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Diane Newman: Welcome to UroToday's Bladder Health Center of Excellence. I'm Diane Newman, the center's editor. I'm also at the University of Pennsylvania in Philadelphia. And I'm really excited today because I have a colleague of mine here who is going to present some recent research he presented to the American Urologic Association. I want to introduce you to Professor John Heesakkers. He is a urologist. He also does functional urology, and he's also the Secretary General of the International Cotton Society. So, he's got really a big role in that capacity. So I really welcome him. And I want him to talk about a clinical study he did on the BlueWind system for patients with overactive bladder. Welcome.

John Heesakkers: Thank you. I must say, this goes back a long time. When we started doing PTNS in the beginning of 2000 in Nijmegen in the Netherlands where I was that time, we quite soon discovered that it was quite a reasonable treatment, but also that it was quite cumbersome for the clinic and for the patients to come every week to the clinic, have the needle put into the tibial nerve or very close to it, stimulate for half an hour, come back the week later, et cetera, et cetera, et cetera. So, we were developing and thinking about an implant already directly when we started doing that. First we did, of course, transcutaneous tibial nerve stimulation. It means that if you put a stimulator on the skin with stickers, you can, one way or the other, get to the tibial nerve, which is about two centimeters under the skin. But it's not that easy to go through the skin without hurting the patient, because you need quite some current in order to get to the nerve.

So that was a possibility. And, that's also a viable option at the moment. But, we wanted to have, well let's say bluntly, a bit similar to the Medtronic device. We said, "Oh, that's okay. We have something implanted. It stimulates the nerve continuously. It has effect on the bladder, pelvic floor, et cetera. And then, we can make happy patients who don't have to come to the clinic every week, every month, et cetera." So we started working that directly, and we had quite very simple and old-fashioned device that we used as an implant in 2006 for the first time. That time, it was still possible to do things like that. And, it worked. Patients were not bothered that much by the implant because that's one of the questions that we had at that time. "Can you accept something at the ankle for the rest of your life that you have to stimulate that perhaps is becoming difficult when you hurt your leg or something like that?"

And it appeared that the clinical results were quite acceptable. And that the patients didn't have big trouble with the implant. So, that was quite encouraging. And, well, we addressed some companies, developers, startups, et cetera. So, "Are you interested in developing things like that?" And finally, the company that is called BlueWind, who is also a startup from Israel in the beginning said, "Well, we have now good techniques with very small stimulators without battery, easy to handle, easy to implant. And, let's start doing trials with that." That's what we did. The first trial was about safety, is it safe? And of course, we also want to know whether it was working or not. And we were very happily surprised by the results.

Also from a clinical point of view, does it work? Yes, it worked. It worked in about 70, 75% of patients. Do we see any side effects? Yes, of course. There's always side effects. You do a surgery, you have to close the skin, sometimes the skin is a bit swollen, you can have an infection, et cetera. But it was all quite minor. And, based on the results from that study, the big trial was started, of which, I presented the first year results in Chicago in April.

And that's the big step now that we have made that we say, "Okay, we have about 150 patients. They all have an implant at an ankle. We are looking at the results after six months, stimulating by themselves every day, half an hour." We look at adverse events at 6 months, at 12 months, et cetera. And then we see whether we have an acceptable and a good treatment that perhaps can be used in clinical practice. And I think we are at the step now that is the case and that we are very happily surprised by the success rates, also by the minor side effects that we encountered. And, we are happy to continue. That's more or less a study or the history of it. Yeah.

Diane Newman: I did not realize that it originated with you. I did not know that background. Thank you so much for sharing that. Do you happen, John, to have a picture of it or anything? Where does it go in the ankle is what I'm interested in?

