Daniel Litwin:

Hello folks. You're about to dig into another episode of Vital Spark. Though this one is going to be a two parter. So we hope you enjoy this important conversation behind the science of our opioid withdrawal treatment solutions. We're going to be chatting with an important doctor who helped us validate this solution and why we see it being so impactful for the industry. Now let's just jump right in without further ado and make sure you stay tuned for part two, enjoy the episode. Hello everyone. And welcome to another episode of Vital Spark, a Spark biomedical podcast. I'm your host, Daniel Litwin the voice of B2B and folks thanks so much for joining us on another episode of the show. As we continue to explore major innovations and new methodologies to opioid withdrawal treatment and addiction treatment at large, we've got a jam packed episode for you today with a lot of analysis and a lot of research to back up again, the science behind these innovations to withdrawal treatment.

But before we get into the topic, I want to make sure that you're all caught up on previous episodes of the show and that you're tapped into more resources to help you understand the full scope of the science that we're going to be breaking down today. So to do so make sure that you're heading to our website sparkbiomedical.com again, Spark like an electric spark biomedical.com. There you'll find previous episodes of the show. As well as those resources I was mentioning and other pieces of Spark content, including videos, articles, blogs, and more, and you can also subscribe to Spark biomedical on apple podcasts and Spotify. There will be the audio versions there. Video versions on our site. We've already done several episodes with some of the co-founders of Spark biomedical, very insightful in moving conversations there. So make sure you're caught up. Hit subscribe, and you'll find that full catalog of episodes plus notifications when we drop new conversations.

So today's episode of the show is an important one, like I said, but it's important because it's... Excuse me, it's going to be helping validate. We can say with confidence here at Spark biomedical, that the insights on our show and the core science behind neuro stimulation for detoxification treatment are so critical and so useful, and why there is so much trust behind this new generation of treatment. So at Spark biomedical, we pride ourselves in our Sparrow therapy device. For those who are unacquainted, it's a wearable piece of technology for treating opioid withdrawal sits right behind the ear. It's drug free and it's proven to reduce withdrawal symptoms.

So today's episode is going to be digging into that clinical trial to let our audience understand what we saw as the metrics for a successful trial, how we set it up to be an authentic and trusted trial and what the results of the study found that have then informed our rollout and has also supported the adoption of this treatment by physicians and patient's alike. And today I'm very pleased to welcome the study principle investigator to help us break down the study. So the study's title again was Sparks Adult Opioid Withdrawal study, and our guest today, the PI of the study was Dr. Carlos Tirado, he's chief medical officer and founder of CARMA health. And he ran the prospective RCT double blind study at a recovery unplugged clinical site. Dr. Tirado, welcome how are you doing today?

Speaker 2:

I'm doing great, Daniel. Great to be here with you today. Really look forward to talking about the Sparrow.

Daniel Litwin:

Absolutely. And I appreciate you taking some time to break this down, being the PI on the study means that you have a complete understanding of the science, the technicalities and the successes which we'll get into here in a little bit, and the results that shape and mold the future of this treatment. So again, thanks for your time. Let's go ahead and jump in. I want to start by first making sure our audience understands your background and your expertise. So can you give us some of that background on the sorts of studies that you've helped conduct in the past and how that informs your bank of knowledge?

Speaker 2:

Sure. Yeah, I'm an addiction psychiatrist. So I completed training in general psychiatry and then did additional training and fellowship in addiction, psychiatry at the university of Pennsylvania. I spent really the first part of my career in academic medicine, both at university of Pennsylvania, and at UT Southwestern medical center in Dallas, Texas. I often describe myself as a recovering academic with a relapsing and remitting research addiction. I left academia somewhat around 2014 and started a practice that eventually became CARMA health. CARMA's actually with a C, it stands for collaborative addiction, recovery management, and assistance. It's a practice that integrates primary care and psychiatry to treat people with substance use disorders. I actually met the founders of Spark at an American society of addiction medicine conference a few years back. And just by chance, we struck up a conversation.

