNS. This data is an 

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independent record of the expected device performance and treatment adherence and will be used 
for confirmation purposes and planned analyses, not for confirming adherence in real time. Study 
participants will not be withdrawn by the study staff for significant treatment non-adherence. 
7 Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal 
7.1 Discontinuation of Study Intervention 
All AEs will be evaluated by site personnel on an individual basis to determine whether the 
occurrence may be related to device use. Any issues related to safety concerns will promptly be 
referred to the site principal investigator, who can terminate the participant’s further participation 
in the study if necessary.  
Should a serious adverse event occur that is deemed to be likely related to device use, the potential 
for the universality will be assessed within 48 hours.  If evidence suggests that treatments with the 
device could create a safety concern for participants, as deemed by the medical monitor, the study 
will be paused or stopped early, as appropriate.  
It should be noted that the above scenario is considered to be highly unlikely.  The device has been 
designated as NSR by the FDA, and there were no reports of serious or unexpected AEs that were 
potentially related to device in either the PD single-site RCT or the episodic migraine RCT.   
7.2 Participant Discontinuation/Withdrawal from the Study 
7.2.1 Withdrawal Criteria 
Participants must be withdrawn from the clinical trial if any of the following events occur: 
 the participant is significantly non-adherent to the requirements of the protocol (principal 
investigator & Sponsor decision), 
 the participant develops an illness or condition that would interfere with his/her continued 
participation, 
 the participant withdraws his/her consent, 
 the participant’s study partner withdraws his/her consent and no replacement can be found 
 the principal investigator feels that it is the participant’s best interest to be withdrawn, 
 SNS discontinues the study or has achieved the targeted enrollment, 
If the participant is discontinued from the participation in the study for any reason, the principal 
investigator must make every effort to perform all evaluations for the final visit, even virtually, 
if necessary, collect the device from the participant and document the reasons for 
discontinuation.   If the participant withdraws from the study due to an adverse event that is 
potentially related to use of the device, the study staff should continue to follow up with the 
participant at regular intervals, and at least every two weeks until the AE resolves or until the 
participant withdraws consent for the follow-up procedure.  
If a participant’s study partner withdraws their consent from the study, a new study partner 
who meets the criteria [See Section 5.1] may be identified and consented to the study.  If a 
suitable study partner cannot be found, the participant will be withdrawn from the study.  

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Participants that withdraw early will be excluded from the per protocol analysis. 
7.2.2 Lost to Follow-Up 
If a participant misses a visit, the study staff should call the participant/study partner within 24 
hours to reschedule, and the visit should be rescheduled for as soon as possible after the missed 
appointment and within 5 business days.  The reason for rescheduling should be noted.  If there 
is no response from the participant or their study partner the study staff will continue to contact 
the participant/study partner daily for 1 week or until contact is made, then weekly for 3 weeks. 
If the prior steps are unsuccessful, a certified letter should be sent to the participant requesting 
they contact the study staff immediately. The participant is considered lost to follow-up if all 
the prior steps are performed with no contact made.  Documentation of all phone calls, and 
copies of all correspondence should be maintained in the participant’s source documentation. 
8 Safety Oversight 
8.1 Device Deficiency 
A device deficiency is an inadequacy of a medical device related to its identity, quality, durability, 
reliability, safety, or performance, such as malfunction, misuse or use error and inadequate 
labeling. 
All device deficiencies will be documented, and the device will be returned to the device 
manufacturer for analysis, if possible.  Device deficiencies are NOT to be reported as AEs. 
However, if there is an AE that results from a device deficiency, that specific event would be 
recorded on the appropriate CRF. 
8.2 Adverse Events (AEs), Adverse Device Effects (ADEs), Serious AEs (SAEs), 
Serious Adverse Device Effects (SADEs), Unanticipated Adverse Device Effects 
(UADE) and Unanticipated Problem Reporting 
8.2.1 AEs, ADEs, SAEs, SADEs and UADEs will be defined per ISO14155:2020 
and/or 21 CFR Part 812, as described below.8.2.1 Adverse Event (AE): 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in participants, users, or other 
persons, whether or not related to the investigational medical device. This definition 
includes events related to the investigational medical device and the events related to the 
procedures involved. For users and other persons, this definition is restricted to events 
related to the investigational device. AEs will be collected starting from the time the 
participant signs informed consent until the follow-up period is completed. 
8.2.2 Adverse Device Effect (ADE): 
An Adverse Device Effect (ADE) is an AE related to the use of an investigational medical 
device. This definition includes AEs resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device. This definition includes any event resulting from use error 
or from intentional misuse of the investigational medical device. 