John Heesakkers: Yeah, I have a picture. Yeah. Let me see. So, first anatomy, because we are urologists and urogynecologists, we are not very familiar with legs. But what you see here is the inside of the leg, and this is the tibial nerve. It runs behind the tibial bone. So, on the dorsal side, about two centimeters deep. And, if you make a small incision here, that's what we do. We do an open surgery. So, under local anesthesia, that's quite an advantage also. So, we make an incision of five centimeters here. We go to the fascia, under which the tibial nerve is located. Then we open the fascia, and then you can really see the nerve, which is quite exciting for urologists, because we never see nerves. Then you take... Well, this is the first generation implant of this BlueWind device. BlueWind RENOVA™, that's the name.

And, if you put a stimulator at the tibial nerve, so you see it's more or less depicted here, this is three centimeters long only. And, this is about five millimeters. These are wings that you can use to suture the implant to the fascia. And then, it is located here. Well, you close the skin, and then you let it heal. And then finally, the big thing comes in. This is called the external control unit, or the variable it's called also. And, this gives radiofrequency signals to this stimulator. It is picked up, because the stimulator is without battery. And then, it starts activating this nerve, stimulating the tibial nerve.

What also is modern, at the moment, which we didn't have in 2004 or when we started developing it, that this external control unit is connected to some kind of a computer, can be anything by Bluetooth. And what you can see is how many times the patient was stimulating, with which current, with frequency, et cetera, in order to find out whether the stimulating parameters were optimized. And also, we tried to deduct in the future what parameters we should choose in order to have the best effect.

Now, I can show you that as well. So, this was the first study, which you can see here in only 16 patients, 75% success after three years. That's good. This is how it is done at the moment. So we have the variable here. We have some kind of a connector to the iCloud. And what you can see here is what patients did. So, whether they stimulated on Wednesday, and for how long time, Saturday, et cetera, et cetera, which parameters, they can also put their clinical data in if they want to. And then, we can continue with using this treatment. So, it works quite well.

Diane Newman: Now, I've done PTNS for many years, and what I've always felt is that it took a while to see that improvement. Now, you're doing it daily. So, you may see the improvement much more quickly.

John Heesakkers: Yeah.

Diane Newman: But I also found that the one symptom I saw a lot of help with was nocturia. Are you seeing one symptom be better than any of them, or is there urgency incontinence, or what is the data leaning towards?

John Heesakkers: I can show you this slide. That's a very good question, because we were wondering also, "What are we doing here? Are we treating in a different way than with PTNS?" And I think, that if you have the implant on the good position of the nerve, that means that every time you stimulate, you have the optimal stimulation, which is, perhaps not the case with the needle, because it has to be put in every time again, quite often by a different people. Some are very good in it, some are perhaps not that good in it. So, that's quite some variation there. So, when we did the analysis here, this is more or less what you can see, primary endpoint, that's the classical primary endpoint that we always use for neuromodulation. You look at more than 50% improvement of the primary symptom.

Well, these were old ladies, had urgency urinary incontinence, and they needed to have at least more than 50% reduction. Now, if you look at this primary endpoints, 76% success after six months, 78 after 12 months. But if you look under here, then you can see that it's a bit different. So, for instance, the improvement in urgency episodes and voids, which is not incontinence, but that's of course, the feeling that they have. It is good after 6 months and even better after 12 months. Whether these data are very, very much... I don't know. I think it's more or less every time the same. But what you can see that it also works very well on large volumes of urinary loss, even 88% of those large volumes are improving with more than 50%. And that's quite impressive.

What we also tried to look at in the first, let's say, small study with 35 patients was, do we have PTNS as a responder here? Can we say, "Okay, if we have a good PTNS patient, does that mean that he or she will respond very well to this implant?" And, we could not make that happening in the group of 35 patients in our own group. So we did 15 of the first study. We saw that it was a predictor. So, if they are responding well to PTNS in our group, they also responded well in the implant group. And I think, when this is introduced in clinical practice, of course, this device has a price, and that means that if you want to be selective, then most likely you'll do PTNS first in some patients, when they respond well, you go for the implant. That will be... I think, but that's speculation of course, that will be the case in clinical practice. And then you can use it as a respondent.

Diane Newman: Well, now you have your 12 months. How far now are you following these women out?

