Auricular Muscle Zone Stimulation for Parkinson Disease

Study Overview
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Brief Summary
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A Multicenter, Randomized, Blinded, Electronic Device in Subjects with Parkison Disease.

Detailed Description
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This study is a multi-center, prospective, randomized, double-blinded, sham-controlled, within-subject design, 3-treatment, 3-period cross-over study involving 38 subjects with Parkinson's Disease who have the wearing-off phenomenon on oral levodopa therapy. All participants will receive three treatments on different days, each with different stimulation conditions. All subjects will wear the Earstim device on the ear ipsilateral to the side of the body more affected by Parkinson's Disease for 120 minutes during each of the three treatment applications.

Official Title
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Auricular Muscle Zone Stimulation for Parkinson Disease (Earstim-PD)

Conditions
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Parkinson Disease

Intervention / Treatment
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* Device: Earstim - Active Stimulation
* Device: Earstim - Sham Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is a male or female ≥18 years of age. Subject has Parkinson's Disease and is on levodopa therapy. Subject experiences OFF periods with an ON score ≥20% better than the OFF score as measured by the MDS-UPDRS motor score (MDS-UPDRS Part III). The subject's daily OFF time duration is ≥2 hours per day. The subject's Hoehn-Yahr stage when OFF must be less than Stage 4 (i.e., subject must be able to walk without the use of an assisted device, such as a cane or a walker). Subject receives levodopa at least TID with a minimum of 100 mg levodopa administered with each dose. Subject can tolerate 2 hours in an OFF period without requiring rescue medication. Subject is willing and able to not change Parkinson's Disease medications or dosages during the up to 2 week study therapy period. Subject is willing to provide Informed Consent to participate in the study. Subject is willing and able to comply with all study procedures and required availability for study visits. Exclusion Criteria: Subject has a medical or psychiatric comorbidity that can compromise participation in the study. Subject has cognitive dysfunction defined by a Montreal Cognitive Assessment (MoCA) score <24. Subject has moderate levodopa-induced dyskinesias as indicated by a score >2 on items 4.1 and/or 4.2 in the MDS-UPDRS Part IV. Subject has clinically significant depression as determined by the Beck Depression Inventory-II score >15. Subject is pregnant as determined by a urine pregnancy test at the screening visit. Subject is of childbearing potential and is not surgically sterilized or does not use a reliable measure of contraception. Subject has a form of Parkinsonism other than Parkinson's Disease, such as Drug-induced Parkinsonism or Multiple System Atrophy. Subject has an implanted deep brain stimulator (DBS). Subject is receiving direct intestinal infusions of levodopa. Subject has epilepsy. Subject medications are anticipated to change during the two (2) week study period (Note: the study requires stable medications during the device testing period). Subject has a cardiac pacemaker or defibrillator, bladder stimulator, spinal cord stimulator or other active electronic medical device.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Stimulation 20 minutes<br>Intramuscular stimulation | Device: Earstim - Active Stimulation<br>* Intramuscular stimulation<br>|
| Active Comparator: Active Stimulation 60 minutes<br>Intramuscular stimulation | Device: Earstim - Active Stimulation<br>* Intramuscular stimulation<br>|
| Sham Comparator: Sham Stimulation 20 minutes<br>Muscle-free-zone stimulation | Device: Earstim - Sham Stimulation<br>* Sham stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Score) at 20 minutes | The primary efficacy endpoint is the overall change from baseline to 20 minutes after onset of stimulation in MDS-UPDRS motor score (MDS-UPDRS Part III), comparing the sham arm vs the average 20-minute change of the 20-minute and 60-minute auricular stimulation. Each parkinsonian sign or symptom is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment. | Baseline, 20 minutes after the stimulation is initiated | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve | The area under the curve (AUC) of change from prior to stimulation in MDS-UPDRS Part III total motor score over the entire 120 minute post-stimulation follow-up interval, comparing the sham treatment to the 20 and 60 minute treatments with auricular muscle zone stimulation by subject and by treatment group. | 120 minutes after stimulation is initiated. | 
| Maximal improvement in MDS-UPDRS motor score (MDS-UPDRS Part III) from prior to stimulation to any of the follow-up time points up to 120 minutes after onset of stimulation. | Maximal improvement in MDS-UPDRS motor score (MDS-UPDRS Part III) from prior to stimulation to any of the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). Each parkinsonian sign or symptom is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment | 120 minutes after stimulation is initiated. | 
| Patient Global Impression of Change (PGIC) scored by the subject prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Patient Global Impression of Change (PGIC) scored by the subject prior to stimulation and at the follow-up time points (20,40, 60, 90, and 120 minutes after onset of stimulation). Seven point Likert scale ranging from 1= much worse to 7= much better | 120 minutes after stimulation is initiated. | 
| Timed Get Up and Go test prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Timed Get Up and Go test prior to stimulation and at the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). | 120 minutes after stimulation is initiated. | 
| Clinical Global Impression of Change (CGIC) prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Clinical Global Impression of Change (CGIC) prior to stimulation and at the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). Seven point Likert scale ranging from 1= much worse to 7= much better | Baseline, 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Finger Tapping Speed Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Rest Tremor Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Averaged Finger Tapping Speed and Resting Tremor Scores comparison between each study arm at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | The finger tapping speed scores and resting tremor scores were averaged and provided as one score ranging from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Postural Tremor Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Finger Tapping Amplitude Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Hand Grasp Speed Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Hand Grasp Amplitude Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Rapid Alternating Movement Speed Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Rapid Alternating Amplitude Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Kinesia-ONE™ Variable: Dyskinesia Score comparison between the three different treatments at the specified times of just before stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Kinesia-ONE scores ranged from 0 to 4 (where 0 is normal and 4 represents severe abnormalities), with negative change from Baseline scores indicating improvement in disease symptoms. | 120 minutes after stimulation is initiated. | 
| Determination by the investigator of dyskinesia severity by MDS-UPDRS Part IV prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Determination by the investigator of dyskinesia severity by MDS-UPDRS Part IV prior to stimulation and at the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). dyskinesia severity is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment | 120 minutes after stimulation is initiated | 
| Determination by a consensus between subject and investigator of whether the subject is OFF or ON prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Determination by a consensus between subject and investigator of whether the subject is OFF or ON prior to stimulation and at the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). | 120 minutes after stimulation is initiated. | 
| Change in mood as measured by the Depressed Mood Score from baseline to 120 minutes after onset of stimulation. | Change in mood as measured by the Depressed Mood Score in Part I of MDS-UPDRS from pre-stimulation to 120 minutes after onset of stimulation. | 120 minutes after stimulation is initiated. | 
| Change in mood as measured by the Anxiety Mood Score from baseline to 120 minutes after onset of stimulation. | Change in mood as measured by the Anxiety Mood Score in Part I of MDS-UPDRS from pre-stimulation to 120 minutes after onset of stimulation. | 120 minutes after stimulation is initiated. | 
| Change in subjects' sense of well-being as measured by an exploratory ordinal scale prior to stimulation and at the follow-up time points up to 120 minutes after onset of stimulation. | Change in subjects' sense of well-being as measured by an exploratory ordinal scale prior to stimulation and at the follow-up time points (20 ,40, 60, 90, and 120 minutes after onset of stimulation). Scores ranged from +3 to -3 (+3 represents more comfortable - much greater peace of mind; and -3 represents more uncomfortable and have a much greater worse peace of mind | 120 minutes after stimulation is initiated. |