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Traditional, diagnostic CVS has been used for roughly a century, and there are no reports 
in literature of significant adverse events.  
Therapeutic CVS has been studied for use in prevention of episodic migraine and in 
treatment of symptoms of Parkinson’s Disease. Results of these studies (including one 
multisite RCT and one single-site RCT, respectively), resulted in neither serious nor 
unanticipated/unexpected adverse events related to the study device. Additionally, there 
was no reduction in balance and no negative change in either mood or cognition. 
The following AEs are known, possible side effects of using the investigational device: 
More likely:  
 Dizziness (whirling or spinning sensation; may also be called “giddiness” or 
vertigo) 
 Drowsiness 
 Treatment site discomfort (skin itching, skin irritation felt within the ear 
canal or around the ear area or pressure felt within ear canal) 
Less likely: 
 Nausea 
 Vomiting 
 Headache  
 Tinnitus 
All of the potential AEs noted above are expected to resolve soon after use of the 
investigational Device is stopped. 
8.2.3 Serious Adverse Event (SAE): 
A Serious Adverse Event (SAE) is an AE that has 
 Led to death, 
 Led to serious deterioration in the health of the participant, that either resulted in 
1. A life-threatening illness or injury, or 
2. A permanent impairment of a body structure or a body function, or 
3. In-patient or prolonged hospitalization, or 
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
8.2.4 Serious Adverse Device Effect (SADE):  
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
8.2.5 Unanticipated Adverse Device Effect (UADE): 
An Unanticipated Adverse Device Effect is a serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 

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problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of participants. 
8.2.6 Procedures for AEs: 
8.2.6.1 Documentation and assessment  
 Following the informed consent process, clinical study participants will be routinely 
questioned about AEs at all visits from the clinical research staff. All AEs, regardless 
of treatment group or suspected causal relationship to the investigational device, will 
be recorded in the participants’ source documentation.  
 For all AEs, sufficient information will be obtained as to 1) determine the severity of 
the event; 2) assess the casual relationship between the adverse event and the 
investigational device; and 3) determine the outcome of the event.  
 AEs will be followed until the event (or its sequelae) resolves or stabilizes at a level 
acceptable to the investigator and sponsor. 
 
8.2.6.2 Causality and severity assessment 
 The investigator will promptly review documented AEs to determine 1) if there is a 
reasonable possibility that the adverse event was caused by the investigational device 
or other study treatments and 2) if the adverse event meets the criteria for “serious.” 
 If the investigator’s final determination of causality is “possible or probable 
relationship to the investigational device or other study treatments,” the adverse effect 
will be classified as associated with the use of the investigational device or other study 
treatments for reporting purposes.  If the investigator’s final determination of causality 
is “not related to the investigational device or other study treatments,” this 
determination and the rationale for the determination will be documented. 
8.2.6.3 Investigator Reporting AEs to the Sponsor and responsible IRB/REC 
Reporting to the Sponsor:  
 Adverse events will be submitted to the Sponsor. 
 All serious and/or unanticipated adverse events will be submitted to the Sponsor as 
soon as possible, but no later than 10 days after the Investigator’s first knowledge of 
the event.  
 All serious and/or unanticipated/unexpected adverse events that involve a death must 
be reported within 24 hours of discovery. 
Reporting to the IRB / REC: 
 U.S. Investigators are additionally required to submit to their IRB a report of 
Unanticipated Adverse Device Effect (UADE) as soon as possible, but in no event later 
than 10 working days after the investigator first learns of the event (21 CFR 
812.150(a)(1)). However, if the UADE involves a death, it must be reported within 24 

