A Prospective, Randomized, Staggered-onset, Double Blinded, Sham-Controlled Study to Evaluate Peripheral Vibrotactile Coordinated Reset (CR) Stimulation for Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Peter Tass, MD, PhD

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A Prospective, Randomized, Staggered-onset, Double 
blinded, Sham-controlled Study to Evaluate Peripheral 
Vibrotactile Coordinated Reset Stimulation  
 for Parkinson’s Disease 
 
 
Stanford Neurosurgery 
 
 
Protocol Version 2.1 
 
NCT03857867 
 
Protocol Version / Date:    
 October 1, 2018 
 
 
Sponsor:  
 
 
 
Stanford University 
 
 
 
 
 
 
 
 
 
 
 
Stanford, CA 94305 
 
 
 
 
 
 
 
 
Protocol Director: 
 
 
Casey H. Halpern, MD 
 
 
Funding Source: 
 
 
Stanford University  
 
 
 
 
 
 
School of Medicine 
 
 
 
 
 
 
Department of Neurosurgery 
 
 
 

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A Prospective, Randomized, Staggered-onset, Double 
blinded, Sham-controlled Study to Evaluate Peripheral 
Vibrotactile Coordinated Reset Stimulation  
 for Parkinson’s Disease 
 
 
 
Stanford Neurosurgery 
 
 
Investigator’s Agreement 
 
 
 
By signing below I confirm that I have read this protocol and agree that it contains all 
necessary details for conducting this study.  I will conduct the study according to the 
procedures described in this protocol. 
 
 
 
 
_________________________________________          ______________ 
Principal Investigator’s Signature  
 
 
 
Date 
 
 
_________________________________________ 
Principal Investigator’s Name              
 
 
_________________________________________          ______________ 
Principal Investigator’s Signature  
 
 
 
Date 
 
 
_________________________________________ 
Principal Investigator’s Name              
 
 
 
Site Address:  
Stanford University Medical Center 
 
 
 
300 Pasteur Drive  
 
 
 
Stanford, CA 94305   
 
 
 
 
 
 
 
 
 

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Our study to evaluate peripheral vibrotactile coordinated reset stimulation for 
Parkinson’s disease seeks to explore the safety and efficacy of an experimental non-
invasive method to aid in the symptoms of Parkinson’s disease. The purpose of the 
study is to verify the safety and tolerability of non-painful sensory (tactile) vibratory 
stimulation delivered to the fingertips of patients with Parkinson’s disease.  
 
BACKGROUND 
 
Parkinson’s disease 
Every year over 50,000 people in the US are diagnosed with Parkinson’s disease (PD) 
and about half a million people have the disease. Because the rate of PD increases in 
older adults, the burden will increase unless prevention and treatment improve. Current 
treatments for Parkinson’s disease include both medications and surgical measures. 
Levodopa is still the mainstay of drug therapy in the form of carbidopa/levodopa 
(Sinemet, Rytary, Duodopa). Additional drugs are available that complement levodopa 
therapy, including dopamine agonists such as ropinirole (Requip) and pramipexole 
(Mirapex), COMT inhibitors such as entacapone (Comtan) and tolcapone (Tasmar), 
anticholinergics such as trihexyphenidyl (Artane) and benztropine mesylate (Cogentin), 
MAO inhibitors such as selegiline and amantadine (Symmetrel). Despite the use of 
these drugs singularly or as combination therapy, none significantly slow the underlying 
neurodegeneration and many can include intolerable side effects, especially when taken 
at higher doses as the disease progresses.  
Patients with symptoms who become refractory to medication therapy can undergo 
Deep Brain Stimulation (DBS) surgery. DBS improves symptoms of PD by electrically 
stimulating brain cells in movement control areas of the brain through chronically 
implanted electrodes connected to a subcutaneous pulse generator typically placed 
below the clavicle. However, there are risks associated with this type of operation 
including risk of stroke, infection, seizure, hemorrhage or others we may not 
anticipate. Needless to say, less than 10% of surgical candidates for DBS with PD 
actually undergo the surgery, emphasizing the need for less invasive options. 
(https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=109) 
In a previous first in man study five subjects with idiopathic Parkinson’s disease were 
treated with vibrotactile CR stimulation during three consecutive days for 4 h per day 
(Syrkin-Nikolau et al., 2018) This study demonstrated tolerability as well as feasibility of 
our method, and revealed a significant improvement of gait and bradykinesia, persisting 
for at least one month after three days of vibrotactile coordinate reset (CR) stimulation.  
 