I heard about this exciting technology and frankly came at it from a pretty skeptical mindset with the exception of electroconvulsive therapy, transcranial magnetic stimulation and to a lesser degree vagal nerve stimulation. There hadn't been a lot of very successful rigorously proven treatments that involve electrical stimulation and psychiatry. So after some conversations and really understanding the depth of the scientific underpinnings of the transauricular device and the targeted application to opioid withdrawal, which is really my bailiwick, I really decided to take the plunge and collaborate with the founders to design our clinical trial.

Daniel Litwin:

Now, let's get a little bit more background on neuro stimulation for withdrawal treatment in the first place. How was this treatment option brought to your attention? And I guess before the study, were you aware that this was a pioneering method for withdrawal treatment? I guess just breakdown your association with it before the study.

Speaker 2:

Yeah, that's a great question. The application of neuro stimulation for the treatment of withdrawal is it's both old and new and emerging. And I say that because there'd been a body of literature dating quite a while back, up from the '40s, up to the '80s on the utilization of electrical stimulation, in different forms for mitigation of opioid withdrawal symptoms, that went kind of quiet for a while until the 2000s in which you saw the reemergence of some interest in utilizing neuro stimulation for mitigation of opioid withdrawal. I think, sadly the opioid crisis that we've been in now, I don't even know if you'd call it a crisis, because it's been going on for 15 years. I think, spurred a lot of interest in applying some of these non invasive electro stimulation procedures for mitigation of withdrawal symptoms, which is incredibly important clinically if you're trying to treat people with opioid use disorder.

Daniel Litwin:

So then with this in mind, let's talk about what it takes then to validate this kind of treatment and make it so that it can be mass produced and then pushed out to market as a viable and trusted solution and treatment option. So can you help our listeners understand the rigor that goes into bringing a new or novel treatment option into the opioid addiction space specifically? And what are some of the unique specs that are required to validate something for specifically new addiction treatment?

Speaker 2:

Yeah, well the gold standard really is FDA authorization or approval. The rigor that's required to be able to pass muster through an FDA process is really the best indicator that we have of the safety and effectiveness of really any medical treatment, right? Be they pharmacologic treatments to device therapies. So the goal really was to design a trial with the appropriate randomization and blinding to be able to demonstrate treatment effect, get to our primary endpoint. And then of course be able to demonstrate safety as well. So that FDA level of rigor is really what we all strive for.

Daniel Litwin:

Does the addiction treatment space have any unique barriers to entry or any added layers that have to be considered beyond just FDA approval?

Speaker 2:

Well, in my world, I've been in involved in both clinical medication trials, psychotherapy trials, and now device trials for various substance use disorders, not just opioid use disorders. And some of the areas that we kind of run up against in terms of success of treatment trials really boils down to recruitment and retention, designing studies that are able to recruit a substantial cohort of individuals with the identified problem, like opioid use disorder. And then retaining them in the trials is very critical, obviously for data analytics reasons, but also just from a clinical standpoint, we want to make sure that we are doing right by individuals that volunteer for these research trials. One of the things that we incorporated in the study in addition to the randomization of stimulation conditions, and then the blinding of the assessors to that condition was to follow these people out after they completed the trial to determine whether or not they were safe and continuing to pursue some form of accepted treatment after their participation in this study.

So those are some of the unique challenges, if you will, to doing research with these cohorts. It's not like say, a diabetes medication trial where once they finish your study, you're not really worrying so much, right, that they're going to have a sudden negative medical outcome, right. With a person who's in an opioid withdrawal treatment study, you do have to think about, wow, what's going to happen to this person after they leave. What we know is that people are at risk for overdoses, right? So being able to ensure that we're managing those people appropriately was critical. And it was something that we went into intentionally in the conduct of the trial.

Daniel Litwin:

Yeah. And I guess with that length of treatment or that timeline for treatment in mind and the careful approach that has to be taken with treating opioid addiction, can you walk us through the science of TAN or transcutaneous auricular neurostimulation as a refresher for our audience? What are the aspects of this science when translated into specific treatment methods that need to be tested for efficacy in a clinical trial?