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hours of discovery.  
 U.K. Investigators are additionally required to submit to their REC all reports of 
UADEs within 15 days of the chief investigator becoming aware of the event.  
UADEs will require unblinding but written permission must first be obtained from the 
study sponsor. 
8.2.6.4 Sponsor Reporting AEs to the FDA or Competent Authority 
Upon receiving a report of a serious or unanticipated adverse device effect (or unexpected 
serious adverse device event), the Sponsor will immediately conduct an evaluation of the 
event/effect and report the results as follows: 
 All serious adverse events, whether initially considered to be device related or not will 
be reported to the U.K. MHRA within 15 days of the Chief Investigator being notified. 
 The Sponsor will report the results of an UADE to FDA, MHRA, all reviewing 
IRBs/RECs, and participating investigators within 10 working days after the sponsor 
first receives notice of the effect (21 CFR 812.46[b], 21 CFR 812.150[b][1]). 
Thereafter, the sponsor shall submit such additional reports concerning the effect, as 
needed.  
 If the Sponsor determines that an UADE presents an unreasonable risk to participants, 
the Sponsor shall terminate all investigations or parts of investigations presenting that 
risk as soon as possible, no later than 5 working days after the sponsor first received 
notice of the effect. 
 
8.3 Protocol Deviations 
A protocol deviation/violation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. An investigator shall notify the sponsor and the 
reviewing IRB (21CFR56.108(a) (3) and (4)) or Research Ethics Committee of any deviation from 
the investigational plan to protect the life or physical wellbeing of a participant in an emergency. 
Except in such an emergency, prior approval by the sponsor is required for changes in or deviations 
from a plan, and if these changes or deviations may affect the scientific soundness of the plan or 
the rights, safety, or welfare of human participants, FDA and IRB approval in accordance with 
21CFR812.35(a) is also required. 
All protocol deviations/violations must be recorded by the study staff and be reported to the 
Sponsor. Each sites IRB reporting requirements for protocol deviations must also be documented 
to confirm compliance with local regulations. 
8.4 Clinical Monitoring 
The Sponsor will monitor the study to ensure the rights, safety, and well-being of study participants 
are being protected, and study data is being collected in compliance with the currently approved 
protocol, ICH GCP, and federal and international regulatory requirements. (21CFR 814.20 c). 
Study monitors will ensure trial data are accurate, complete, and verifiable, by conducting regular 
review of the data via remote or on-site monitoring visits as described in the Sponsor’s Site 
Monitoring Plan. 

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All clinical data, including source documents, case report forms and other relevant information 
generated during the study will be promptly and fully provided to the Sponsor via EDC data entry 
and available for monitoring as noted. Source data (both electronic and paper) should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained if necessary. 
9 Statistical Considerations 
9.1 Sample Size Determination 
The sample size for this study was set to achieve > 90% power to detect the minimal clinically 
important difference (MCID) of -2.64 points in the MDS-UPDRS: Part 160.  The estimated group 
sample sizes of 83 and 83 (166 total) to complete assumes a rate of attrition of 10% during the 
RCT and was set to achieve 89% power to detect a difference of -2.64 points in the MDS-UPDRS 
Part I total score between the null hypothesis that both group average change scores are equal and 
the alternative hypothesis that the average change score of the treatment group is -2.64 points less 
than that of the passive treatment group with estimated within group standard deviation of 5.32 
points and with a 2-sided significance level (alpha) of 0.05.  Competitive enrollment will close 
once 184 participants have been randomized into the RCT.  This number allows for the 
maintenance of 89% power to detect the estimated MCID at the end of the RCT and at the end of 
the first treatment period in the OLE assuming 10% attrition during each of those two periods.  
Note that the primary endpoint is the MDS-NMS, not the MDS-UPDRS: Part I.  However, the two 
scales are highly correlated (rs=0.75)1, and the MDS-UPDRS: Part I has a pre-established MCID 
59 whereas the MDS-NMS does not. The sample size (184 to randomize), derived from the MDS-
UPDRS: Part I achieves >90% power to detect the estimated MCID of -35 points in the MDS-
NMS. Participants will continue to be enrolled in the RCT until at least 184 participants have 
randomized, and if there are additional participant withdrawals, they will not be replaced. 
Participants who have entered the baseline period but have not yet randomized when the 
competitive enrollment target is achieved may be withdrawn from the study prior to randomization  
and, as a result, would not be included in any of the analyses. Data from all randomized study 
participants will be evaluated for analyses of safety and efficacy. 
9.2 Statistical design 
The scientific and analytic team as well as the product development team, responsible for Study 
Device maintenance, at Scion will be unblinded or will have the potential to become unblinded to 
treatment allocation prior to data base lock (DBL) for RCT and OLE. No one from the Clinical 
Affairs team, including Study Monitors will be unblinded. Details regarding Statistical 
considerations including blinded interim analyses may be found in the Statistical Analysis Plans 
(SAPs). The RCT and OLE SAPs may be available to site investigators upon request. 
10 Confidentiality and Privacy 
Data obtained as part of this clinical trial will be kept confidential. Each study participant will be 
granted a Study Participant ID and all study related documentation for the participant will be 
recorded using the ID. Study sites are required to keep a key code to identify the study participant 
and will not share this code with the Sponsor or any site staff not delegated by the PI.  