John Heesakkers: We had the last patient coming in last October. And we had our six-month result presented at AUA. We will follow that up for more than three years. The primary endpoint was after 6 months for efficacy and 12 months for safety.

Diane Newman: Right. Yeah, because sometimes we'll bring them back three months later and do what we call booster. So, this will be nice that the individual will have that implant and then can maybe go back to doing again if they see their symptoms change.

John Heesakkers: Yeah.

Diane Newman: Are you seeing any issues? Is there a certain ankle that's best to do this in? I saw that nice looking ankle that you showed there. But, I don't know. I don't see a lot of those nice ankles on everybody.

John Heesakkers: No, that's also good question. That's the selection criteria. If you have a lean leg, that's the best one. It doesn't mean that you cannot do it in a leg that has, well, more than a certain centimeters diameter. The issue is that you have to get to the implant. If it picks up the signal, then you're fine. And I think this device can do that quite easily also with thicker ankles. So, I'm not that afraid of it. Perhaps it's a healing issue, that it heals not that well.

What we also did in the meantime, and that's also interesting to know, is that, we had five patients from the first group who had to be changed with implant, because they want to continue stimulation, but they needed another generation implant. And it was easy to take the old implant out and put a new one in on the same spot. So, that also is possible. We did it in five. That's not the rule. But okay, it's quite an indication. And, I think that finally, if you can master the area that you're operating in, that you can have a safe series, and also good results in many patients that are, well, quite easy to help them, as compared to other types of stimulation.

Diane Newman: When is this going to be available?

John Heesakkers: Ah, also good question. There is a process going on with the FDA to have approval. It is expected to be there in October. The answer for it. Yes or no?

Diane Newman: Yeah, that's good.

John Heesakkers: If that's the case, then I expect... But okay, I'm not from U.S., so I don't know how those rules are and how the logistics are. Then I expect it will be available beginning next year.

Diane Newman: Is it available now in Europe though, where you're practicing?

John Heesakkers: We are also in a process of getting approval for it. Perhaps we will get that. In every country in Europe, that's different. So, that's not that easy. But I think, that these results in a big group with quite some follow-up already. Well, this is quite convincing, so I think that it'll be accepted in many countries.

Diane Newman: Oh, great. Well, listen, thank you so much. I mean, you really answered all my questions, but also I think this is a really exciting advancement, right, for neuromodulation. I mean, because you're right, coming back every week for PTNS every week is really an issue. We have a practice in the city and patients complain about it all the time. They can't get in, parking, that type of thing, and they want to go on with their lives, right? And sometimes, it's difficult to make that appointment. So the fact that we have something to implant that. And also, I like the fact that you can do it yourself, right? I think that's great. Now, with compliance, was compliance that... You say they could do it daily, how often do they really do it though? That's what I was wondering.

John Heesakkers: We are looking at that now, because half the patients stimulates three times a week and another group is stimulating all week. In the first group, patients had to stimulate six days a week, and on Sunday they had off. And then, quite often, when they came back into the clinic, they said, "Well, I want to have that extra day of stimulation also because that's what I need." So I think, one day of stimulation per day, that's quite a good frequency. They can do it, well, everywhere they want more or less. It is also good from a compliance point of view, because I think, if you remember every day that you have to do something that's better than once a month, or once a week, or once in 10 days, et cetera. And, that perhaps is also a good stimulus for the patients to continue.

Diane Newman: And this device has not migrated then. I mean, because I'm thinking of people that maybe are runners, or exercise, or put on boots, or whatever.

John Heesakkers: No, it is sutured to the fascia with unresolvable sutures. And so, it stays there. I also think that if it is encapsulated, it does not move. And that's what we saw, for instance, in our first primitive implants, that they were encapsulated on the same spot. And, even after 17 years, because we followed them for 17 years, it was not moving. So, I think it's quite robust in its location.

Diane Newman: Okay. Well, thank you so much for presenting this. We're really excited to have it. I know our viewers are going to like it because this is such a growth area for urology, and especially for patients who have overactive bladder. Thanks.

John Heesakkers: Yeah. Thank you. Thank you. Bye-Bye.