Simple, Home-use Neurostimulation tReatment for Parkinson's Disease dEmeNtia
Phase: NA
Conditions: Parkinson Disease Dementia
Sponsor: Scion NeuroStim

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 .
 
 
SCION NEUROSTIM, INC (SNS) 
Protocol Title: Simple, Home-use neurostimulAtion tReatment for Parkinson’s disease 
dEmeNtia 
 
Protocol Short Title: SHARPEN 
 
Protocol Identifiers: 
SNS-PD-004 
 
Protocol Version: February 12, 2024 v3.0 
 
National Clinical Trial Identifiers: NCT05987540 
 
Medical Monitor: Dr. Lesco Rogers 
Scion NeuroStim, Inc 
3225 Surrey Road, Suite B 
Durham, NC 27707 USA 
Phone: (984) 286-9048 
sharpen@scionneurostim.com 
 
 

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PROTOCOL APPROVAL FORM 
Protocol Title: Simple, Home-use neurostimulAtion tReatment for Parkinson’s 
disease dEmeNtia 
Short Title: SHARPEN 
Version: 3.0 
Date: February 12, 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 
Simple, Home-use neurostimulAtion tReatment for Parkinson’s disease 
dEmeNtia 
Protocol Short Title 
SHARPEN 
Protocol Identifiers 
SNS-PD-004 
Version Date 
February 12, 2024 
Revision 
3.0 
 
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 
1.2 Abbreviations .............................................................................................................. 12 
2 
Schema ................................................................................................................................. 14 
3 
Introduction ......................................................................................................................... 15 
3.1 
Sponsor Introduction: ........................................................................................... 15 
3.2 
Background: .......................................................................................................... 15 
3.2.1 Parkinson’s Disease Dementia .................................................................... 15 
3.2.2 The Vestibular System .................................................................................. 15 
3.2.3 Caloric Vestibular Stimulation .................................................................... 16 
3.3 Study Population ......................................................................................................... 18 
3.4 Risk Benefit Assessment .............................................................................................. 18 
3.5 Description of Study Intervention ............................................................................... 19 
4 Objectives and Endpoints ....................................................................................................... 21 
4.1 Primary endpoint ........................................................................................................ 21 
4.1.1 Objectives: ................................................................................................... 21 
4.1.2 Endpoint:...................................................................................................... 21 
4.2 Secondary endpoints ................................................................................................... 21 
4.2.1 Objectives: ................................................................................................... 21 
4.2.2 Endpoints: .................................................................................................... 21 
4.3 Exploratory Endpoints ................................................................................................ 22 
4.3.1 Objectives: ................................................................................................... 22 
4.3.2 Endpoints: .................................................................................................... 22 
5 
Study design: ....................................................................................................................... 23 
5.1 
Study Schedule and Activities ............................................................................... 23 
5.1.1 Study Activities .......................................................................................... 23 
5.2 Injury/Illness-Related Schedule Deviations ................................................................ 28 
5.3 Justification for Treatment Protocol ........................................................................... 28 
5.4 End of Study Definition ............................................................................................... 28 
6 
Study population ................................................................................................................. 30 

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6.1 Inclusion Criteria ........................................................................................................ 30 
6.2 
Exclusion Criteria ................................................................................................. 30 
6.3 Concomitant Therapy.................................................................................................. 31 
6.3.1  Approved Concomitant Medications ........................................................... 31 
6.3.2 Excluded concomitant medications, drugs and supplements ....................... 32 
6.4 
Approved Contraception ....................................................................................... 33 
6.5  Screen Failures .......................................................................................................... 33 
6.6  Strategies for Recruitment and Retention .................................................................. 34 
7. 
Study Intervention .............................................................................................................. 34 
7.1 Study Intervention Administration .............................................................................. 34 
7.2 Preparation/Handling/Storage/Accountability ........................................................... 35 
7.3  Device Allocation ....................................................................................................... 35 
7.4  Study Intervention Adherence .................................................................................... 36 
8. 
Study Intervention Discontinuation and Participant Discontinuation/Withdrawal .... 36 
8.1 Discontinuation of Study Intervention ........................................................................ 36 
8.2  Lost to Follow-Up ...................................................................................................... 36 
8.2.1 Withdrawal Criteria ..................................................................................... 36 
8.2.2 Lost to Follow-Up ........................................................................................ 37 
9 
Safety Oversight .................................................................................................................. 37 
9.1 Device Deficiency ....................................................................................................... 37 
9.2 Adverse Events (AEs), Adverse Device Effects (ADEs), Serious AEs (SAEs), Serious 
Adverse Device Effects (SADEs), Unanticipated Adverse Device Effects (UADE) and 
Unanticipated Problem Reporting .................................................................................... 37 
9.2.1 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): ............ 37 
9.2.2 Adverse Device Effect (ADE): ..................................................................... 38 
9.2.3 Serious Adverse Event (SAE): ...................................................................... 38 
9.2.4 Serious Adverse Device Effect (SADE): ...................................................... 40 
9.2.5 Unanticipated Adverse Device Effect (UADE): ........................................... 40 
9.2.6 Procedures for AEs: ..................................................................................... 40 
9.2.6.1 Documentation and assessment ............................................................................ 40 
9.2.6.2 Causality and severity assessment ........................................................................ 40 

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9.2.6.3 Investigator Reporting AEs to the Sponsor and responsible IRB ......................... 40 
9.2.6.4 Sponsor Reporting AEs to the FDA or Competent Authority .............................. 41 
9.3 Protocol Deviations .................................................................................................... 41 
9.4 Clinical Monitoring .................................................................................................... 41 
9.6 Data Safety Monitoring – Independent Medical Monitor ........................................... 42 
10 Statistical Considerations ...................................................................................................... 43 
10.1 Sample Size Determination ....................................................................................... 43 
10.2 Statistical design ....................................................................................................... 44 
11Confidentiality and Privacy ................................................................................................... 44 
12 Study Files and Record Retention ........................................................................................ 44 
Appendix: .................................................................................................................................... 46 
1.0 Schedule of Events ...................................................................................................... 46 
2.0 Protocol Version History ............................................................................................ 48 
13 References ............................................................................................................................... 50 
 

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1. Protocol Summary 
1.1. 
Synopsis 
Protocol 
Identifying 
Number 
 SNS-PD-004 
Title  
Simple, Home-use neurostimulAtion tReatment for Parkinson’s disease 
dEmeNtia (SHARPEN) 
Objective 
Primary Objective: The primary objective will be to evaluate the safety 
and feasibility of time varying caloric vestibular stimulation (tvCVS), 
delivered with a solid-state TNM™ Device, in people with mild/moderate 
Parkinson’s disease dementia (PDD). 
Secondary Objective: This study will also seek to assess the effects of 
tvCVS on cognition in people with mild/moderate PDD. 
Exploratory Objective: This study will also seek to further assess the 
effects of tvCVS on cognition and other signs and symptoms in people 
with mild/moderate PDD. 
 