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Confidential information that is collected as part of the study may be shared with the Sponsor, 
study monitors, and study vendors, as well as the IRB and/or FDA as required. Any publications 
that result as part of the study will not identify participants in any manner.  
11 Record Retention 
An investigator shall retain records required to be maintained for a period of 2 years following the 
date a request for De Novo classification or CE Mark has been made; or, if no application is to be 
filed or if the application is not approved for such indication, until 2 years after the investigation 
is discontinued and FDA is notified. Records must be made available to the Sponsor or FDA 
throughout this time period, if necessary. 
The in-person MDS-UPDRS III scores from the in-clinic visits will be scored by blinded central 
raters/assessors.  Scores by central raters will provide data for the primary analysis of this 
secondary endpoint, unless noted otherwise in the Statistical Analysis Plans.   
 
 

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pedunculopontine nucleus is related to visual hallucinations in Parkinson's disease: preliminary 
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Cai J, Lee S, Ba F, et al. Galvanic Vestibular Stimulation (GVS) Augments Deficient 
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Different Stimuli. Front Neurosci 2018;12:101. 
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51. 
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Dieterich M, Brandt T. Functional brain imaging of peripheral and central vestibular 
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Baertschi AJ, Johnson RN, Hanna GR. A theoretical and experimental determination of 
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Wilkinson D, Ade KK, Rogers LL, et al. Preventing Episodic Migraine With Caloric 
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Martinez-Martin P, Rodriguez-Blazquez C, Mario A, et al. Parkinson's disease severity 
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Appendix: 
1.0 Schedule of Events 
1.1 STEM-PD RCT 
STEM-PD RCT 
Assessment  
Screen 
Study 
Center 
Baseline 
1 
Virtual 
PC 
PRO 
Baseline 2 
Study 
Center 
PC 
PRO 
TX 1 
Virtual 
PC 
PRO 
TX 2 
Virtual 
PC 
PRO 
EOT 
Study 
Center 
Day  
-14 to –1 
0 
(+/- 3 days) 
15 
(+/- 
1 
day) 
28 
(+/- 1 
day) 
29 
(+/- 3 days 
43 
(+/- 1 
day) 
56 
(+/- 1 
day) 
57 
(+/- 3 
days) 
71 
(+/- 1 
day) 
84 
(+/- 1 
day) 
85 
(+/- 3 
days) 
99 
(+/- 1 
day) 
112 
(+/- 1 
day) 
113 
(+/- 3 days) 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med Hx and ConMed 
Hx Review  
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test-Urine  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Educational Video and 
question/answer  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ear Exam  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Height/Weight (height 
only at screen) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
MoCA  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 

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STEM-PD RCT 
Assessment  
Screen 
Study 
Center 
Baseline 
1 
Virtual 
PC 
PRO 
Baseline 2 
Study 
Center 
PC 
PRO 
TX1 
Virtual 
PC 
PRO 
TX2 
Virtual 
PC 
PRO 
EOT 
Study 
Center 
Day  
-14 to –1 
0 
(+/- 3 days) 
15 
(+/- 1 
day) 
28 
(+/- 1 
day) 
29 
(+/- 3 days 
43 
(+/- 1 
day) 
56 
(+/- 1 
day) 
57 
(+/- 3 days) 
71 
(+/- 1 
day) 
84 
(+/- 1 
day) 
85 
(+/- 3 
days) 
99 
(+/- 1 
day) 
112 
(+/- 1 day) 
113 
(+/- 3 days) 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
UPDRS I 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
MDS-UPDRS I 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
MDS-NMS  
 