Based on this study, we propose to deliver vibrotactile CR stimulation during a longer 
treatment period, in order to assess durability and efficacy vs. a sham vibrotactile 
approach. This study is designed to best assess vibrotactile CR stimulation compared to 
sham as an alternative to best medical therapy for Parkinson’s disease. With our 

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project, we are hoping to establish a simple, non-invasive treatment that will provide 
ongoing relief with minimal side effects or inconvenience to the patient.  
 
Sham control 
 
Parkinson's patients are particularly vulnerable to the placebo effect. The best method 
of reducing placebo effects in a placebo effect prone population is to blind the 
participants. In order to do this, sham participants will receive a non-stimulation (0 
amplitude) chip that is inserted into the vibrotactile device. All participants will be told 
that they will receive 1 of two chips, 1 is regular vibrotactile reset and the other (sham) 
is called Stochastic resonance vibrotactile coordinated reset. The patient will learn that 
Stochastic resonance treatment is most effective when the patients vibratory stimulus 
threshold (i.e the minimum perception thresholds) is set as 90% . This means that the 
patient should not feel the vibrations on their fingers if they receive vibratory stochastic 
resonance. We will take vibrotactile threshold measurements from patients to make this 
story convincing and to add another dependent measure. If placed into the sham 
condition, the patient will receive no stimulation, however they will be convinced that 
they are receiving stimulation 
 
Vibrotactile CR stimulation therapy system is a commercially available (though not yet 
FDA-approved), non-invasive, battery-operated mobile device. The device consists of a 
handheld component with vibro-tactile stimulators (tactors) and is fitted and programmed 
by a qualified healthcare professional familiar with Parkinson’s disease treatment (e.g., 
physicians, advanced practice providers, nurses and/or their clinical research assistants). 
 
Several brain diseases are characterized by abnormal neuronal synchronization.  
CR stimulation was developed to specifically counteract neuronal synchronization (Tass 
2003). CR stimulation is a spatio-temporally patterned desynchronizing stimulation 
technique. According to computational studies CR stimulation induces a reduction of the 
rate of coincidences and, mediated by synaptic plasticity, an unlearning of abnormal 
synaptic connectivity (Tass & Majtanik 2006). A sustained desynchronization is 
achieved by shifting the neuronal system from a pathological to a physiological attractor 
(Tass & Majtanik 2006). It was shown computationally that CR is effective regardless of 
whether it is delivered directly to neuronal somata or indirectly via excitatory or inhibitory 
synapses (Popovych & Tass 2012). Accordingly, it was hypothesized that CR 
stimulation can be realized using both invasive and non-invasive stimulation modalities 
(Popovych & Tass 2012).  
 
In accordance with theoretical predictions, electrical deep brain CR stimulation has 
pronounced therapeutic after-effects in Parkinsonian monkeys (Tass et al., 2012a) as 
well as cumulative and lasting therapeutic and desynchronizing after-effects in 
Parkinsonian patients (Adamchic et al., 2014a).  
 
In patients with tinnitus, acoustic CR stimulation leads to a significant clinical 
improvement (Tass et al., 2012b) as well as a decrease of pathological neuronal 
synchrony in a tinnitus-related network of auditory and non-auditory brain areas (Tass et 

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al., 2012b; Adamchic et al., 2014b( along with a normalization of tinnitus characteristic 
abnormal interactions between different brain areas (Silchenko et al., 2013; Adamchic 
et al., 2014c).  
 