Endpoint 
Primary Endpoints: The primary endpoint will be the following:  
• 
Safety will be evaluated by determining whether tvCVS is 
associated with a worsening of PD signs and symptoms according 
to The International Parkinson and Movement Disorder Society 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Total 
Score: composite score of Parts I, II and III 1.  
Adverse events will also be monitored.  
• 
Feasibility:  
• 
Retention rate or the percent of participants that complete 
assessments required for analysis of the secondary endpoint:  
• High retention:  >90%  
• Moderate retention: 60-90 %  
• Low retention: < 60 %   
• 
Treatment adherence rate during the 12-week treatment 
period:   
• High adherence:  >84%  
• Moderate adherence: 55-84 %  

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• Low adherence: < 55 %  
Secondary Endpoint: The secondary endpoint will be the change from 
baseline in the Montreal Cognitive Assessment (MoCA).  
Exploratory Endpoints: The exploratory endpoints evaluate changes in 
the following:   
• 
The Zarit Burden Interview of Caregivers (ZBI)  
• 
The Patient Global Impression – Improvement (PGI-I)  
• 
The Neuropsychiatric Inventory - Questionnaire (NPI-Q)  
• 
The Modified Schwab and England Activities of Daily Living 
Scale (S &E) 
• 
TNM™ Device usability/satisfaction will also be assessed. 
• 
(Optional Sub-study) A customized cognitive battery which will 
assess the following functions (alternate versions to be used at 
each study visit): 
• Memory 
• Hopkins Verbal Learning Test-Revised (total 
learning) 
• Hopkins Verbal Learning Test-Revised (delayed 
recall) 
• Hopkins Verbal Learning Test-Revised 
(recognition discrimination) 
• Visuospatial 
• Neuropsychological Assessment Battery - Visual 
Discrimination 
•  Language 
• Delis-Kaplan Executive Function System - 
Semantic Fluency 
• Attention  
• Neuropsychological Assessment Battery – Digits 
Forward  
• Hopkins Verbal Learning Test-Revised (Trial 1) 
• Processing speed 
• Oral Symbol Digit Modality 
• Executive Function 
• Delis-Kaplan Executive Function System - 
Semantic Fluency Switching 
• Neuropsychological Assessment Battery – Digits 
Backward 

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Study 
Design/Treatment 
This single arm study will be conducted to evaluate the safety and 
feasibility 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™), in patients with mild/moderate 
PDD and to collect initial evidence to support proof of concept for the 
treatment of mild/moderate dementia in Parkinson’s disease (PD).  
Participants will self-administer (with assistance, if necessary) ~19-
minute BID treatments of tvCVS treatment over a period of 12 weeks 
(84 days). 
Inclusion and 
Exclusion 
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. 
Adults, age 50 years or older, diagnosed with Clinically 
Established or Clinically Probable Parkinson’s disease according 
to the MDS Clinical Diagnostic Criteria2.  
2. 
Participants with a clinical diagnosis of probable PDD 
(criteria defined in Emre et al., 2007)2  according to procedures 
defined in Dubois et al., 20073 (allowing for diagnosis of PD 
defined in Step 1 to be according to the MDS Clinical Diagnostic 
criteria instead of the Queen Square Brain Bank criteria).   
3. 
Participants must be able and willing to consent to 
participate in the study and comply with all study requirements. If 
the participant is unable to consent due to limited capacity, a 
Legally Authorized Representative (LAR) must 
consent. *Capacity for consent must be assessed by a licensed 
clinician with experience with Parkinson's disease dementia and 
documented in the participant’s file.    
4. 
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 and not to 
introduce new medications used to treat PD (motor or non-motor 
symptoms) during the study.   
5. 
The principal investigator, or designee, must have 
confidence in the participant’s ability to reliably use the TNM™ 
device (with assistance, if necessary), and to understand and 
complete the assessments (provided in English only) within a 
given on-state.  
6. 
Participant must have a study partner (defined as 
someone who sees the participant for more than three hours a day, 
5x per week) that is willing to consent and participate in the trial.   
 
Exclusion Criteria Each participant who meets any of the criteria below 
will be excluded from study participation:   

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1. 
Participant and/or study partner anticipates being unable 
to attend all visits and complete all study activities during the trial.  
2. 
Women of child-bearing potential who are pregnant or 
plan to become pregnant during the course of the trial.  ***Women 
of child-bearing potential, who are not abstinent or exclusively in 
same sex relationships must test negative for pregnancy as indicated 
by a negative urine pregnancy test and agree to use an approved 
contraception method listed in section 6.4 for the entirety of the 
study.  
3. 
Has any significant co-morbidity/condition, planned 
surgery or participation in another clinical trial which may either 
prevent safe participation in the study procedures or interfere with 
the evaluation of safety or efficacy of the study Device as a potential 
treatment for PDD.   
4. 
In the Investigator’s opinion, has severe dementia, (e.g., 
MMSE (at screen visit) <15 and/or requires significant assistance 
with activities of daily living (ADLs) due to cognitive deficits).  
5. 
Has experienced a myocardial infarction, angina, or 
stroke within the past 12 months, transient ischemic 
attack (TIA) within the past 6 months or has a documented 
aspiration event in the medical records. 
6. Are receiving late-stage therapies for PD (e.g., deep brain 
stimulation or pump infusion therapies) or are being treated with 
another neurostimulation device.  
7. History of interventional brain surgery or have received 
magnetic resonance guided high intensity focused ultrasound.  
8. Demonstrate suicidality at screening (scores ≥ 4 on 
the Columbia- Suicide Severity Rating Scale (C-SSRS) Baseline 
“In the past Month” section). ***Participants that respond 
affirmatively to questions 4 or 5 on the C-SSRS should receive a 
referral for mental health counseling according to local site 
regulations and standards. 
9.  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.   
10. Use any drugs excluded in the Excluded Medications List. 
11. Use of antipsychotic medications listed in the Approved 
Concomitant Medications (i.e., pimavanserin and quetiapine) 
that have not been taken for more than 180 days and does not 
have medical record documentation of normal QTc interval (i.e., 
no prolongation of the QTc interval) as measured via 
electrocardiogram after starting the medication. 

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12. Have active ear infections, perforated tympanic membrane or 
labyrinthitis, as identified by a general ear examination 
performed by medically qualified Investigators or have chronic 
tinnitus that has been ongoing for at least 3 months. 
13. Have a cochlear implant, myringotomy tubes or hearing aids that 
cannot be easily/reliably removed for treatment.   
14. Clinically significant abnormalities in B12, thyroid function, 
blood count, comprehensive metabolic panel or urinalysis results 
tested at the study screen. Screening tests are not required in 
cases where test results within normal range within 6 months of 
study screen are documented in the medical records. 
      
Sample Size 
This study will enroll participants until 12 participants have received at 
least one (1) treatment with the TNM™ Device prior to competitive 
enrollment closing. Both intention-to-treat (ITT) and per-protocol (PP) 
data will be analyzed. 
Clinical Sites 
The study will be conducted at approximately 2 study centers in the 
United States. The sites will include movement disorder specialty 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. 
 
.  
 
 

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1.2 Abbreviations 
ADLs: activities of daily living  
AEs: adverse events  
BID: twice daily  
BL: baseline 
CBC: complete blood count 
CCB: Customized Cognitive Battery 
CFR: Code of Federal Regulations 
CMP: comprehensive metabolic panel 
CRA: Clinical Research Associate  
C-SSRS: Columbia Suicide Severity Rating Scale 
CVS: caloric vestibular stimulation   
D-KEFS: Delis-Kaplan Executive Function System 
DRT: dopamine replacement therapy 
EMR: electronic medical records 
FDA: United States Food and Drug Administration  
GCP: Good Clinical Practice  
HVLT-R: Hopkins Verbal Learning Test-Revised 
IB: Investigator’s Brochure 
ICF: informed consent form 
ICH: International Conference on Harmonisation of Technical Requirements  
ID: identification  
IRB: Institutional Review Board  
ITT: intention-to-treat  
IUD: Intrauterine device 
LAR: legally authorized representative 
LED: light emitting diode  
MDS: International Parkinson and Movement Disorder Society 
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  

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MDS-UPDRS II: International Parkinson and Movement Disorder Society Sponsored Unified 
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 Total: Composite of the International Parkinson and Movement Disorder Society 
Sponsored Unified Parkinson’s Disease Rating Scale Parts I, II and III  
MMSE: Mini Mental State Examination 
MoCA: Montreal Cognitive Assessment  
NMS: non-motor symptom  
NPI-Q: Neuropsychiatric Inventory - Questionnaire 
NSR: non-significant risk  
PD: Parkinson’s disease  
PDD: Parkinson’s disease dementia 
PGI-I: Patient Global Impressions of Improvement  
PGI-S: Patient Global Impressions of Severity 
PP: per-protocol  
RCT: randomized clinical trial  
SAE: serious adverse event  
SADE: serious adverse device effect 
SAP: statistical analysis plan  
S&E: Modified Schwab and England Activities of Daily Living Scale  
SOE: schedule of events 
SNS: Scion NeuroStim, Inc  
TNM™: ThermoNeuroModulation  
TSH: thyroid stimulating hormone 
tvCVS: timed-varying caloric vestibular stimulation  
UADE: unexpected adverse device effect  
USB: universal serial bus 
VN: vestibular nuclei   
WHO: World Health Organization 
ZBI: Zarit Burden Interview 
 
