Potential Benefit for Non Invasive Vagus Nerve Stimulation Using GammaCore in the Treatment of Raynaud's Phenomena.

Study Overview
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Brief Summary
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Raynaud's phenomenon (RP) is a common vascular disorder that affects approximately 10% of the general population. RP is associated with significant morbidity that may include loss of the digits due to repeated episodes of vasospasm of the digital arteries in addition to significant impairment of quality of life. It is well known that cold exposure precipitates episodes of RP, but the mechanism for cold sensitivity is not known, and treatment of RP is not satisfactory to the patients and their physicians. The goal in this study is to test the possibility that non invasive vagus nerve stimulation (nVNS) with gammaCore which is already approved by the FDA for headaches and migraines may be an effective and well tolerated therapy for Raynaud's Phenomenon.

Detailed Description
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Raynaud's phenomenon (RP) is a common vascular disorder that that affects approximately 10% of the general population. RP causes some areas of the body (i.e. fingers and toes) to feel cold and numb in response to cold exposure or emotional stress. Raynaud's phenomenon is characterized by reversible vasospasm of the fingers and toes. This reversible narrowing of the small arteries induces episodes of color changes of the fingers and toes. During an attack of Raynaud's, affected areas of the skin usually first turn white, then they often turn blue and feel cold and numb (pins and needles). As the fingers warm and circulation improves the affected areas may turn red, throb and tingle. Moreover, Raynaud's phenomenon can be associated with significant morbidity that may include ulceration of fingers and loss of the fingers and toes due to repeated episodes of reversible narrowing of arteries supplying blood to the finger and toes. It is well known that cold exposure leads to episodes of RP, but the mechanism for cold sensitivity is not known, and treatment of RP is not satisfactory to the patients and their physicians. Raynaud's phenomenon is classified as Primary Raynaud's phenomenon (PRP) in the absence of other vascular or connective tissue disease. Raynaud's phenomenon is classified as Secondary Raynaud's phenomenon (SRP) if it is associated with connective tissue disease, like systemic sclerosis (SSc, Scleroderma). Treatment of Raynaud's phenomenon is not satisfactory in general, as current therapy employing calcium channel blockers and other vasodilators are frequently ineffective or not well tolerated, due to significant side effects. Noninvasive vagus nerve stimulation (nVNS) is currently FDA approved for therapeutic uses in patient ages 12 and above to treat cluster and migraine headaches. Recent studies have shown that vagal nerve stimulation has vasodilatory and anti-inflammatory properties which has led to more preclinical research examining vagus nerve stimulation as treatment for a wider range of inflammatory and autoimmune disorders. Vagus nerve stimulation has shown promising results in treating chronic inflammatory disorders such as sepsis, lung injury, rheumatoid arthritis, and diabetes. Although there are no direct data to demonstrate vagus nerve stimulation's effect in Raynaud's phenomenon, the investigators believe that VNS's success in treating headache and migraine attacks indirectly support its use in Raynaud's phenomenon by its direct effect on vasospasms (narrowing of blood vessels). In fact migraine has been found as a risk factor for the development of Raynaud's phenomenon further supports this notion. GammaCore is a safe and effective non-drug treatment approved for treating cluster and migraine headaches. It is a patented device that activates the vagus nerve with gentle electrical stimulation. The vagus nerve is an important highway of communication between the brain and many parts of the body, it plays an important role in regulating pain. Noninvasive vagus nerve stimulation with GammaCore is believed to help block the pain signals that cause migraines and cluster headaches. Unlike traditional vagus nerve stimulation therapies, gammaGore stimulates the vagus nerve through the skin at the side of the neck without the need for surgery. This non-invasive method avoids many side effects and inconveniences associated with injectable, inhaled or pill-based medication. The investigators' goal is to test the possibility that noninvasive vagus nerve stimulation using gammaCore may be an effective and well tolerated therapy for Raynaud's phenomenon. The investigators aim to gain a fundamental understanding of the role of noninvasive vagus nerve stimulation as a potential therapy for Raynaud's phenomenon, a truly unmet medical need.