X 
 
 
X NMF 
 
 
X 
 
 
X 
 
 
X NMF 
MDS-UPDRS II  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
MDS-UPDRS III (on-
state)  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Mini-BESTest  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
10m TUG   
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
3m TUG & Finger 
tapping (Encephalog 
tests)  
 
---------------------------------------------------------------------------X*----------------------------------------------------- 
 
PDQ-39  
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Modified Schwab & 
England  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Pro-PD  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
56 
 
STEM-PD RCT 
Assessment  
Screen 
Study 
Center 
Baseline 
1 
Virtual 
PC 
PRO 
Baseline 2 
Study 
Center 
PC 
PRO 
TX1 
Virtual 
PC 
PRO 
TX2 
Virtual 
PC 
PRO 
EOT 
Study 
Center 
Day  
-14 to –1 
0 
(+/- 3 days) 
15 
(+/- 1 
day) 
28 
(+/- 1 
day) 
29 
(+/- 3 days 
43 
(+/- 1 
day) 
56 
(+/- 1 
day) 
57 
(+/- 3 days) 
71 
(+/- 1 
day) 
84 
(+/- 1 
day) 
85 
(+/- 3 
days) 
99 
(+/- 1 
day) 
112 
(+/- 1 day) 
113 
(+/- 3 days) 
oSDMT  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
PDSS-2  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
ESS  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
PAS  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
FACIT-F  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
GDS  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Transition 
Questionnaire 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
CGI-I (overall and 
focused) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
UPDRS IV 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Zarit Burden Interview 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Device Usability 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Unpowered Device 
Fitting 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
57 
 
STEM-PD RCT 
Assessment  
Screen 
Study 
Center 
Baseline 
1 
Virtual 
PC 
PRO 
Baseline 2 
Study 
Center 
PC 
PRO 
TX1 
Virtual 
PC 
PRO 
TX2 
Virtual 
PC 
PRO 
EOT 
Study 
Center 
Day  
-14 to –1 
0 
(+/- 3 days) 
15 
(+/- 1 
day) 
28 
(+/- 1 
day) 
29 
(+/- 3 days 
43 
(+/- 1 
day) 
56 
(+/- 1 
day) 
57 
(+/- 3 days) 
71 
(+/- 1 
day) 
84 
(+/- 1 
day) 
85 
(+/- 3 
days) 
99 
(+/- 1 
day) 
112 
(+/- 1 day) 
113 
(+/- 3 days) 
Device Randomization 
and Training  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Device Return 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Home Assessment and 
ePRO Training  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Med & AE 
Review  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit Scheduling and 
Assessment Review  
X 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Treatment Period  
  
  
  
  
-----------------------------------------------------------------------X------------------------------------------ 
X performed twice a day 
 
X* performed weekly 
 
 
 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
58 
 
 
1.2 STEM-PD OLE 
STEM-PD OLE 
Assessment 
Baseline 
OLE 
Study 
Center 
PC 
PR
O 
TX1 
Virtual 
PC 
PR
O 
TX2 
Virtual 
PC 
PR
O 
EOT1 
Study 
Center 
PC 
PR
O 
FU 1 
Virtual 
PC 
PR
O 
FU 2 
Virtual 
PC 
PR
O 
FU3 
Study 
Cente
r 
PC 
PR
O 
EOT 
2 
Study 
Cente
r 
Day 
113 
(+/- 3 days) 
127 
(+/- 1 
day) 
140 
(+/- 1 
day) 
141 
(+/- 
3 
days) 
155 
(+/- 1 
day) 
168 
(+/- 1 
day) 
169 
(+/- 3 
days) 
183 
(+/- 1 
day) 
196 
(+/- 1 
day) 
197 
(+/- 3 
days) 
211 
(+/- 1 
day) 
224 
(+/- 1 
day) 
225 
(+/- 3 
days) 
239 
& 
253  
 (+/- 
1 
day) 
266 
(+/- 1 
day) 
267  
 (+/- 3 
days) 
281 
& 
295  
 (+/- 
1 
day) 
308 
(+/- 1 
day) 
309  
 (+/- 3 
days) 
323 
337 
& 
351  
 (+/- 
1 
day) 
364 
(+/- 1 
day) 
365 
(+/- 3 
days) 
Informed 
Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med Hx and 
ConMed Hx 
Review  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ear Exam  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
PGI-I 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
MoCA  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
MDS-NMS  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
MDS-
UPDRS I 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
UPDRS I 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MDS-
UPDRS II  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
MDS-
UPDRS III 
(on-state)  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Mini-
BESTest  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
59 
 