 

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2 Schema  
Figure 2. Visit Schedule  
  
 
 
 
 

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3 Introduction 
3.1 
Sponsor Introduction: 
Scion NeuroStim, Inc (SNS) is committed to improving the lives of those suffering from diseases 
and disorders of the central nervous system through the development of innovative and easy-to-
use, non-invasive neuromodulation medical devices. 
3.2 Background: 
3.2.1 Parkinson’s Disease Dementia 
Dementia is a condition characterized by a loss of intellectual function.  Dementia in PD can lead 
to deficits across multiple domains including executive functions, memory, attention, and 
visuospatial abilities4. Approximately 10% of PD patients will develop dementia each year with a 
lifetime risk of Parkinson’s disease dementia (PDD) of 75%. PDD not only significantly worsens 
the quality of life for PD patients and caregivers, but it also has substantial economic 
consequences2. Furthermore, gold standard therapies used to treat the motor impairments in PD 
often worsen cognitive function, yet stopping treatment is typically not recommended. Exelon 
(rivastigmine) is the only FDA-approved treatment for PDD. Unfortunately, it provides only short-
lived and modest benefits in PDD and presents significant tolerability issues for many patients3. 
Therefore, new safe and effective treatment options for PDD are greatly needed, while treatments 
that improve motor function without worsening cognition would also provide a significant advance 
in the treatment of PDD. 
3.2.2 The Vestibular System 
The vestibular system is evolutionarily ancient and 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 
neurostimulation.   
Furthermore, the vestibular system has expansive connectivity throughout the brain (see Figure 1).  
Vestibular stimulation has been associated with release of a number of neurotransmitters including 
serotonin5, histamine6, acetylcholine7, 8 and GABA9.  It has also been shown to modulate various 
networks and nuclei in the brain including the basal ganglia10 cerebellum, brainstem, hippocampus, 
insula11, hypothalamus12, thalamus13, locus coeruleus14 and prefrontal cortex15, suggesting 
significant potential for vestibular stimulation to modulate both motor and non-motor functions 16.  
Furthermore, tracing studies17-20, 21 have demonstrated monosynaptic or polysynaptic connectivity 
of the vestibular nuclei (VN) to several regions involved in the non-motor symptoms (NMS) of 
PD including: 
1. the sensory association cortices, temporal-parietal regions, peri-sylvia, PPN, prefrontal 
cortex and hippocampal structures implicated in memory and cognition20, 22, 23,  
2. the corticolimbic network (anterior cingulate cortex, dorsolateral prefrontal cortex, 

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amygdala and hippocampus), the dorsal raphe nucleus (DRN) and the parabrachial 
nucleus which have all been implicated in depression and anxiety11, 17, 21 
3. the periaqueductal gray implicated in blood pressure/ orthostatic hypotension24 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 
cortex25), and  
4. the PPN and DRN implicated in sleep and arousal23, 26-29.  A role for the PPN and 
thalamus in visual hallucinations in PD has been established30.  Furthermore, galvanic 
vestibular stimulation, a related approach, has been shown to increase deficient 
functional connectivity of the PPN in PD31 
The VN also provides direct and/or indirect inputs to many regions implicated in the motor 
symptoms of PD, including: 
 
1. the dorsolateral striatum (caudate/putamen) via the thalamus and cortex32 where an 
imbalance in striatonigral and striatopallidal output due to loss of dopamine 
transmission is thought to underlie the bradykinesia symptoms in PD33, 
2. the pedunculopontine nucleus (PPN) located within mesencephalic locomotor region 
of the reticular formation 34, 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 PD23, 27, 35, and 
3. the cerebellum which has been implicated in the expression of levodopa-induced 
dyskinesia36, 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 nuclei37.   
 
3.2.3 Caloric Vestibular Stimulation 
Caloric vestibular stimulation (CVS) is a century-old technique, but traditional application 
methods have limitations. CVS has been used to diagnose balance disorders or evaluate brainstem 
function and traditionally uses water or air irrigators to warm or cool the external auditory canal 
of patients. Warming temperatures increase while cooling temperatures decrease the tonic firing 
rate of the vestibulocochlear nerves to modulate neural activity in many brain areas. Despite the 
long-standing history of safe use of CVS in the diagnostic setting, the therapeutic potential of 
traditional water or air irrigation methods has been hampered by challenges associated with 

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Figure 1. The effects of CVS on the vestibulocochlear nerves and the connectivity of the 
vestibular nuclei to both cortical and subcortical brain regions.  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. This figure was developed to show 
connectivity to brain regions implicated in Parkinson’s disease and episodic migraine and does 
not show all connectivity to all regions implicated in dementia (e.g., hippocampus, 
parahippocampal gyrus, temporoparietal cortex). 

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modulating temperatures specifically or rapidly, the inability to precisely control dose and 
adaptation that results in response to constant temperature CVS. Furthermore, irrigation CVS, 
which uses water or saline, requires that treatments be administered in the clinical setting, further 
complicating therapeutic applications. As a result, an exploration into the therapeutic potential of 
CVS has been limited. Scion has overcome the limitations of CVS with the development of the 
ThermoNeuroModulation (TNM™) Device (Figure 2) which delivers time-varying caloric 
stimulation (tvCVS); see Description of Study Intervention for additional details. The TNM™ 
Device administers temperature variation through earpieces that comfortably insert in the ear canal 
in a headphone-like device.  
 
3.3 Study Population 
This single arm study seeks to evaluate the safety and feasibility of twice-daily treatments with the 
TNM™ Device in for patients with mild/moderate Parkinson’s disease dementia (PDD) who are 
currently taking stable doses of oral dopamine replacement therapies (DRTs) and other treatments 
for the management of motor and non-motor symptoms in PD. 
3.4 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. 
Unlike many modes of neuromodulation (e.g., deep brain stimulation or transcranial magnetic 
stimulation), the propagation of the tvCVS signal flows through the brain using the same 
endogenous networks that are activated when the sensory system responds to normal motion. This 
factor enables the engagement of natural adaptive processes that prevent potential damage from 
overstimulation, thus mitigating any potential risks with longitudinal tvCVS treatments.  
The low incidence of AEs potentially related to Device use in PD and 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 trials34, 36, 37 further 
supports the safety of longitudinal tvCVS treatments in PDD. As with earlier models, the 
Generation 4.0 TNM™ Device, that will be used in this study, is intended for home-use.   
An earlier version of the TNM™ Device (3.2) was granted De Novo market entry by the United 
States 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 European Union as a 
Class IIa device for the prevention of episodic migraine in adults.  Furthermore, the Sponsor has 
designated the device as non-significant risk (NSR) for this study and the US FDA has agreed with 
this designation for other studies in PD, including Scion NeuroStim’s pivotal trial in non-demented 
people living with PD (NCT04797611).  This is notable given that demented and non-demented 
individuals with PD demonstrate similar demographics and comorbidities, and therefore, are 
expected to have a similar non-significant risk profile. Of note, aspiration can become a concern 
in the later stages of PD when dementia also becomes more prevalent, however, the exclusion of 
severe dementia in this study is likely to limit or prevent potential participation by those at risk of 
aspiration events.  Nevertheless, to mitigate risk of aspiration events that may result from the 
requirement for participants to treat with the study device in the supine orientation, participants 
with documented records of aspiration events in their medical records will be excluded from this 

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study. The TNM™ Device is not implantable (i.e., it is non-invasive).  The TNM™ Device is not 
purported nor represented for use in supporting or sustaining human life.  Furthermore, although 
the TNM™ Device may be of substantial importance in treating disease or in otherwise preventing 
some impairment of human health, the TNM™ Device represents no potential risk to the health, 
safety or welfare of a study participant.  Notably, the TNM™ Device possesses several fail-safes 
(e.g., lockouts that prevent administration of treatment beyond the prescribed frequency, hardware 
that stops device treatment if thermistors in earpiece are not active or if temperatures exceed the 
safety limits, etc.) that provide additional safeguards for cognitively impaired users.  
As such, the TNM™ Device is designated by the Sponsor as Nonsignificant Risk (NSR) for this 
study in mildly to moderately demented people diagnosed with PD.  
3.5 Description of Study Intervention 
This study will investigate the safety and feasibility and explore the efficacy of tvCVS treatments 
for the management of symptoms related to PDD.  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 waveforms to modulate neural areas, including the brainstem, by means of 
CVS. 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 2A).  Specific details regarding 
the Device design have been previously published38. 
All study participants will receive the active tvCVS treatment, and the same time varying thermal 
waveform will be the same for all study participants throughout the study.  Participants will receive 
this treatment 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.  
      

