Voice-over: Welcome to Spotlight on Migraine, a podcast series hosted by the Association of Migraine Disorders. Through personal stories and interviews with experts, we expose the true scope of migraine by exploring symptoms, treatments, research topics, and more.
In this episode we hear a presentation by Dr. Blake Gurfein, chief scientific officer at Tivic Health. Dr. Gurfein speaks about Tivic’s neuromodulation device for sinus care called ClearUp, which received over-the-counter FDA approval in January of 2019. He explains how to use the device and how it works to relieve symptoms for people with rhinosinusitis or allergy, as well as its potential to help with migraine.
Dr. Blake Gurfein: My name is Blake Gurfein. I’m the chief scientific officer of Tivic Health. I’m also on the faculty at UC San Francisco.
So Tivic has developed ClearUP Sinus Pain Relief, which is a handheld peripheral nerve neuromodulation device for sinus care. In January of this year, Tivic was able to procure a FDA clearance for the temporary relief of sinus pain associated with allergic rhinitis, and this was an over-the-counter clearance for the device. So it’s available without a prescription.
Our planned indication for this device includes sinus pain, pressure, and congestion associated with both allergic rhinitis and sinusitis. And so some of you may be wondering why I’m talking about allergic rhinitis and sinusitis at a migraine conference, and you will see the story come full circle by the end of the talk, I promise.
So in the United States, there are more than 60 million people that are affected by sinus and nasal symptoms. 10% of the population is diagnosed with sinusitis, another 15% of the U.S. population is diagnosed with allergic rhinitis, and almost 50% of these folks experience these symptoms daily. And our research suggests that this population is quite dissatisfied with their current options for treatment, which are predominantly drugs. And so together, this paints an important picture about the impact on quality of life that sinus and nasal pathology are having.
So the ClearUP device works by holding the device in your hand and placing the electrode in contact with the skin. As you glide the device around the ocular cavity, it finds area of low impedance, and these areas, which we describe as treatment points, correspond to where there are nerve fibers under the skin. So when a treatment point is identified by the device, it vibrates to tell the user to hold the device in place for about 7 seconds, and it passes a weak electrical microcurrent into the tissue at that point. Then after the 7 seconds elapses, the user continues around the treatment path. And so with 2 1/2 minutes of treatment on each side of the face, you end up with a 5-minute treatment, which is what we’ve used clinically, and I’ll be sharing some data on what the results look like.
So essentially, what we’re doing with this ClearUP stimulation is stimulating trigeminal nerves and sympathetic fibers in the face. And so as I mentioned, the device identifies areas of low impedance that correspond to foramina, which are holes in the skull, predominantly below and above the eye, where there are dense bundles of nerves that come out through the skull subcutaneously. And in particular, we’re stimulating nerves that innervate the sinus and nasal cavity.
And so the mechanisms of action that we understand to be at work here are twofold. The first is what you could consider a classical neuromodulation effect. So we’re stimulating branches of the trigeminal nerve that communicate sensation and pain to the brain. And so we’re in a way interfering with the pain message and sensations of pressure that are experience by the patient. The second pathway is related to vasoconstriction. So research on neuromodulation has shown that at the level of energy and the frequency that we’re using, you can stimulate sympathetic fibers and cause a mild vasoconstrictive response, which can shrink the swelling that occurs in the nasal mucosa and reduce the sensation of congestion.
For those of you who are interested in the engineering about a device like this, you’ll see an image on the right there of the device. And so the tip is the stimulation electrode that’s in contact with your skin, but the housing is actually made of a conductive metal and represents the return electrode. So you can think about it as the current path is going from the electrode tip deep into the tissue and returning to the device through the arm. So this allows us to get the stimulation deeper into the tissue than you would normally find in a bipolar design of a device.
So I’ll go over a couple of clinical studies that we have carried out. This was our pivotal trial for FDA clearance that was run at the Stanford Sinus Center. It was a double-blind, randomized, sham-controlled trial of 71 patients that were predominantly allergic rhinitis and chronic rhinosinusitis patients. The key inclusion criteria were presentation of sinus pain of 4 points or greater out of 10, and this was an acute study, so we were looking at pain and congestion before and after a 5-minute use of the device.
So in the far left figure, we’re looking at the change in pain after the 5-minute treatment. The time point was 10 minutes after the 5-minute treatment. And so after a single use of the device, we see a pretty rapid reduction of 30% pain, which was statistically significant and greater than the sham device. That was the primary endpoint for our FDA submission, and so that allowed us to go forward with the clearance. We also looked at the proportion of patients that had high responses, and so patients with 3 points or more out of 10 reduction in pain. And we saw about a 24% — 24% of the active group fell into that category, whereas none of the sham patients showed that magnitude of response.