Speaker 2:

Yeah, it's a very fascinating science, actually, the basis behind the TAN device involves stimulation of some key branches of cranial nerves. We have a system of cranial nerves that control various motor functions, but we also know some of these cranial nerves have innovations of that control other parts of the brain. So in the case of the Sparrow, the three regions of stimulation that are occurring are preferentially stimulating branches of cranial nerves, 5, 7, 9, and 10. Okay. You've got three areas that the electrode is stimulating, and I'll try not to point at my ear the whole time. Well, I guess I will point at my ear the whole time. You know, you've got the cymba, which is this little shelf of cartilage, right over the entrance to your ear. Then you have the tragus, which is that little flap in the front of your ear that you sometimes see people pierce these days.

And then you've got the auricle, which is just the back part, kind of that hard bony part of your ear. And each area has innovations that lead to what we call the nuclei of those four cranial nerves. And then from there, you get a branching to other brain regions, and that's kind of the business end, if you will, of why we believe that auricular stimulation actually translates to tangible reductions in opioid withdrawal symptoms. Some of the areas that we know are critical in opioid withdrawal are one region called the lo the locus ceruleus, which just means blue spot. It's one of the areas of the brain that's very highly packed with norepinephrine neurons. We know that during withdrawal, there's a lot of up regulation of norepinephrine, predominantly from the locus ceruleus. We know that it drives some of the stimulation that people experience during the opioid withdrawal syndrome.

Also, an area called a periaqueductal gray, which modulates pain regulation, and pain sensitivity, and then another area called the hypothalamus, which is actually responsible for regulating a lot of body functions. One of the most critical is what we call gut motility. Okay. So if you think about those areas, they map very neatly to the known opioid withdrawal syndrome, which is characterized by GI distress, nausea, vomiting, diarrhea, pain, so diffuse pain, all throughout your body and in your joints, and then stimulation, right? Anxiety, restlessness, goose bumps, kind of this fight or flight type reaction. So by being able to modulate those areas, importantly, by actually up regulating your body's own opioid system, your endogenous opioids, endorphins, and [inaudible 00:17:00] actually can help reduce the amount of activation that's occurring from the withdrawal syndrome and thereby cause these decreases in symptoms.

Daniel Litwin:

And like you mentioned earlier, this kind of connection between external stimulation to the brain and well, I guess just treating in general, but also more specifically opioid withdrawals or addiction treatment does have a long history. Though it was only until more recently that it became focused in, on the kind of therapy that we see today. And so what I also want to do, Dr. Tirado is lay out some of the previous benchmarks in treatment innovation and other clinical studies that kind of informed Spark and CARMA health's round of research. So I'm wondering if you can't just walk us through some of the most critical ones that set the stage. I know electro sleep devices were first developed in the USSR in like 1947 or so. And then that creates a timeline all the way to a 2020 review article on auricular neurostimulation for opioid detox. So what are some other key benchmarks that at least help inform your perspective and study?

Speaker 2:

Well, I mean, I think I alluded to earlier, that there are other conditions for which certain types of electrical stimulation, or even electromagnetic stimulation have translated to therapeutic benefits. So we know that conditions like depression, obsessive compulsive disorder are good examples are conditions that have actually shown to respond to different types of electrical or electromagnetic stimulation. So the opioid withdrawal syndrome, we know just from what you had cited earlier, we've had various times in which there have been trials looking at this very issue all the way up to, as you had mentioned 2020. We have a more recent review article kind of recapping a lot of that information. One of a kind of a previous device which had data published in 2018 involved incorporation of actual needle electrodes kind of almost like an acupuncture type of model that also stimulated certain auricular regions.

So one of the things that I believe that Sparrow has done is kind of leapfrogged that invasive technology to creating a purely wearable and unobtrusive device. Something that an individual end user can adjust or apply, right, without having to go to literally an expert technician to be able to troubleshoot or reinsert electrodes, for example, right? So the Sparrow technology really allows a pure individual consumer use type of model for mitigation of opioid withdrawal.