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Nineteen-minute treatments will be delivered twice-daily in the home setting. Wedge pillows will 
be provided to orient the horizontal semicircular canal in the optimal orientation.  Participants are 
to remain supine for the duration of treatment, but they may engage in other activities during 
treatment such as reading, listening to music or watching television (Figure 2B).  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 to three days for 
phone calls, +/- five days for virtual and clinic visits, and + 10 days for illness/injury-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 PD34, 37. Both studies demonstrated high tolerability of tvCVS 
treatments. 
 
 
Figure 2. 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 
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4 Objectives and Endpoints 
4.1 Primary endpoint 
4.1.1 Objectives:  
The primary objective of this study will be to evaluate the safety and feasibility of time 
varying caloric vestibular stimulation (tvCVS), delivered with a solid-state TNM™ 
Device, in people with mild/moderate Parkinson’s disease dementia (PDD). 
4.1.2 Endpoint:   
The primary endpoints of this study are the following:   
● 
Safety will be evaluated by evaluating whether tvCVS is associated with a 
worsening of PD signs and symptoms according to The International Parkinson and 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale Total Score: 
composite score of Parts I, II and III. 
 
Adverse events will also be monitored. 
 
● 
Feasibility:   
o 
Retention rate or the percent of participants that complete assessments 
required for analysis of the secondary endpoint:   
▪ 
High retention:  >90%   
▪ 
Moderate retention: 60-90 %   
▪ 
Low retention:< 60 %    
o 
Treatment adherence rate during the 12-week treatment period:    
▪ 
High adherence:  >84%   
▪ 
Moderate adherence: 55-84 %   
▪ 
Low adherence: < 55 %   
4.2 Secondary endpoints 
4.2.1 Objectives:  
The secondary objective of this trial is to assess the effects of tvCVS on cognition in people 
with mild/moderate PDD. 
4.2.2 Endpoints:  
The secondary endpoint will be the change in the Montreal Cognitive Assessment 
(MoCA) between the baseline and end of treatment visit (Day 84) after 12 weeks of 
treatment.  3 different versions of the MoCA (8.1, 8.2, and 8.3) will be used to avoid 
learning effects, and the ordering of the version for a given participant will be 
randomized.  The MoCA is a rapid screening instrument for detecting cognitive 
dysfunction and dementia in patients with neurologic disorders including PD. 
 
 
 

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4.3 Exploratory Endpoints 
4.3.1 Objectives:  
This study will also seek to further assess the effects of tvCVS on cognition and other symptoms 
in people with mild/moderate PDD. 
4.3.2 Endpoints:  
The exploratory endpoints will evaluate changes in the following between the baseline and end 
of treatment visit (Day 84) after 12 weeks of treatment, unless otherwise noted:    
• 
The Zarit Burden Interview of Caregivers (ZBI) – a measure of caregiving burden completed 
by caregivers  
• 
The Patient Global Impression of Improvement (PGI-I) - a patient reported outcome 
assessment for how much the patient's illness has improved or worsened relative to a baseline 
state at the beginning of the intervention.  * This version will require input from the study 
partner and will provide a single consensus score between the study participant and study 
partner. 
 
• 
The Neuropsychiatric Inventory - Questionnaire (NPI-Q) – a brief questionnaire completed by 
caregivers to evaluate behavioral disturbances in dementia patients – to be completed by the study 
partner 
 
• 
The Modified Schwab and England Activities of Daily Living Scale (S & E)45 - clinical 
outcome assessment of an individual’s ability to function in activities of daily living  
 
Treatment adherence and TNM™ Device usability/satisfaction will also be assessed. 
Optional Sub-study: 
For those that consent to this optional sub-study: A customized cognitive battery (CCB) 
which will assess the following functions (alternate versions to be used at each study visit):  
● 
Memory  
o Hopkins Verbal Learning Test-Revised (total learning)  
o Hopkins Verbal Learning Test-Revised (delayed recall)  
o Hopkins Verbal Learning Test-Revised (recognition discrimination)  
● 
Visuospatial  
o Neuropsychological Assessment Battery - Visual Discrimination  
● 
 Language  
o Delis-Kaplan Executive Function System - Semantic Fluency  
● 
Attention   
o Neuropsychological Assessment Battery – Digits Forward   
o Hopkins Verbal Learning Test-Revised (Trial 1)  
● 
Processing speed  
o Oral Symbol Digit Modality  
● 
Executive Function  

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o Delis-Kaplan Executive Function System - Semantic Fluency Switching  
o Neuropsychological Assessment Battery – Digits Backward  
5 Study design: 
5.1 Study Schedule and Activities 
The phases and activities of the study are listed below, and sites are encouraged to break up the 
visit into multiple parts, as necessary, to reduce participant and study partner burden.  
5.1.1 Study Activities 
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-21 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 Informed 
Consent Form (ICF) and an ample opportunity to have all questions answered. Capacity to 
provide consent must be assessed and documented by a clinician with experience working 
with Parkinson’s Disease patients, and determination should be made if a Legally 
Authorized Representative (LAR) is required. Potential participants and LARs should be 
given a private space to review the ICFs and receive ample opportunity to have all questions 
answered. As this study population may have diminished capacity, open ended questions to 
confirm understanding should be used. The ICF should be signed and dated by both the study 
participant (or the LAR as necessary) and the authorized study staff performing the informed 
consent process. A signed and dated copy of the ICF should be provided to the participant (or 
LAR) prior to any study related activities being conducted.   
 
Additionally, the protocol-required study partner will also be provided an ICF to review and 
discuss. The purpose of the informed consent for the study partner is to ensure that they 
understand and agree that they should attend all visits, are required to answer specific questions 
by the study staff related to the participant’s overall health and activities of daily living, as well 
as mechanically assist the participant with the administration of the device (as necessary). 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, and the rater assessments in the order noted below. 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 

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for screen failure in the study documentation.  
 
▪ Mini-Mental State Examination (MMSE) 
▪ Intake of medical history and concomitant medications  
▪ Ear exam- The purpose of the exam (by otoscope) is to ensure that there are no 
contraindications to placing the device earpieces into the ear canals such as signs 
of inflammation, drainage, perforation of tympanic membrane, or excessive 
cerumen build up. Additionally, visual inspection for obvious structural 
abnormalities of the ear structure and ear canal should be included. As delegated 
by the PI, medical professionals who hold licenses/credentials, and have 
appropriate training and experience may conduct the ear exam. 
▪ Columbia Suicide Severity Rating Scale (C-SSRS) - questionnaire regarding suicidal 
thoughts 
▪ Urinalysis- this does not need to be performed at the screening visit if there are normal 
range values documented in the medical record within 6 months of the screening visit. 
▪ Blood draw for screening labs - B12, TSH, CMP, and CBC w/differential may be 
required. These labs do not need to be performed at the screening visit if there are 
normal range values documented in the medical record within 6 months of the 
screening visit.  
▪ Review of Inclusion and Exclusion Criteria  
▪ Review of the general study schedule and timeline, with assessment scheduling. 
Baseline Visit- day 0:  The baseline activities should be performed per the SOE in the 
appendix maximizing the time between administration of the MoCA (to be completed first) 
and the Customized Cognitive Battery (alternate versions to be used at all study visits). 
Assessments followed by (SP) should be completed by the Study Partner only. 
• 
Confirmation of timing of last dopamine replacement therapy (DRT) dose 
• 
Montreal Cognitive Assessment (MoCA) v8.1 (on-state) +Of note, if the participant has 
completed v8.1 in their standard clinical course within 5 weeks of this administration, they 
should perform v8.2 at this visit, then v8.1 at the interim visit.  
• 
MDS-UPDRS III - clinician-scored motor exam +Of note, the collection of MDS-UPDRS Part 
III data should occur in the 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. 
• 
MDS- UPDRS I –patient and caregiver in equal proportion 
• 
MDS-UPDRS II– patient and caregiver in equal proportion 
• 
PGI-S – should be completed with input from study participant and study partner in equal 
proportion 
• 
PGI-S response documentation: study staff should ask the study participant and study partner to 
give at least three reasons for their score and answers will be recorded and will be provided to the 
study participant and study partner at future administrations of the PGI-I. 
• 
S&E 
• 
NPI-Q (SP) 
• 
ZBI (SP) 
• 
Ear Exam 
• 
Concomitant medication and adverse event review 