Official Title
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Potential Benefit for Non Invasive Vagus Nerve Stimulation (nVNS) Using GammaCore in the Treatment of Raynaud's Phenomena.

Conditions
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Raynaud Phenomenon, Primary Raynaud Phenomenon, Raynaud Disease, Raynaud Syndrome

Intervention / Treatment
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* Device: gammaCore Sapphire
* Device: Sham Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Clinical Diagnosis of Primary Raynaud's Phenomenon Exclusion Criteria: Less than 18 years of age Pregnant women Current smokers Have Digital ulcers Diagnosed Pulmonary hypertension Currently on vasodilators (i.e. Phosphodiesterase type 5 inhibitors, prostacyclin, nitroglycerine, or other nitric oxide derivatives) Currently on Calcium Channel Blockers

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At randomization subjects are randomized to 2 groups, the Experimental group and the Sham group. The Experimental group will use the study device from randomization to the end of the study. The Sham group will use the Sham device for 4 weeks after randomization then be switched to the study device for the rest of the study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham Device Group<br>15 patients will be randomized to the Sham device for the first half of the treatment window then switch to the gammaCore Sapphire device (study device) for the rest of the study. The Sham device will look exactly like the gammaCore Sapphire device but will not deliver non invasive vagus nerve stimulation. | Device: gammaCore Sapphire<br>* gammaCore SapphireTM (non-invasive vagus nerve stimulator) is intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. gammaCore provides a mild electrical stimulation to the vagus nerve, which runs through the neck and carries information to the central nervous system. Subjects will be instructed to use the gammaCore Sapphire to stimulate 2 minutes on each side of the neck, twice a day, every day. The subject controls the intensity level of the electrical stimulation.<br>Device: Sham Device<br>* The Sham device delivers no electrical stimulations but subjects randomized to the Sham device will received the same instructions to use the Sham device to stimulate 2 minutes on each side of the neck, twice a day, every day for the first 4 weeks after randomization.<br>|
| Experimental: gammaCore Sapphire (Study Device) Group<br>15 patients will be randomized to the gammaCore Sapphire device for the full length of the treatment window. | Device: gammaCore Sapphire<br>* gammaCore SapphireTM (non-invasive vagus nerve stimulator) is intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. gammaCore provides a mild electrical stimulation to the vagus nerve, which runs through the neck and carries information to the central nervous system. Subjects will be instructed to use the gammaCore Sapphire to stimulate 2 minutes on each side of the neck, twice a day, every day. The subject controls the intensity level of the electrical stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the clinical efficacy of the gammaCore nVNS device at preventing vasospasms, thus reducing the number of and duration of Raynaud's attacks in patients with Primary Raynaud's Phenomenon. | Evaluate the clinical efficacy of gammaCore (15 patients) vs sham device (15 patients) in preventing vasospasms in 30 PRP patients. The clinical efficacy of the nVNS device will be accessed through subject reported outcomes by way of the diary that will be handed out to subjects for the duration of the study, both before and after subjects have started using the gammaCore device. The diary will track daily the number of attacks of Raynaud's phenomenon and the duration of these attacks each day. The combination of the number of RP attacks and their duration will be used to evaluate the efficacy of the nVNS device at preventing vasospasms by analyzing changes in frequency and duration of RP attacks in subjects before and after they have started using the gammaCore device. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate improvements in Raynaud's condition scores after using the gammaCore nVNS device. | Evaluate the clinical efficacy of gammaCore (15 patients) vs sham device (15 patients) on Raynaud's symptoms and chronic PRP in 30 patients for four weeks using Raynaud's condition score. The Raynaud's Condition Score is presented in the diary that will be handed out to subjects for the duration of the study. The Raynaud's Condition Score will ask subjects from a scale of 0 to 10, 0 being no difficulty, 10 being extreme difficulty, the number that best indicates the difficulty the subjects had each day with Raynaud's condition. The Raynaud's Condition Score is for subjects to rate how much difficulty the subjects had with Raynaud's each day by considering how much pain, numbness or other symptoms the Raynaud's caused in subjects' fingers and how much Raynaud's alone affected the use of the subjects' hands each day | 12 weeks |