So the hope and expectation is that we'll be able to see wearable individually adjusted and applied a device for individuals to use in the home or in the context of a treatment program, based on the foundation that we've established with its efficacy, with our clinical trial. As a clinician, who treats people with opioid use disorder, we have to understand that there are multiple pathways that individuals take in order to get stable or get sober in recovery.

All of those, unfortunately converge on managing withdrawal. Okay. One of the things I often tell residents when they work with me is opioid users will avoid withdrawal the way a vampire avoids sunlight. It's that aversive to go through. It's a really terrible experience for people. Some people say it's the worst flu you've ever had. I've had patients say it's worse than that. Trust me, it's worse than that.

So having to navigate this very difficult terrain of withdrawal is critical. And the device in the trial was able to demonstrate significant meaningful reductions in withdrawal symptoms, both subjective and objective reported symptoms within as little as an hour and 120 minutes of stimulation. So in the hands of a clinician, being able to dramatically reduce subjective suffering and objective signs really gets you on the right foot with patients. And it allows you to engage them in a meaningful way to have that opportunity, have that time to be able to help the patient make a rational decision about their treatment.

Daniel Litwin:

All right, Dr. Tirado, I think it's time to jump into the specifics of the Spark clinical study to validate this broader style of treatment and just to connect the dots one more time. The first RCT double blind study on CET for heroin withdrawals was actually done in France in 1987. So now we're coming up on, well, let me do some quick mental math, almost 40 years, right? 35 plus years on that study. And we're starting to see the mass validation of this because of Sparked clinical trial. So let's jump in and get into the nitty gritty, the fun stuff. Right. I want to start with the basics. Can you recap us on when this trial was conducted, for how long and how many patients had to be sourced for it to be considered a complete and a trusted study?

Speaker 2:

Sure. Well, we started the trial in 2019 and conducted it miraculously through COVID and were able to recruit a little over a little over 40 patients for the trial. Just by our preliminary analysis of 26 subjects gave us a very representative sample of opioid users, average age, about 34 years old, primarily male, which is very consistent with the cohorts that we seek of self referring for treatment. Usual use or average use was for 12 years. So these are individuals who are not newcomers. So these are people who had been using opioids for quite some time. So again, pretty representative of what we see. And as you had mentioned, primarily intravenous heroin users, there was a considerable comorbid depression about 40% or so had comorbid depression, same thing with anxiety and about 30% or so actually had a known diagnosis of bipolar disorder.

So we had a naturalistic cohort. We weren't cherry picking patients on any level. This is pretty much all comers for the trial. And I alluded earlier to our primary endpoint, which was clinically meaningful reduction in symptoms of within the first hour and then 120 minutes. The way we measured that was by utilizing something called the clinical opioid withdrawal scale, or the COW scale. It's a standard metric, a clinical assessment metric that's done by an individual clinician rater. Essentially rating 11 core signs and symptoms of withdrawal anywhere from pulse to restlessness, anxiety, sweating, GI upset, et cetera. So that COWs measurement is used commonly in the field. If you look at really any major opiod withdrawal to study, it's been done in the last probably 10 years, they're utilizing the COWs.

So that reduction in COW score was the primary endpoint for the trial. We actually had a pretty robust inclusion criteria. People had to have a COW score of 13 or greater. We had a couple exceptions here and there based on clinical symptomology, but a score of 13 is kind of getting into a moderate level of withdrawal. So that means the patient is significantly uncomfortable from withdrawal signs and symptoms. And then at that point, the patient was randomized to either a delayed condition. In other words, the patient without their knowing was actually delayed in their first stimulation event, or they got immediate live stimulation. And what that blinding did was essentially take out that placebo effect in terms of our statistical analysis, right. We know that the belief that you're going to get something, be it a medication treatment or a stimulation can in fact be quite powerful in terms of providing symptom relief. So creating that delayed condition is what helped us control for placebo response effects. So then...