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Customized Cognitive Battery (CCB) Form 1 -– optional substudy *** The best practice is to 
collect this data at the baseline visit, however, if participant is unable to complete the CCB at the 
baseline visit, he/she may complete the CCB at the Early Treatment Period Visit 1 - day 3 visit as 
an alternative.  The CCB must be collected at a single study visit and at the study center. Data 
collection of the CCB should not occur in Off-state.  Tests should be administered in the 
following order: 
 HVLT-R (Trials 1-3) 
 NAB Digits Forward 
 NAB Digits Backward 
 NAB Visual Discrimination 
 Oral SDMT 
 HVLT-R (Trial 4 and Recognition) 
 D-KEFS Category Fluency (skip Condition 1-Letter Fluency for this study) 
 D-KEFS Fluency Switching 
• 
Review of inclusion/exclusion criteria  
• 
Device dispensation and training  
• 
First device administration with confirmation of understanding 
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 device 
dispensation. If they do not, the reason for screen failure should be noted in the study 
documentation.  
Device dispensation will occur only after all scheduled assessments and activities have 
been completed. The participant and study partner will be trained on how to use and care 
for the Device.  The participant (with the assistance of the study partner as appropriate) 
should complete the first treatment administration at the study site to demonstrate to study 
staff an understanding of how to set-up, use, and cleanthe study Device.  The participant 
will then take the study Device home, treat once more for the day, and continue with twice 
daily treatments for the duration of the treatment period. 
Treatment Period: The 12 weeks (~84 days) following the pre-treatment baseline period 
constitute the treatment period.  Participants will self-administer treatments twice daily 
with at least an hour in between treatment sessions, for the full treatment period up until 
the scheduled end of treatment visit.  Treatment adherence will be recorded by the Device.   
Phone contact (Day 1, +/- 1 day) 
The first day (Day 1) after Device allocation, the study staff should contact the 
participant/study partner to confirm that treatments have been administered, that there are no 
questions or concerns about the Device and to review concomitant medications and potentials 
adverse events. 
Early Treatment Period Visit 1 - day 3 (+/- 3 days): This in-clinic visit may be completed 
virtually at the participant and study partner’s request if the customized cognitive battery 
does not need to be collected.  The participant and study partner should return to the clinic 
with the study device.  The study participant (with the assistance of the study partner as 

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appropriate) should complete a treatment administration at the study site to demonstrate to 
study staff an understanding of how to use the study Device.  If participants and their study 
partners do not meet the criteria specified in the Treatment Administration Verification 
Form, the participant and study partner will be re-trained on how to use and care for the 
Device.   The participant will then take the study Device home, treat once more for the day, 
and continue with twice daily treatments for the duration of the treatment period. 
CCB (if not collected at the Baseline day 0 visit)- Data collection of the CCB should not occur 
in Off-state.   Tests should be administered in the following order: 
 HVLT-R (Trials 1-3) 
 NAB Digits Forward 
 NAB Digits Backward 
 NAB Visual Discrimination 
 Oral SDMT 
 HVLT-R (Trial 4 and Recognition) 
 D-KEFS Category Fluency (skip Condition 1-Letter Fluency for this study) 
 D-KEFS Fluency Switching 
If the CCB could not be performed at Day 0 or Day 3, then no further attempts should occur and the 
participant is not considered as part of the sub-study. 
 
Virtual visits will be performed, as necessary, using the site’s standard of care telemedicine 
platform. 
Early Treatment Period Visit 2 - day 6 (+/- 3 days) – as needed: This in-clinic visit may 
be completed virtually at the participant and study partner’s request. This visit only needs 
to be completed if the study participant and study partner required retraining on use of the 
study device at the Early Treatment Period Visit 1 - day 3. The participant (with the 
assistance of the study partner as appropriate) should complete a treatment administration 
at the study site to demonstrate to study staff an understanding of how to use the study 
Device. If participants and their study partner meet the criteria specified in the Treatment 
Administration Verification Form, the participant will then take the study Device home, 
treat once more for the day, and commence again with twice daily treatments. If 
participants and their care partners do not meet the criteria specified in the Treatment 
Administration Verification Form, the participant will be withdrawn from the study. 
Phone contacts: (Days 14, 28, +/- 3 day) 
During phone calls scheduled every 2 weeks, study staff will review concomitant medications, 
potential adverse events, potential issues impacting Device treatment adherence and any other 
issues with the study participant (and study partner, as appropriate). Care should be taken to 
not over-engage or impact feasibility of protocol adherence with reminders or contact outside 
of the protocol-defined visits/calls.  
Interim treatment Visit: (Day 42 +/- 5 days) 
The visit activities should be performed per the SOE. Assessments followed by (SP) should 
be completed by the study care partner only. 
• 
Confirmation of timing of last DRT dose 

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• 
MoCA v8.2 (on-state) 
• 
MDS-UPDRS III - clinician-scored motor exam +Of note, the collection of MDS-
UPDRS Part III data should occur in the 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. 
• 
MDS- UPDRS I - patient and caregiver in equal proportion 
• 
MDS-UPDRS II - patient and caregiver in equal proportion 
• 
NPI-Q (SP) 
• 
ZBI (SP) 
• 
S&E 
• 
Ear Exam 
• 
Concomitant medication and adverse event review 
Phone contacts: (Days 56, and 70 +/- 3 day) 
The study staff should continue phone calls scheduled every 2 weeks to review concomitant 
medications, potential adverse events, potential issues impacting Device treatment adherence 
and any other issues with the study participant (and study partner, as appropriate).   
End of Treatment Visit or Early Termination Visit: (Day 84 +/- 5 days) 
The visit activities should be performed per the SOE in the appendix maximizing the time 
between administration of the MoCA (to be completed first) and the Customized Cognitive 
Battery. Assessments followed by (SP) should be completed by the study partner only. 
• 
Confirmation of timing of last DRT dose 
• 
MoCA v8.3 (on-state) 
• 
MDS-UPDRS III - clinician-scored motor exam +Of note, the collection of MDS-
UPDRS Part III data should occur in the 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. 
• 
MDS- UPDRS I - patient and caregiver in equal proportion 
• 
MDS-UPDRS II - patient and caregiver in equal proportion 
• 
PGI-S/PGI-I 
• 
NPI-Q (SP) 
• 
ZBI (SP) 
• 
S&E 
• 
Device Useability Questionnaires (Study Participant and Study Partner) 
• 
Ear Exam 
• 
Customized Cognitive Battery (Form 2) -optional sub study. The best practice is to 
collect this data in the way it was collected at baseline. For instance, if a participant completed 
the CCB at the Baseline Visit – day 0 they should complete the CCB at the end of treatment 
visit.  If the first CCB was collected at the Early Treatment Period Visit 1 - day 3, the best 
practice would be to have them return for a separate visit within 5 days of the end of treatment 
visit, while continuing to treat with the study device.  The CCB must be collected at a single 
study visit. Data collection of the CCB should not occur in Off-state.  Tests should be 
administered in the following order: 
 HVLT-R (Trials 1-3) 

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 NAB Digits Forward 
 NAB Digits Backward 
 NAB Visual Discrimination 
 Oral SDMT 
 HVLT-R (Trial 4 and Recognition) 
 D-KEFS Category Fluency (skip Condition 1-Letter Fluency for this study) 
 D-KEFS Fluency Switching 
• 
Concomitant medication and adverse event review 
• 
Device Return - used Devices will be promptly shipped back to the distributor using 
the Device Return form. ** Device return should occur after completion of the Customized 
Cognitive Battery, if the participant consents to this sub-study and cannot complete the 
CCB on the same day.  
 