STEM-PD OLE 
Assessment 
Baseline 
OLE 
Study 
Center 
PC 
PR
O 
TX1 
Virtual 
PC 
PR
O 
TX2 
Virtual 
PC 
PR
O 
EOT1 
Study 
Center 
PC 
PR
O 
FU 1 
Virtual 
PC 
PR
O 
FU 2 
Virtual 
PC 
PR
O 
FU3 
Study 
Cente
r 
PC 
PR
O 
EOT 
2 
Study 
Cente
r 
Day 
113 
(+/- 3 days) 
127 
(+/- 1 
day) 
140 
(+/- 1 
day) 
141 
(+/- 3 
days) 
155 
(+/- 1 
day) 
168 
(+/- 1 
day) 
169 
(+/- 3 
days) 
183 
(+/- 1 
day) 
196 
(+/- 1 
day) 
197 
(+/- 3 
days) 
211 
(+/- 1 
day) 
224 
(+/- 1 
day) 
225 
(+/- 3 
days) 
239 
& 
253  
 (+/- 
1 
day) 
266 
(+/- 1 
day) 
267  
 (+/- 3 
days) 
281 
& 
295  
 (+/- 
1 
day) 
308 
(+/- 1 
day) 
309  
 (+/- 3 
days) 
323 
337 
& 
351  
 (+/- 
1 
day) 
364 
(+/- 1 
day) 
365 
(+/- 3 
days) 
10m TUG   
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
3m TUG & 
Finger 
tapping  
(EncephaLo
gTM tests)  
 
 
-----------------------------------------------X*-------------------------------------------------- 
 
 
 
 
 
 
 
 
 
 
 
 
PDQ-39  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Modified 
Schwab & 
England  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Pro-PD  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
oSDMT  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
PDSS-2  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
ESS  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
PAS  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
FACIT-F  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
GDS  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CGI-I 
overall and 
focused) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
UPDRS IV 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
60 
 
STEM-PD OLE 
Assessment 
Baseline 
OLE 
Study 
Center 
PC 
PR
O 
TX1 
Virtual 
PC 
PR
O 
TX2 
Virtual 
PC 
PR
O 
EOT1 
Study 
Center 
PC 
PR
O 
FU 1 
Virtual 
PC 
PR
O 
FU 2 
Virtual 
PC 
PR
O 
FU3 
Study 
Cente
r 
PC 
PR
O 
EOT 
2 
Study 
Cente
r 
Day 
113 
(+/- 3 days) 
127 
(+/- 1 
day) 
140 
(+/- 1 
day) 
141 
(+/- 3 
days) 
155 
(+/- 1 
day) 
168 
(+/- 1 
day) 
169 
(+/- 3 
days) 
183 
(+/- 1 
day) 
196 
(+/- 1 
day) 
197 
(+/- 3 
days) 
211 
(+/- 1 
day) 
224 
(+/- 1 
day) 
225 
(+/- 3 
days) 
239 
& 
253  
 (+/- 
1 
day) 
266 
(+/- 1 
day) 
267  
 (+/- 3 
days) 
281 
& 
295  
 (+/- 
1 
day) 
308 
(+/- 1 
day) 
309  
 (+/- 3 
days) 
323 
337 
& 
351  
 (+/- 
1 
day) 
364 
(+/- 1 
day) 
365 
(+/- 3 
days) 
Zarit Burden 
Interview 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Device 
Usability 
Questionnair
e  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Med & 
AE Review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 
Scheduling 
and 
Assessment 
Review  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device 
Allocation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Device 
Return 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment 
Period  
-------------------------------------------------X----------------------------------------- 
 
 
 
 
 
 
 