And then last but not least, we used a instrument called the Nasal Obstruction Symptom Evaluation, which is a validated way to measure nasal congestion, and we found that the active device significantly reduced congestion, again greater than sham. So together, these data show that the device, after a single use, can effectively reduce pain and congestion. And in the next slide, I’ll go into what some of the longer-term outcomes look like.
So this was another study that we did with 30 patients, again predominantly allergic rhinitis and unknown causes of pain. In this study, we used a 5 out of 10 as the threshold for pain at entry, and these patients were a bit more chronic, so having sinus symptoms at least twice a week for at least a month, and many of them had symptoms for 3 or more months. And so in this study, we looked both at acute outcomes and longitudinal outcomes, including pain and congestion. And after the acute aspect of the study, every patient took the device home for 4 weeks and was instructed to use the device once daily and up to 4 times daily as needed based upon their symptoms.
So on the far left panel, we’re looking at acute pain relief after the first use of the device, so these are all naïve users. And what you see is a nice accumulating benefit of stimulation in terms of pain reduction that peaks at about 4 hours, and this is actually quite competitive with most of the drugs that are available for alleviating sinus pain. We also looked at weekly pain using a numeric rating scale, and again, we see with every week of use, there’s an accumulating benefit of pain reduction that peaks at minus 43% from enrolment. And then lastly, on the far right, we used a instrument called the Congestion Quantifier Seven, which is used to measure congestion on a weekly basis, and we found that again, after 4 weeks of use, there’s almost a 50% reduction in congestion in these patients.
So on to why I’m talking about this at a migraine conference. As I’ve started to engage with the ENT, neurology, and allergy community, what I’ve learned is that there’s a great deal of concern that there is misdiagnosis between sinus pain or sinus headache and migraine. And so this is one example of a very large study. This is 3,000 patients that have a history of self-described or physician-diagnosed sinus headache. And so they took this cohort of patients and then put them through another battery of diagnostic criteria and found that 80% of these patients actually met IHS criteria for migraine headache. And so that’s an enormous potential overlap there between these two populations. So there are a number of studies that have confirmed this in different types of settings, but this one, because of the N, I think is quite compelling.
So why is there such a confusion between these conditions, migraine and then veritable causes of sinus pain such as allergic sinus pain or sinusitis? So the first couple of reasons are they both present with facial pain and pressure quite frequently. Also, patients with real sinus pathology have nasal congestion or rhinorrhea, and research indicates that migraineurs tend to have greater parasympathetic tone, which means that they have more vasodilation, more swelling of the mucosa, and symptoms of what they would normally think are nasal congestion. And so this is, I think, one of the key drivers for why there’s so much confusion here. And then last but not least, both of these populations actually respond to decongestants. So obviously, sinusitis and allergy sufferers respond to decongestants, but also, at least for a limited amount of time, migraineurs have also been able to find benefit with decongestant medications.
So going back to some of the data that we generated with the ClearUP, in our most recent study, the 4-week at-home study, I actually included some questions that helped us identify the folks that are likely migraine sufferers. Some of them were actually diagnosed, and some of them met criteria that make them very likely to be migraine sufferers. And so in that population, without recruiting them specifically, we found that 40% of the study subjects were actually migraine sufferers. And just to remind you, we saw a 43% reduction in pain in this population. One interesting thing was during our exit interview, without any prompting, one of our subjects volunteered that she had less frequent migraines as a product of using the device, and again, this was not one of the focuses of the trial.
So why might this be that our electrostimulation device may have some benefit here? And when you go back to the mechanisms that I described at the beginning of the talk, stimulation of the trigeminal nerve is one of the primary analgesic pathways that we understand to be at work, and the trigeminal nerve is one of the primary transducers of migraine pain. And additionally, the vasoconstrictive effect has been found to be helpful in a heterogenous collection of migraine patients. So it makes sense that there may be some really nice applications of this type of technology in the migraine population.
So as far as the future directions, we’re still at the beginning of trying to get our arms around if there’s a benefit here, which subpopulation of the migraine community might benefit. We’re definitely interested in exploring the potential for ClearUP as an over-the-counter solution for migraine, which I think would really bring a novel strategy into this area, especially with respect to devices. In the clinical trials that we have upcoming in allergic rhinitis and sinusitis patients, we’ll continue to include screening questions to identify the migraine subgroups so that we can look and see whether or not they’re more likely to respond favorably to the intervention. And then lastly, part of the reason I’m here and will continue to engage with the neurology and headache community is to start to develop research collaborations and advisor relationships that will help us push this potential research direction forward.
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