5.2 Injury/Illness-Related Schedule Deviations 
Additional protocol approved timing deviation can be considered for enrolled participants due to 
illness or injury. Participants meeting these requirements may be afforded additional time windows 
for in-person study visits of up to 10 days.  If the injury or illness prohibits the participant from 
coming to the clinic during the 10-day window, but the participant is able to complete some 
assessments virtually via video call or phone call, data should be collected using this format with 
a note to file detailing the reasons for the virtual data collection. 
5.3 Justification for Treatment Protocol 
The results from the single-site RCT provide evidence to support the safety and effectiveness of 
TNM™ Device treatments for managing the symptoms associated with PD, experienced by those 
that have PDD.  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 
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.  The selection of a longer treatment interval was based on the 
finding that the treatment response, including measures of relevance to PDD, 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. 
5.4 End of Study Definition 
Participants will continue to be enrolled in the study until at least 12 participants have been 
dispensed a study Device.  The study will end when all study participants have completed their end 

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of treatment (or early termination/withdrawal) visit or safety data support early termination of the 
study. 
 
 

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6 Study population 
6.1 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. Adults, age 50 years of older, diagnosed with Clinically Established or Clinically 
Probable Parkinson’s disease according to the MDS Clinical Diagnostic Criteria2. 
2. Participants with a clinical diagnosis of probable PDD (criteria defined in Emre et al., 
2007)2 according to procedures defined in Dubois et al., 20073 (allowing for diagnosis of PD 
defined in Step 1 to be according to MDS Clinical Diagnostic criteria instead of the Queen 
Square Brain Bank Criteria). 
3. Participants must be able and willing to consent to participate in the study and comply 
with all study requirements.  If the participant is unable to consent due to limited capacity, a 
Legally Authorized Representative (LAR) must consent. *Capacity for consent must be 
assessed by a licensed clinician with experience with Parkinson’s disease dementia and 
documented in the participant’s file. 
4.  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 and not to 
introduce new medications used to treat PD (motor or non-motor symptoms) during the 
study. 
5. The principal investigator, or designee, must have confidence in the participant’s ability 
to reliably use the TNM™ device, and to understand and complete the assessments 
(provided in English only) within a given on-state.  
6. Participant must have a study partner (defined as someone who sees the participant for 
more than three hours a day, 5x per week) that is willing to consent and participate in the 
trial. 
6.2 Exclusion Criteria 
Exclusion Criteria: Each participant who meets any of the criteria below will be excluded from 
study participation:   
  
1. Participant and/or study partner anticipates being unable to attend all visits and 
complete all study activities during the trial.  
2. Women of child-bearing potential who are pregnant or plan to become pregnant 
during the course of the trial.  ***Women of child-bearing potential, who are not 
abstinent or exclusively in same sex relationships must test negative for pregnancy 
as indicated by a negative urine pregnancy test and agree to use an approved 
contraception method listed in section 6.4 for the entirety of the study.  
3. Has any significant co-morbidity/condition, planned surgery or participation in 
another clinical trial which may either prevent safe participation in the study 

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procedures or interfere with the evaluation of safety or efficacy of the study Device 
as a potential treatment for PDD. 
4. In the Investigator’s opinion, has severe dementia, (e.g., MMSE (at screen visit) 
<15 and/or requires significant assistance with ADLs due to cognitive deficits). 
5. Has experienced a myocardial infarction, angina, or stroke within the past 12 
months, transient ischemic attack (TIA) within the past 6 months or has a 
documented aspiration event in the medical records. 
6. Are receiving late-stage therapies for PD (e.g., deep brain stimulation or pump 
infusion therapies) or are being treated with another neurostimulation device. 
7. History of interventional brain surgery or have received magnetic resonance 
guided high intensity focused ultrasound. 
8. Demonstrate suicidality at screening (scores ≥ 4 on the Columbia- Suicide 
Severity Rating Scale (C-SSRS) Baseline “In the past Month” section).  
***Participants that respond affirmatively to questions 4 or 5 on the C-SSRS should 
receive a referral for mental health counseling according to local site regulations 
and standards. 
9. 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.   
10. Use any drugs excluded in the Excluded Medications List. 
11. Use of antipsychotic medication(s) listed in the Approved Concomitant 
Medications (i.e., pimavanserin and quetiapine) that have not been taken for more 
than 180 days and does not have medical record documentation of normal QTc 
interval (i.e., no prolongation of the QTc interval) as measured via 
electrocardiogram after starting the medication. 
12. Have active ear infections, perforated tympanic membrane or labyrinthitis, as 
identified by a general ear examination performed by medically qualified 
Investigators or have chronic tinnitus that has been ongoing for at least 3 months. 
13. Have a cochlear implant, myringotomy tubes or hearing aids that cannot be 
easily/reliably removed for treatment.  
14. Clinically significant abnormalities in B12, thyroid function, blood count, 
comprehensive metabolic panel or urinalysis results tested at the study screen. 
Screening tests are not required in cases where test results within normal range 
within 6 months of study screen are documented in the medical records. 
6.3 Concomitant Therapy 
6.3.1  Approved Concomitant Medications 
● 
The use of the FDA-approved pharmaceutical medications to treat the cognitive 
symptoms including cholinesterase inhibitors, glutamate N-methyl-D-aspartate (NMDA) 
receptor regulators and combination therapies will be permitted during the study so long 

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as the type or dose does not change during the study or the 4 weeks immediately 
preceding the study screening visit. 
● 
The use of the following medications used to treat motor and non-motor symptoms 
associated with PD will be permitted during the study so long as the type or dose does not 
change during the course of the study or the 4 weeks immediately preceding the study 
screening visit: oral levodopa-based therapies, transdermal DRTs (e.g., rotigotine 
transdermal system), dopamine receptor agonists, MAO-B inhibitors and COMT 
inhibitors.  
● 
The use of selective serotonin reuptake inhibitors or other anti-depression/anti-anxiety 
medications not specifically excluded in the Excluded Medications list 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 screening visit. 
● 
The use of orexin receptor antagonists for the treatment of insomnia will be permitted 
during the study so long as the type or dose does not change during the study or the 4 
weeks immediately preceding the study screening visit. 
● 
The use of pimavanserin and quetiapine QHS at doses that do not produce cognitive 
deficits or daytime sleepiness will be permitted during the study so long as the 
medication has been taken for > 180 days and the type or dose does not change during the 
study or the 4 weeks immediately preceding the study screening visit.  
● 
Medications prescribed for other concomitant illnesses are allowed so long as they are 
not listed in the Excluded Medications list.  
● 
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 
or cognition, physicians will be encouraged to utilize the one that is least likely to impact 
symptoms assessed in the trial.  In particular, the central anticholinergic properties of 
medications should be considered.  
● 
Changes to medications for symptoms associated with cognition are not permitted during 
the trial. Participants will be advised that during the trial, 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 will be 
recorded as concomitant medications and participants will continue in the study. Reasons 
for changes in medications used to treat cognitive symptoms will be recorded and 
participants who make changes to these medications or add new medications likely to 
modulate symptoms associated with cognition during the study will be included in the 
ITT analysis but excluded from the PP analysis.    
6.3.2 Excluded concomitant medications, drugs and supplements 
• Off-state rescue medications (e.g., apomorphine injections or levodopa-based inhalers) 
are not permitted on days of study center visits but may be used at other times. Protocol 
deviations will not be accepted, and the visit should be rescheduled in circumstances 