The somatosensory neuronal response to vibratory stimuli [Weiss et al., 2009] provides 
a dynamic stimulus response characteristics required to robustly deliver CR stimulation 
[Tass 2017]. As abnormal neuronal synchrony appears to play a major role in 
Parkinson’s disease [Hammond et al., 2007], desynchronization of abnormal synchrony 
represents a possible target for intervention in Parkinson’s patients. It was therefore 
hypothesized that vibratory CR stimulation might cause a desynchronization of 
abnormal neuronal synchrony in Parkinson’s disease patients and, in turn, induce a 
decrease of abnormal synaptic connectivity, ultimately giving rise to a sustained relief of 
symptoms [Tass 2017]. In a first-in-human study in five subjects with idiopathic 
Parkinson’s disease tolerability and feasibility of vibrotactile CR stimulation therapy was 
demonstrated [Syrkin-Nikolau et al., 2018]. Subjects received 2x2-hour vibrotactile CR 
stimulation per day during three consecutive days. The CR treatment caused significant 
effects on gait and bradykinesia, as shown by off medication kinematic assessments 
during the three treatment days as well as at a one-week and a four-week follow up visit 
[Syrkin-Nikolau et al., 2018].  
 
Primary Hypothesis   
Vibrotactile CR stimulation is not expected to cause discomfort or pain in patients as 
confirmed in a prior study with Parkinson’s disease (IRB# 45096; Syrkin-Nikolau et al., 
2018). It is expected to lead to a decrease in severity of motor symptoms from baseline 
to 6 months, as measured by the Movement Disorders Society’s Unified Parkinson’s 
Disease Rating scale (MDS-UPDRS) part III and patient motor diaries to capture mean 
time when patients’ medications have worn off and are not controlling symptoms (OFF 
time), time when patients’ medications are working effectively to control symptoms (ON 
time), ON time with troublesome dyskinesia, and sleep time – all factors which can be 
affected by Parkinson’s disease. As secondary endpoints, we expect this may result in 
the patient’s ability to reduce reliance upon dopaminergic medications, therefore we will 
measure changes in levodopa dose equivalency. Additionally, we will assess for 
improvement in non-motor symptoms of Parkinson’s disease, ability to perform activities 
of daily living and reduction in dyskinesia, which will be measured by the Movement 
Disorders Society’s Unified Parkinson’s Disease Rating scale (MDS-UPDRS), parts 1, 2 
and 4 and the Schwab and England Activities of Daily Living score. We expect patient 
quality of life will increase after stimulation, which will be measured by the Parkinson’s 
Disease Questionnaire-39 (PDQ-39) scale. To get a general sense of symptom change, 
we will assess the patient and clinician Global Rating of Change (GRC) scale and the 
Patient Global Impression of Change. We will also asses speech using comprehensive 
speech evaluations. We predict that this decrease in symptoms will be apparent within 1 
month of vibrotactile stimulation and that this treatment will be durable as assessed up 
to 1-months post-stimulation. 
 

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Relevance 
If the results of this study suggest that vibrotactile CR stimulation is safe and effective for 
the treatment of Parkinson’s disease, this non-invasive treatment approach would have 
a substantial impact on Parkinson’s disease.  
 
Patient Population 
Patients presenting Parkinson’s disease as identified by Stanford physicians in clinic, will 
be eligible for participation in this study. Patients will be screened and selected from the 
population of people with Parkinson’s disease who are routinely seen in the Stanford 
Neuroscience Clinic. It should be emphasized that patients will be allowed to continue 
any oral medications once stimulation is initiated for their Parkinson’s disease symptoms. 
The doctor and/or research coordinator may introduce the study to potential candidates 
in-person at Stanford’s Neuroscience Clinic, and the research coordinator can also 
contact potential candidates by the phone after the doctor’s referral.   
 
Study Sites 
The Stanford University Medical Center will be the Coordinating Center for this study.  
Stanford’s Neuroscience Outpatient Clinic will be used for study visits and assessments.  
 
Inclusion Criteria 
1) Age 18 and older 
2) Diagnosis of idiopathic Parkinson’s disease. 
3) Levodopa responsiveness as defined by at least a 30% reduction in MDS-UPDRS 
motor subscale (excluding tremor scores) in the ON vs OFF medication state.  
4) Willing to participate in the vibrotactile stimulation sessions for 2 consecutive days 
initially and willing to return for follow-up visits 
5) Able to provide informed consent. 
6) Appropriate social support  
 
Exclusion Criteria 
     1)  Hoehn and Yahr stage greater than 3 in the on medication state 
2) Presence of other forms of non-idiopathic parkinsonism, including but not limited 
to 
atypical 
parkinsonism, 
medication 
induced 
parkinsonism, 
vascular 
Parkinsonism 
3) Any illness that in the investigator’s opinion precludes participation in the study 
4) Subjects unable to communicate with the investigator and staff 
 
