Mark Q Niederauer, PhD discusses the continuous diffusion of oxygen (CDO) on diabetic foot ulcers and supports his lecture with data from random controlled fully blinded trials (RCT). Dr Niederauer offers comparisons of the effects of CDO with results of other therapies such as moist wound therapy (MWT) and placebo use.
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Mark Niederauer is and employee of EO2 Concepts.
TAPE STARTS – [00:00]
Speaker: We heard a talk earlier this morning about topical oxygen therapy and there are many different types of topical oxygen therapy. One of them is continuous effusion of oxygen. And there has been a recent paper published by our next speaker using one of the technologies that we also had experience using and title of the next talk is going to be the "Effective CDO", that's continuous diffusion of oxygen on DFUs and results of the fully-blinded RCT. And our presenter is Mark Niederhauer, PhD, came out of Iowa State University. He has a PhD in biochemical engineering and he presented a very nice paper on this that I would love to hear him discuss. So Dr. Niederhauer, where are you? There he is. Let's welcome Dr. Niederhauer to hear this presentation.
Mark Niederhauer: Good afternoon everybody. My name is Dr. Niederhauer. I am the chief technology officer and COO of EO2 Concepts. And today what we are going to do is we are going to talk about not only the study we have published but also in general about oxygen, how it works in wound care. So in the topic today what we are going to talk about is starting with oxygen delivery, so not only how oxygen works in wound care but how it gets in and the various modalities of how we can get oxygen into wounds. And then from that, we will transition into a study talking about a continuous modality for providing oxygen into wound care and not only talking about the results of the study but also how the study was designed. One thing I want to emphasize is that this is a study that's first of its kind to be published in wound care.
It's a fully blinded study with placebo control. So the learning objectives for today are to talk about the basic mechanisms of how oxygen gets in the body and that is universal. It may surprise people that it's basically no matter how you deliver it, the basic mechanism is the same. And then we will talk about once the oxygen is in the body, how it can affect wound healing in various mechanism of action. So specifically, how does it interact and achieve wound healing. And then we will cover the various modalities that are available to deliver oxygen to wounds and with the last one we will talk about being the continuous delivery or diffusion of oxygen in wound beds. We will focus on that with the most recent published trial with the fully blinded study. Dr. Frykberg said I'm the COO of EO2 concepts full disclosure. So we will start off with the importance of oxygen levels. One thing is if you look at in a tissue, 3 to 4 mm deep in the tissue, you can see that the standard oxygen levels are about 45 to 55 mmHg. Now, as you start to decrease in that oxygen, you will see various effects happen. Things that start to stop functioning. For example, at below 30, you will see cell division either stop or be hindered. Around 25, see the proline hydroxylation for collagen formation cease. And if you get below 20, you are not in a truly chronic state where you got anaerobic and it's just the matter of time before the wound become necrotic. Now, one thing to focus on is on the flipside, if you increase the oxygen level above normobaric, what you will see is that you actually can of course increase a lot of mechanism of action for how oxygen works in wounds. So the first aspect is really how do you get it in. And if you look at the body, the way we are all breathing right here in this audience is that you are taking oxygen from a gaseous state in air, 21% and then pulling out to your lungs, which is in alveolar surface of about tennis court and then it converted through the alveolar membrane into the liquid state and they get picked it by the blood, distributed to the body and then re-diffuse back out from the blood stream to your tissues.
So diffusion is on both ends, a very critical factor for what goes on. And we liken what happens in getting oxygen to a moist wound similar to how we currently breathe. If you look at this slide, here we talk about -- we can show, for example, the effect of different oxygen gradients and if you look at 21% oxygen, you are going to get fairly good concentration gradient down to the tissue. It's what we experience with breathing. However, if you look at chronic wound bed, you think about that's exposed oxygen you might get this, but it's typically going to be covered with moist wound therapy. So you have completely blocked the oxygen now. So if you have an ischemic wound or wound that has a localized blood supply issue, you are not going to get that oxygen level back up again from any other source than the blood supply. However, if you can supply oxygen to that wound bed, you can now increase it, get it very high concentration of oxygen, get it very fast driving force, so not only do you increase the oxygen level, but you also increase the rate in which the oxygen goes in. And one of the interesting studies was done in PIC model where they actually did partial incision of the wound bed, put a probe 2-mm deep in and then went from oxygen in the air, which is 21% to pure oxygen supplying it here and in 4 minutes, they got fourfold increase in the oxygen concentration. So it not only shows that you get fast effect in lungs but you also get it in skin tissue as well. So mechanism of action, the one that I think brings well with everybody is that oxygen is an energy source. It's required for metabolism. That's also used in wound care but it's not specific to wound care. It's also going through the four effects that really are specific to wound care, the first one being self-proliferation and re-epithelialization. One thing when I talked about these, I want to emphasize is that the rate and quality of these mechanisms has been show in multiple literature references and we have these available and they are also available with this presentation to show that these effects are real and they have been shown in multiple models that work.