Daniel Litwin:

Let me...

Speaker 2:

We essentially... Yeah, go ahead.

Daniel Litwin:

Oh, well, I was going to ask real quick with a COW score of 13 or greater. Were there any struggles in finding patients to participate or were there any other metrics that made it difficult to round out that study, if you don't mind just adding that context and then you can continue with your breakdown?

Speaker 2:

No, not really. The condition under which the patients were presenting was as people seeking treatment for opioid use disorder. So they were checking into what we call a detox unit, a free standing, medically assisted withdrawal treatment unit. You had mentioned the name of the facility earlier Recovery Unplugged. So we are actually recruiting patients who are presenting for treatment of opioid use disorder, who are having to go through an opioid withdrawal treatment. So once a person starts going into withdrawal, the symptoms start increasing really hour by hour, depending on what kind of opioid they're using.

It can either be a delayed onset or pretty rapid onset. Since most of these patients were heroin users, they're reliably will start going into significant withdrawal within as little as eight hours after their last use. So these are individuals who came in with the expectation of receiving opioid withdrawal treatment. The COW score of 13 therefore was really set as a benchmark to really be certain that we're measuring real withdrawal, right. If you go too low and you just have an anxious restless person, you could score a certain score that may or may not be withdrawal. So when you're at 13 or above, you're looking at real observable physical signs in addition to self-reported symptoms.

Daniel Litwin:

Perfect. I appreciate that context. Now to pick you back up where you left off, you were just breaking down the benefits of the double blind aspect of the study, feel free to continue.

Speaker 2:

Sure. So we controlled for that initial placebo response effectively with that design. And then for primary endpoint, we initiated stimulation. The stimulation actually occurs at two frequencies, one low frequency, and one high. That I don't know if that's been covered in another podcast, but the reasoning behind that has to do with really getting maximal effect and maximal up-regulation of all of the different endogenous opioids. We've got three major classes of them in the central nervous system. So having both high and low frequency stimulation is believed to be able to get kind of across the board and dodging this opioid stimulation. So once we initiated stimulation, we conducted COW score measures at one hour and then 120 minutes. And those were done by assessors who were blinded to the stimulation condition, right. So these are individuals who don't know if they were delayed TAN versus active TAN, again, just to create that added measure of blinding to prevent any kind of initial measurement bias that you would see at 60 and 120 minutes.

Daniel Litwin:

Well, let's dig into the results then. What were you expecting to see with all of that set up and all of the attempts to really highlight the efficacy of the treatment, and again, what results were you expecting based on kind of previous studies, as well as your knowledge of tan and the science behind the treatment method?

Speaker 2:

Yeah. Well, you know based on the initial proof of concept that was done by the Spark team, we were pretty confident that we would see some clinically meaningful reduction in opioid withdrawal symptoms. And sure enough we got a greater than 50% reduction within the first 120 minutes of stimulation. So that was really the key finding of the way in which the study was designed. And then subsequent to that, we had essentially full access to simulation for the subjects from time zero all the way through day five, for those that remained in the entire trial. So the thing that we saw and I think was really helpful and clinically relevant was that we continued to see a day by day clinically meaningful and statistically significant reduction in cows scores all the way through day five.

So that by the end of day five, you had an overall 75% reduction in opioid withdrawal scores. It's important to note, these are individuals who were not receiving any, we call opioid substitution treatment during that time. One of the more conventional approaches to treating withdrawals to do what's called a buprenorphine or the common name is Suboxone taper for patients, which is basically an opioid substitution protocol that gradually reduces their dose of opioid while they're going through the withdrawal state, there are pluses and minuses to that approach. But what we were able to show was that without opioid substitution, with just additional medication support, say for GI upset, or for tremor or nausea or restlessness or insomnia for example, we were able in the stimulation conditions to show a steady downward reduction in symptoms. The reason why I highlight that is because if you look at the curve of what we call natural withdrawal, so kind of untreated withdrawal or even withdrawal that's being treated with non-opioid medications.