Study Procedures  
Once the participant has given informed consent and after baseline screening, the 
participant will be enrolled in the study and will come to Stanford for 4 visits, each visit 
being 2 consecutive days. Participants will undergo a series of motor evaluations, 
speech assessments and EEGs. Participants will be enrolled in the study for 7 months. 
They will receive treatment for 6 months and no treatment for 1 month. Patients will 
return for follow up visits every 3 months up until the 6 month follow up. After the 6 

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month follow up the patient will go off stimulation for 1 month and return for the 7 month 
follow up to asses long term effects.  Data will be accessed only by Stanford 
researchers on-site 
 
PD-related brain oscillations will also be assessed by high density (256-channel; 
Geodesic EEG system, EGI Electrical Geodesics, Inc. EEG recordings. Acute effects of 
stimulation as well as acute after-effects of stimulation on the power of cortical currents 
in different brain areas as well as on phase amplitude coupling between different brain 
oscillations will be studied with methods as in  [I. Adamchic, B. Langguth, C. Hauptmann, 
P.A. Tass: Abnormal brain activity and cross-frequency coupling in the tinnitus network. 
Frontiers in Neuroscience 8 (2014) 284; I. Adamchic, T. Toth, C. Hauptmann, H. Meister, 
M. Walger, B. Langguth, I. Klingmann, P.A. Tass: Auditory coordinated reset stimulation 
has a specific desynchronizing effect on tinnitus related oscillatory brain activity. 
Neuroimage: Clinical 15 (2017) 541-558]. EEG is expected to also provide further 
objective parameters. Moreover, EEG markers may enable predictions of long-term 
stimulation effects by correlating acute electrophysiological effects and after-effects with 
long-term clinical (and electrophysiological) effects of stimulation. We anticipate to 
correlate changes of neural synchrony in different brain areas with different changes of 
motor, cognitive, somatosensory, and visual symptoms. Particular stimulation parameters 
may differentially affect different symptoms. Because of this, there may be changes of the 
finger representation in the somatosensory cortex over time. 
 
Thus, future optimization may be possible by individually calibrating (personalizing) 
stimulation based on biomarkers. This will be the subject of a future study, but we will 
leverage the opportunity the proposed study provides to collect this electrographic data. 
We anticipate that vibrotactile CR counteracts PD-related patterns of EEG power (i.e. 
synchrony) and effective connectivity.  
 
After being trained on how to use the device and administer the traditional physical exams 
and assessments by the study investigators, the PI’s clinical staff will apply the device 
therapy, monitor the participant through the sessions to ensure patient comfort and proper 
device function, and perform the assessments instructed. Dr. Tass will lead the training 
of all key personnel on the use of the E-3 vibrotactile stimulator and the protocol will be 
discussed during an in-service for all research personnel involved in the study to ensure 
that everyone understands the protocol prior to participating in any research activity. A 
patent for vibrotactile CR stimulation is filed and owned by Stanford University. Inventor 
is Peter Tass who will provide as needed consultation to this study at no fee. Stanford 
Office of Technology and Licensing is actively setting up an industrial collaboration for 
this treatment of Parkinson’s disease. 
 
The vibrotactile stimulator will be attached gently to the fingers (thumb excluded) 
bilaterally using a glove with an elastic band a Velcro strip or a similar method. When the 
stimulation is activated, the stimulators will apply gentle vibration to the different fingers 
sequentially. (Figure 1) 
 

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Approximately one week later (Day 7 – this will be 
an optional visit for as needed training) and four 
weeks later (Day 28), the participant will return for 
follow-up physical examinations and assessments 
only, again occurring at the Stanford Outpatient 
Neuroscience 
clinic. 
These 
visits 
will 
last 
approximately two hours. 
 
 
 
 
 
Statistical Analysis 
 
Our primary hypothesis is that vibrotactile CR stimulation (i) will improve the outcome 
measured as On-time at least by 30% compared to the baseline after three months of 
usage.  We also expect that (ii) the relative increase in On-time in the intervention arm 
(using vibrotactile CR stimulation) will be at least 20% compared to the control arm 
(Sham) after three months of usage. In order to test these hypotheses, we will perform 
Welch's t-test (paired t-test for the first hypothesis and unpaired two-sample t-test for the 
second hypothesis). Our power analysis shows that the sample size of 10 patients for 
each arm will provide 85% - 98% of power for detecting statistically significant difference 
based on the mean On Time of 7.3 at baseline and SD of 2-2.5 that were obtained from 
our preliminary study.   
 