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where off-state rescues were taken on the day of a visit.   Off-state rescue medications 
may otherwise be used throughout the trial period. 
• Antipsychotic Medications not specifically listed in the Approved Concomitant 
Medications (i.e., either neuroleptics or atypical antipsychotics). 
● 
Medications producing side effects of cognitive deficits, delirium, psychosis, motor 
impairments or daytime sleepiness. For example, benzodiazepines such as clonazepam 
may produce cognitive deficits, however, these may be avoided at low dosages (i.e., ≤ 
1mg) and/or with QHS administration and therefore would be permitted under these 
conditions. 
● 
Mucuna pruriens supplements    
● 
Anti-emetics (e.g., 5-HT3 receptor antagonists, D2 receptor antagonists, first-generation 
H1 Receptor antagonists, muscarinic antagonists, synthetic cannabinoids or SP/NK1 
receptors antagonists with anti-emetic properties) as well as corticosteroids with 
significant anti-emetic properties prescribed chronically (taken more than 2 times per 
week, consistently)  
● 
Inhaled or ingested cannabinoids (e.g., marijuana, tetrahydrocannabinol, nabilone or 
cannabidiol) within 4 weeks of screening and during the study period.  
● 
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. 
● 
Anticholinergics with definite central activity (acbcalc.com) 
● 
Antibody therapies used to treat cognitive decline in Alzheimer’s disease (e.g., those that 
target amyloid). 
6.4 Approved 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: 
o Male Condom 
o Female Condom 
o Diaphragm 
o Cervical Cap with spermicide 
o Contraceptive Sponge 
o Spermicide 
6.5  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 

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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, 
and participants can re-screen with the original Participant ID. However, participants that were 
excluded due to cognitive screening scores out of range (i.e., MMSE > 25 or <15) or demonstrated 
evidence of suicidality on the C-SSRS at the original screening will not be permitted to rescreen. 
6.6  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.   
A variety of strategies are being utilized to avoid unnecessary attrition. The study design facilitates 
retention as there are only 4 visits requiring travel to the study center, and care was taken to reduce 
study visit length of time, thereby reducing participant and caregiver burden. Additionally, 
participants and study partners will receive stipends to compensate for the travel and time burden 
associated with participation in the study. Participant retention will also be closely monitored, and 
the CRA will work with the site to identify solutions should retention issues arise. 
7. Study Intervention 
Intended Use: The TNM™ Device is intended to stimulate the vestibular system via external ear 
canals using software-controlled thermal waveforms.  
7.1 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 Investigator 
Brochure for more details. The Sponsor has designated this Device as non-significant risk (NSR) 
for participants with PD and PDD.  
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.   
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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 and 
treatments must be separated by at least 1 hour. Participants will only wear the device when 
administering a treatment. Participants will be encouraged to self-administer treatments in the on-
state and at a time when they do not anticipate interruptions that would require them to pause 
treatment. 
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 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.  
7.2 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. 
7.3  Device Allocation 
The Generation 4.0 TNM™ device uses a bar code reader to import a prescription waveform and 
the QR code is not readable by staff members.  Bar codes will be printed on plastic ID cards.  
After eligibility is confirmed and documented and the participant has confirmed comfort of the 
device after trying it on, delegated study staff will scan the bar code. Study staff will load the 
treatment onto the device, record the device number allocated to the participant and will train the 

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participant according to the training script provided.  The first treatment will be performed at the 
study site to confirm understanding of the training by the study participant and study partner, and 
subsequent confirmation of understanding at the next visit will also occur.  
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.     
7.4  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 
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. 
8. Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal 
8.1 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 Sponsor, 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.   
8.2  Lost to Follow-Up 
8.2.1 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, of note requirements relate to participation and 
completion of activities during study visits and do not include adherence of treatments with 
the study device), 
▪ the participant develops an illness or condition that would interfere with his/her continued 
participation, 
▪ the participant withdraws his/her consent, 
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▪ the principal investigator feels that it is the participant’s best interest to be withdrawn, 
▪ the participant and/or their study partner is unable to demonstrate device use at the required 
visits 
▪ 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 may be identified and consented to the study.  If a suitable study partner 
cannot be found, the participant will be withdrawn from the study.  
Participants that withdraw early will be excluded from the per protocol analysis. 
8.2.2 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, certified letters should be sent to the participant and study 
partner 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. 
9 Safety Oversight 
9.1 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. 
9.2 Adverse Events (AEs), Adverse Device Effects (ADEs), Serious AEs (SAEs), 
Serious Adverse Device Effects (SADEs), Unanticipated Adverse Device Effects 
(UADE) and Unanticipated Problem Reporting 
9.2.1 AEs, ADEs, SAEs, SADEs and UADEs will be defined per ISO14155:2020 

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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. 
9.2.2 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. 
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. 
9.2.3 Serious Adverse Event (SAE): 
A Serious Adverse Event (SAE) is an AE that has 
▪ Led to death, 

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▪ 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, 
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9.2.4 Serious Adverse Device Effect (SADE):  
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
9.2.5 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, 
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. 
9.2.6 Procedures for AEs: 
9.2.6.1 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 causal 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. 
 
9.2.6.2 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. 
9.2.6.3 Investigator Reporting AEs to the Sponsor and responsible IRB 
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 
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▪ All serious and/or unanticipated/unexpected adverse events that involve a death must 
be reported within 24 hours of discovery. 
Reporting to the IRB: 
▪ 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 
hours of discovery.  
9.2.6.4 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: 
▪ The Sponsor will report the results of an UADE to FDA and all reviewing IRBs 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 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. 
 
9.3 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)) 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 site’s IRB reporting requirements for protocol deviations must also be documented 
to confirm compliance with local regulations. 
9.4 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 
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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 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. 
It is mandatory that the monitor/auditor have access to all original source documents, including 
all electronic medical records (EMR) at reasonable times and upon reasonable notice. If access to 
the EMR cannot be granted to the monitor, the site must ensure that all certified copies of 
documents are available during monitoring visits for all screened and enrolled subjects. During 
the review of source documents, every effort will be made to maintain the anonymity and 
confidentiality of all subjects during this clinical study.  
 
Scion NeuroStim, Inc. or its authorized representative may perform an audit at any time during 
or after completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Scion NeuroStim, Inc will be available to assist in the 
preparation. All pertinent study data should be made available as requested by the Regulatory 
Authority for verification, audit, or inspection purposes. 
 
9.6 Data Safety Monitoring – Independent Medical Monitor  
Patients with Parkinson’s disease dementia represent a vulnerable population. As such, even 
though the sponsor deems the TNM™ Device to be a non-significant risk for studies in PDD, the 
study will utilize an Independent Medical Monitor (IMM).  
 
The IMM is a physician with expertise in PD and dementia, who is not involved in the study and 
has no conflict of interest with the Sponsor, whose primary responsibility is to provide 
independent safety monitoring in a timely fashion. The IMM may review the research protocol 
and ongoing study activities with emphasis on data integrity, protocol adherence and study 
participant safety issues. The IMM’s review will focus on AEs and reasons for losses to follow 
up, raising any concerns or issues, and recommending to the continuation, modification or 
conclusion of the trial, while protecting the confidentiality of the trial data and the results of 
monitoring. 
 