So there's a medication out there called [Clonidine 00:34:55], there's another one called [inaudible 00:34:57] out there. What you will see is actually a pretty significant increase in withdrawal symptoms, going from day one into day two and three, and then a reduction in symptoms trailing off into day four through seven. Okay. What we showed is that we had a steady decrease all the way through days one through three. That's important because in that day, one through three timeframe, when patients are experiencing increases in their withdrawal symptoms, that is a time when patients will leave treatment.

They'll do what they can to go and continue to use so that they don't have to endure the withdrawal. I talked about vampire avoiding sunlight, right. So being able to have that progressive reduction is very clinically relevant to what we are trying to do and frankly, there's really nothing else that was happening to those patients, other than the stimulation, right in coordination with what we call opioid comfort medications, which is kind of a standard protocol. So that to me as a clinician and a researcher really demonstrates that we have a live effect going on with the simulation.

Daniel Litwin:

As you were reviewing those results. Were there any surprises that stood out to you? Anything that you were expecting maybe something positive, but it was extremely positive or something you were a little doubtful about that actually did turn out to prove itself through the clinical study. And if so, how did that kind of change your perspective on the efficacy of tan for opioid withdrawal treatment?

Speaker 2:

Yeah. You know, a few things, as I had mentioned earlier, I kind of came into this a little bit on the skeptic side, just because of what I had seen over the years in terms of utility of electrical stimulation approaches to treating substance use disorders. So the thing that was initially quite impressive and convincing was the fact that clinicians who were not part of the study, who were just observing the effects of the device were reporting back, they were sending back positive reports that the patients who are getting the stimulation, the patients who are wearing the device are reporting that they're feeling better, that they're not in as much agony, some of them are reporting that it's even surprised them, that they're actually responding to the device.

So that was actually pretty surprised and encouraging. The other thing that I found encouraging was that for those individuals who were able to get beyond day three, especially those who got to day five, they were able to tolerate what we call a Naloxone challenge. So when you are trying to withdraw someone from opioids and start them on an FDA approved treatment, which is an injectable form of naltrexone, which is an opioid blocker, you typically have to wait seven to 10 days before you can start that treatment, because you have to worry about what we call precipitated withdrawal. We were able by day five, when we gave that Naloxone challenge to demonstrate that patients did not go into precipitated withdrawal, and we were able to get them started on the injectable naltrexone, the blocker, two to five days before they might otherwise be able to get started with it. So that was also pretty cool as well.

As I mentioned earlier, there are different pathways that people take to being able to treating their opioid use disorder with medications. The two principle medication routes involve what I alluded to earlier, opioid substitution treatment, right. That's Suboxone, the actual chemical name for that of the buprenorphine or methadone, which is another opioid substitution approach that you have to get out of a special clinic. And then the other path is opioid blockade, right. So you can take an opioid blocker medication naltrexone, and that can actually stay in your system and stay on the receptor and block the effect of an opioid if it's administered.

And it's great that we have these tools, we have now an array of three really good treatments, medication treatments for the disorder. And for those who want to avail themselves of that opioid blockade pathway have to go through that withdrawal and being able to shorten the time that they have to be in withdrawal makes a huge difference for their ability to actually start the medication. So just think the difference between five days for seven to 10 days to be able to start this treatment can make a really big difference for people.

Daniel Litwin:

Unfortunately, like I said, we're going to have to take a pause here. The episode just had so much detail and important context to dig into that we wanted to let all of these insights simmer, and then jump in fresh for a second episode. So while you wait, make sure you're heading for our website sparkbiomedical.com, again, that's sparkbiomedical.com. There we'll drop around two of our conversation with Dr. Tirado, where we'll actually get to hear from a specific clinical trial participant. And in her own words, she'll describe how tan therapy impacted her journey to recovery. So it's going to be some very heartwarming and emotional and grounded stuff, and it's really going to help connect the dots between the human impact and the science behind our treatment methods. So stay tuned for that episode till then I'm Daniel Litwin the voice of B2B and we'll catch you on the next episode of Vital Spark.

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