Based on this power analysis, we are planning to enroll a minimum of 60 patients. 
30 patients will be randomized to receive the real stimulation initially. The 
remaining 30 will be randomized to receive sham stimulation, using dedicated sham 
stimulation pattern.  
 
 
Protocol summary 
 
Day 0: Baseline testing (screening): 
• Patient medical history 
• General physical exam 
• Neurological exam 
• Concomitant and PD medications (Levodopa equivalents in mg)  
• OFF MDS-UPDRS, part III 12 hour washout of short-acting and 24 hour washout 
of long acting levodopa containing medications) 
• ON MDS-UPDRS, part III (1-2 hours after taking levodopa) 
• MOCA and SCOPA  
• Clinically trained staff (MD, PA, or RN) will review the consent form in detail with 
the participant and answer any questions about the study. After consent, the 
participant will be enrolled in the study and randomized to CR or sham. 
Figure 1: Vibro-Tactile System integrated into glove 

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• Blinding form – patient 
• Blinding form – assessing clinician (MD, PA, RN) 
 
Surveys to be completed after accepted into study and prior to the 1st day of enrollment. 
Survey will be completed on medication and sent via email  
1. MDS-UPDRS, Parts I-II, and IV 
2. Parkinson’s Disease Questionnaire-39 (PDQ-39) scale 
3. Schwab and England Activities of daily living score 
5. Beck depression and Anxiety inventory 
 
Day 1: 1-2 weeks after baseline screening  
• Off Medication UPDRS 
• Randomization to CR vs Sham vibrotactile stimulation 
• Vibrotactile threshold measurements 
• EEG recordings to assess PD-related brain oscillation 
• Smell Test 
• Comprehensive speech evaluation  
Day 2 
• Off medication UPDRS 
• In-clinic, wearable accelerometer/gyroscope (Kinesia One; ambulatory parkinsons 
disease monitoring (APDM)) to capture tremor and gait   
• •Patient does stimulation for 2 x2 hours with a break in between  
• •Repeat UPDRS part III to asses acute CR treatment  
• •Repeat In-clinic, wearable accelerometer/gyroscope (Kinesia One; APDM) to 
capture tremor and gait   
 
Weekly Phone Call to assess AE’s, review diary and change in medications 
 
 
 
Month 1- month 6 (daily, at home):  
• 2hr vibrotactile stimulation (CR vs sham), Session 1 morning 
• 2hr vibrotactile stimulation (CR vs sham), Session 2 late afternoon 
• Hauser diary to capture OFF time, ON time, ON time with troublesome 
dyskinesia, sleep time 
 
Patients will return at 3, 6 and 7 months and will follow the same procedures as 
enrollment day 1 and 2 
 
After the 6 month follow up, the patient will receive no stimulation for 1 month to asses 
long term effects and return at 7 months for a follow up assessment.  
 
 

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Vibro-tactile Stimulation Protocol and Device Description 
 
Typical tactile stimulation parameters are cyclic with cycle period between 200ms and 
1000ms. During each stimulation cycle, each tactor delivers vibratory stimulation once, 
with vibration pulse length of up to 250 ms per pulse (1 for each finger). Typical 
cumulative stimulation duration is between 1 and 4, typically 2 hours per day.  
 
Vibro-tactile coordinated reset (CR) neuromodulation therapy system is a commercially 
available, non-invasive, battery-operated mobile device. The device consists of a 
handheld component with vibro-tactile stimulators (tactors) and is fitted and programmed 
by a qualified healthcare professional familiar with treatment of Parkinson’s disease (e.g., 
neurologists and/or their clinical research assistants). 
 
The healthcare professional sets the individual stimulation parameters via a PC 
application called ‘neuro player’ and programs the patient device directly via USB 
connection or via an SD card, which is thereafter plugged into the patient device. The 
patient device is wired to the vibro-tactile stimulators or controllers that can be hung 
around the neck of the patients, which allows free movement of the patient. The 
stimulating tactors (Figures 2 and 3) are implemented inside a glove and are flexibly and 
individually attached to the fingertips (Figure 4) via elastic Velcro bands (Figure 1).  
 