 
---------------X------------------ 
X performed twice a day 
X* performed weekly    
 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
61 
 
 
2.0 Protocol Version History  
Version 
Date 
Description of Change 
Brief Rationale 
v1.0 
March 4, 2021 
N/A 
N/A 
v2.0 
September 14, 
2021 
• Removal of Manage-PD 
questionnaire 
• Addition of UPDRS Part I & IV 
• Addition of Height and Weight 
• Addition of CGI-I global, in 
addition to NMS focused CGI-I 
• Addition of CGI-I to secondary 
endpoints 
• Update to randomization 
procedures 
• Administrative changes to 
protocol body and schedule of 
events 
Protocol has been 
updated to address FDA 
feedback, improve the 
interpretation of study 
endpoints, provide 
additional context on 
study execution, and 
provide measures to 
support the health 
economics of treatment 
for PD. 
 
V3.0 
December 14, 
2021 
• Addition of MDS-UPDRS Part 
I to BL2, RCT EOT, and OLE 
EOT1 
• Addition of the MDS-UPDRS 
Total Score as a secondary 
endpoint 
• Update to exclusion criteria for 
clarity  
• Update to CGI-I term for clarity 
• Administrative changes to 
protocol body and schedule of 
events 
Protocol has been 
updated to address FDA 
feedback, improve the 
interpretation of study 
endpoints, and provide 
clarity on exclusion 
criteria. 
V4.0 
August 15, 
2022 
• Update to inclusion and 
exclusion criteria including 
UK Brain Bank criteria, 
covid-19 vaccination 
requirements, and women 
of childbearing potential 
definitions.   
• Update of Exclusionary 
Medications.  
• Administrative changes to 
protocol body 
Protocol has been 
updated to provide 
clarity on 
inclusion/exclusion 
criteria as suggested by 
the study steering 
committee.   
V5.0 
February 15, 
2023 
• Update to inclusion and 
exclusion criteria related to 
MDS-UPDRS Part I 
Protocol has been 
updated to remove 
criteria and provide 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
62 
 
minimum threshold, covid-
19 vaccination or positive 
test requirements, evidence 
of positive response to 
DRTs, limitations to 
ADLs, Parkinson’s related 
falls, and tinnitus.   
• Removal of NMS-focused 
CGI-I as exploratory 
endpoint. 
• Update of Approved and 
Excluded Concomitant 
Medications. 
• Update to include MDS-
UPDRS Part I as an 
exploratory endpoint.  
• Administrative content to 
Statistical Analysis 
section. 
• Clarification that 196 
participants completing the 
RCT as an alternative 
stopping criterion for study 
recruitment. 
• Administrative change to 
order of Secondary 
Objectives and Endpoints, 
not impacting objectives or 
endpoints collected. 
• Administrative changes to 
protocol body 
clarity on 
inclusion/exclusion 
criteria as suggested by 
the study steering 
committee and medical 
monitor and certain 
inclusion/exclusion 
criteria have been 
modified to broaden the 
study population. 
V6.0 
May 10, 2024 
• Update to Medical Monitor 
Phone number 
• Update to Statistical 
Analysis section for 
sample size including 
removal of 196 
participants completing the 
RCT as an alternative 
stopping criterion for study 
recruitment. 
• Clarification in the naming 
of the secondary endpoint 
that evaluates the summed 
Protocol has been 
updated to reflect a new 
phone number for the 
medical monitor and 
corrections to the sample 
size that overestimated 
the number of successful 
screens and the number 
of participants required 
to achieve >90% power 
for evaluating the 
primary endpoints in 
both the RCT and OLE. 
Clarification has been 

STEM-PD, V6.0 -- CONFIDENTIAL 
Clinician version – not for patient use 
63 
 
score from the MDS-
UPDRS parts I, II and III. 
• Clarification that normal 
findings are to be verified 
by means of the ear exam 
prior to device allocation 
during the RCT and OLE. 
provided to specify that 
the secondary endpoint 
was the combined 
measure of MDS-
UPDRS Parts I, II, and 
III to avoid conclusions 
that the endpoint 
included the MDS-
UPDRS Part IV in the 
summed score. 
Clarification requiring 
normal findings on ear 
exam prior to device 
allocation is to further 
support participant 
safety.