 

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10 Statistical Considerations 
10.1 Sample Size Determination 
This single-arm exploratory clinical trial will continue with competitive enrollment until 12 
participants receive at least 1 treatment with the study Device. An enrollment number of 12 was 
set ensure adequate evaluation of the safety and the feasibility of the study design. Based on the 
Go/No Go Decision criteria for a follow-on Phase II RCT in PDD, this Phase I study would need 
to demonstrate that there were no Serious Adverse Device Effects (SADEs) and that at least 75% 
of the participants completed the end of treatment visit.  This second criterion would mean that at 
least 9 participants complete the MoCA at the end-of-treatment visit without any SADEs.  Utilizing 
a Poisson distribution, fulfilling these two criteria would yield 95% probability that the true 
probability of a serious adverse event among the PDD population would be less than 0.33.  If all 
12 participants completed the MoCA at the end-of-treatment visit without any SADEs, then the 
study would yield 95% probability that the true probability of a SADEs among the PDD population 
would be less than 0.25.  This relationship is depicted in the following figure:  
 
 
 
The likelihood of the population mean being at least that of the outcome’s MCID can be 
determined as a function of the average change in MDS-UPDRS Total score among the sample.   
The figure below depicts the relationship between the sample (n=12) mean change in MDS-
UPDRS Total Score and the likelihood that the true population mean change is 6.70 points 
(MCID). To illustrate the usefulness of the below figure, if the average change in MDS-UPDRS 
Total Score among the sample is 12.9 points, then there would be a 90% likelihood that the true 
population mean change is 6.70 points (i.e., the MCID value) indicating a clinically meaningful 
worseing of Parkinson’s disease signs and symptoms 
 
 

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10.2 Statistical design 
Details regarding Statistical considerations may be found in the Statistical Analysis Plan (SAP), 
which is available upon request. 
11Confidentiality 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. Assessments and interviews completed by the study partner will also be 
associated with the Participant ID. Study sites are required to keep a key code to identify the study 
participant and study partner and will not share this code with the Sponsor or any site staff not 
delegated by the PI.  
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.  
12 Study Files and Record Retention 
The investigator must keep a record of all subjects who have consented to enroll in the study. For 
those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded. The investigator/study staff must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently verified. 
Essential documentation includes, but is not limited to, the IB, signed protocols and 
amendments, IRB approval letters (dated), signed investigator agreements (e.g., Form FDA 
1572s or equivalent) and Financial Disclosures, signed ICFs (including subject confidentiality 
information), study treatment and accountability records, shipping records of medical device and 
study-related materials, signed (electronically), dated and completed case report forms 
(CRFs)/electronic case report forms (eCRFs), and documentation of CRF corrections, SAE 
forms transmitted to Scion NeuroStim, Inc. And notification of SAEs and related reports, source 
0
10
20
30
40
50
60
70
80
90
100
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Likelihood Population Mean Equals MCID [%]
Sample Mean Change in MDS-UPDRS Total Score
Likelihood Population Mean Equals MCID
6.70 points in MDS-UPDRS Total Score
n = 12     σ = 15.8007

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documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study.  
 
All essential documents will be retained by the investigator 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.  
 
Scion NeuroStim, Inc must be notified in advance of, and must provide express written approval 
of, any change in the maintenance of the foregoing documents if the investigator wishes to move 
study records to another location or assign responsibility for record retention to another party. If 
the investigator cannot guarantee the archiving requirements set forth herein at his or her study 
site for all such documents, special arrangements must be made between the investigator and 
Scion NeuroStim, Inc. To store such documents in sealed containers away from the study site so 
that they can be returned sealed to the investigator for audit purposes.  
   

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Appendix: 
1.0 Schedule of Events 
SHARPEN SOE 
Assessment  
Screen  
Baseline   Phone 
Calls  
Early 
Treatment 
Period V1 
Early Treatment 
Period V2 (ONLY 
if needed) 
Interim 
Treatment 
Visit   
Phone 
Calls 
End of 
Treatment/ 
Early 
termination 
  
Day -21 to -1  
Day 0  
Biweekly, 
Day 1 
(+/-1 day) 
Day 28 
(+/- 3 
day)  
Day 3 (+/- 3 days)  
Day 6 (+/- 3 days) 
Day 42 (+/- 5 day)  Biweekly, Day 
43& 70 (+/- 3 
days) 
Day 84 (+/- 5 
days)  
Visit Location 
Study Center 
Study 
Center 
PC 
Study Center or 
Virtual via video 
call 
Study Center 
Study Center 
PC 
Study Center 
Informed Consent (participant and study partner) 
X  
  
  
  
 
 
MMSE  
X  
  
  
  
 
 
  
C-SSRS  
X  
  
  
  
 
 
  
Medical History and concomitant medications  
X  
  
  
  
 
 
  
Screen Blood draw - B12, TSH, CMP, CBC 
w/diff,  
X * 
  
  
  
 
 
  
Urinalysis  
X * 
  
  
  
 
 
  
Inclusion/exclusion criteria  
X  
  
  
  
 
 
  
* Only performed if no normal range value labs are available with formal documentation within 6 months of screen. 

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Ear physical exam  
X  
X  
  
 
X 
 
 
X  
MoCA (on-state)-alternate versions 
  
X  
  
 
 
X 
 
 
X  
PGI-S** 
  
X  
  
 
 
 
X  
PGI-I** 
 
 
 
 
 
X  
PGI-S response documentation 
 
X 
 
 
 
 
 
MDS-UPDRS I ** 
  
X  
  
 
X 
 
X  
MDS-UPDRS II ** 
  
X  
  
 
X 
 
X  
MDS-UPDRS III (on-state) 
  
X  
  
 
X 
 
X  
Neuropsychiatric Inventory Questionnaire (NPI-
Q)  (SP) 
  
X  
  
 
X 
 
X  
Customized cognitive battery  
 
X*** 
 
X-as 
needed*** 
 
X*** 
Device Useability Questionnaire  
  
  
  
  
 
 
X  
Zarit Burden Interview (ZBI) (SP) 
  
X  
  
 
X 
 
X  
Modified S&E 
 
X 
 
 
X 
 
X 
Device training  
  
X  
  
  
 
 
  
Device Training confirmation of understanding 
 
 
 
X 
As needed 
 
 
Study Center Treatment Administration 
 
X 
 
 
 
 
Device use at home 
 
--------------------------------------------X--------------------------------------------- 
Device Return 
 
 
 
 
 
X 
Review concomitant medication, AE reporting, 
treatment adherence   
  
X  
  
X  
X  
 
X 
 
X 
 
X 
 
X 
*** cognitive battery can be performed at Day 0 or Day 3, or at EOT conducted on another day in window-as needed to avoid data collection in the "off-state". 
Must be conducted at study center 

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2.0 Protocol Version History  
Version 
Date 
Description of 
Change 
Brief Rationale 
v1.0 
10Jan2023 
N/A 
N/A 
v2.0 
6Nov2023 
• Clarification to 
inclusion/exclusion 
criteria 
• Clarification to 
approved and 
excluded 
medications 
• Addition of visits  
• Change of primary 
endpoint of safety 
to include the 
MDS-UPDRS 
Total 
• Removal of 
exploratory 
endpoints to have 
cognitive battery 
as an optional 
substudy, 
exchange of 
exploratory 
endpoints of CGI-I 
to PGI-I, and 
addition of 
Modified Schwab 
and England to 
exploratory 
endpoint. 
• Administrative 
changes 
Minor changes and 
clarifications were 
made to provide 
clarity on the study 
population.   
The safety portion 
endpoint of the 
Primary Objective 
was changed to 
MDS-UPDRS Total 
as a clinically defined 
outcome. Exploratory 
endpoints were 
added, removed and 
exchanged to reduce 
participant burden. 
Additional visits 
were added for 
verification that 
treatments can be 
appropriately 
administered in the 
home setting in this 
patient population 
and to allow for 
reductions in patient 
fatigue. 
v3.0 
12Feb2024 
• Clarification to 
inclusion/exclusion 
criteria, order of 
the CCB 
• Extension of phone 
call visit window 
• Update to Medical 
Minor changes and 
clarifications were 
made to provide 
clarity on the study 
population and order 
of tests within the 
CCB. The phone call 

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Monitor’s phone 
number 
• Administrative 
changes 
• Modification of 
sample size 
justification 
visit window was 
extended during the 
treatment period to 
accommodate 
participant schedules. 
The Medical 
Monitor’s phone 
number was updated 
to reflect best form of 
contact, and other 
administrative 
changes were made 
for clarity. The 
sample size was 
updated to address 
change in primary 
endpoint. 
 
 
 

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