 
 
Figure 2: Fingertip Stimulator 
Figure 3: Individual Tactor  

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A display presents information about battery status and 
progress of the schedule therapy application. Via a push 
button, the device and the therapy it delivers can be turned 
on or off.  
 
Risks 
 
The same tactile stimulator system has been studied in a 
pilot and published in 2018 (Syrkin-Nikolau et al., 2018; 
Stanford IRB-approved study, IRB# 45096). —at the time 
not yet integrated into a glove—was already IRB approved 
and successfully used in epilepsy patients under the 
supervision of Prof. Robert Fisher in the research study at 
Stanford University performed under protocol #31684. 
Preliminary testing by the researchers has not indicated 
any discomfort or worsening of symptoms. Therefore, Neurotherapies Reset has 
determined that the vibro-tactile CR therapy does not pose a significant risk to the human 
subjects; the vibro-tactile CR device, therefore, has been classified as a non-significant 
risk (NSR) device. However, given that the device is not yet FDA approved, and has not 
been tested under this exact protocol before, there is a possibility the stimulation could 
be uncomfortable or even painful for some patients, could worsen one’s symptoms or 
could have other unexpected effects including psychological complications. See the 
Withdrawal section below for no-go criteria. If there is any discomfort, the researchers 
can shut off tactile stimulation at any time.  
 
Benefits 
The patient’s Parkinson’s disease symptoms may be reduced, and quality of life may be 
increased, as a result of the vibratory stimulation, either for a transient period of time such 
as a few hours post-stimulation, or possibly even for several weeks to months. Ultimately, 
this pilot study could provide evidence that vibro-tactile stimulation is a safe and effective 
method to treat symptoms of Parkinson’s disease, which would provide a much-needed 
alternative to medication, surgery and other invasive procedures in the future.  
 
Withdrawal 
Each Subject, the Sponsor or its designee and the Investigator reserve the right at any 
time to terminate a Subject’s participation in the clinical investigation. 
Possible reasons for withdrawal from the study: 
1. Subject voluntarily withdraws consent 
2. Subject develops an Adverse Event (AE) that would not allow him or her to continue 
in the study 
3. Subject has an AE which in the opinion of the Investigator warrants withdrawal from 
the study. Such an AE would include anything unexpected that requires 
hospitalization. The Sponsor or its designee must be notified within 2 business days 
4. A decision is made by the Subject and/or Investigator that the Subject should be 
withdrawn from the study 
Figure 4: Fingertip definition 

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Alternative to Participation 
There are several alternatives to participation that each potential study candidate should 
discuss with their physician. The alternatives include not participating and seeking no 
other treatment, or not participating and seeking a variety of combinations of the 
following, standard-practice treatments: oral medications for central pain, invasive 
surgical therapies, and adjunctive therapies. Additionally, however, candidates should 
understand that choosing to participate is not mutually exclusive with receiving any other 
treatments.  
 
Data collection, transfer and storage 
Clinical data: We will complete a log that documents all patients who are treated with 
vibro-tactile stimulation.  For patients who are considered but not enrolled in this trial, 
the reason for exclusion will be recorded. The data collection process will entail site staff 
completing case report forms (CRFs) for the initial capture of research data during 
participant encounters and the data will be entered into a secure database.  Clinical 
data obtained on the case report forms will include patient demographics, previous 
medical conditions, Concomitant and PD medications (Levodopa equivalents in mg), 
MDS-UPDRS, Parts I-II, Off MDS-UPDRS, part III 12 hour washout of short-acting and 
24 hour washout of long acting levodopa containing medications), On MDS-UPDRS, 
part III (1-2 hour after levodopa medication), MDS-UPDRS, part IV, Collect data from 
electronic motor diary – wearable (accelerometer/gyroscope) to capture off time, on 
time, on time with troublesome dyskinesia, sleep time, PDQ-39, Schwab and England 
Activities of daily living score, Patient and clinician Global Impression of change scale 
and speech assessments.  
All data will be accessed only by Stanford researchers on-site. 
 
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