So with that, you can actually get faster closure and close that wound quicker. The next one is collagen synthesis and tensile strength. To do collagen synthesis, there is actually three different enzymes that form the fibrils due to cross-linking and form the full collagen. All three of those are oxygen dependent and what you find when you get an excess of oxygen, you can actually increase the rate of collagen deposition, so you can get faster repair, you can increase the tensile strength by having better cross-linking through those enzymes and that results in reduced recurrence by having a stronger wound bed repair. And then finally, also with this increased organization through that tensile strength, you can get a better appearance or reduced scarring of wounds. The next one is antibacterial. If you think about anaerobic bacteria, the oxygen will directly kill those but lot of bacteria are aerobic and how that works really is the macrophages, phagocytes, leukocytes, they surround the organism and they use oxygen as a fuel source to create reactive oxygen species such as superoxide hydrogen peroxide. They flood that chamber, break down the organism, consume it and move onto the next one. So that's really how it works with antibacterial. And then finally, angiogenesis re-vascularization. If you have a wound that's going to a chronic state, what has been found is that you introduce oxygen back in that wound bed, the cells start producing VEGF and you actually get angiogenesis going on and localize in the wound bed. So it's not going to be systemic or anything back up the pipeline but local to that area, the wound bed and the tissue. And with that, what we've seen is not only do we get the better rate and quality of angiogenesis but also it increased the amount of exudate initially as those capillaries are forming to be very leaky and lot of exudate coming out. So let's go into how oxygen is delivered into wound beds. Comparison of the different oxygen therapies. The best one known is really the hyperbaric oxygen therapy. If you look at this, what we are trying to show here is basically one-day timeframe.
So just thinking about the onset of the therapy for all three therapies we are going to talk about, it starts right here. Hyperbaric oxygen therapy is a 90-minute dive. So you can see during that entire 90 minutes, it's increasing and going up until they cut the oxygen off while they bring the person out of chamber. At that point, now your body is consuming oxygen, it's going to down in a fairly linear rate until it's consumed. And the literature showed that in skin tissue that this elevated effect only lasted about three hours. And I want to point out here down bottom. What we are trying to show here is this green line is what you would typically have for oxygen levels in non-compromised tissue that healed normally and the red line is supposed to indicate either compromised tissue, chronic tissue, etc or lower is to what that will return to. So with an intermittent technology like hyperbaric oxygen what you get is you get a spike that lasts for about three hours and then there are 21 hours where it's back to its chronic state. Newer technology is topical oxygen therapy and these are done in chambers or bags. And here you see a chamber, required to remove the dressing so that you can have oxygen access to the wound but you see here it's a similar effect where it comes up pretty quickly. They typically follow the hyperbaric oxygen regimen with a 90-minute dive. The body then consumes it and then you are again approximately 21 hours without oxygen. So the one we are talking about today in the next portion of the talk with the study is CDO and what CDO does is it's a portable device that can be worn and supplies oxygen directly either into a dressing or underneath the dressing to the wound bed. And with this regimen, you actually apply the oxygen with the dressing and once you have applied until you remove that dressing again, you got an oxygen pad over that wound the entire time. So we liken in this the fact that your wound will now breathe more normal like you do. It can breathe all the time.
So with that, let's move into the study design. It's a fully blinded randomly-controlled trial. What I mean by fully blinded and you probably saw slide flash blank. And we will talk about that more in a minute but what we did was we designed the study in concert with Center for Medicare and Medicaid as a post market surveillance study because this device is FDA cleared but this is in order to basically prove more evidence and gain acceptance for payment modalities. So we actually have an active and placebo arm and I will show you more -- it's easier to show when I do the picture slide. And we do this in 34 centers across the United States with Dr. David Armstrong as the principal investigator and statistician, Joel Michalek at the UT Health, San Antonio. So the study design involves basically the device, a foam dressing, occlusive layer and then offloading groove. And this was identical in both arms. There is only one brand of each allowed to be used and then we optionally allowed to have a calcium alginate to be used initially in case of the excessive exudate. But this is what the patients, the nurses, the doctors and the sponsor all saw was basically the devices and setup in both arms were identical. So there is no way to tell that you are apart. These devices they actually produce oxygen at a flow rate. It's 3 to 15 mL per hour. So it's a flow rate you can't actually feel or sense coming out. These were set to 3 mL per hour based on the size of the wound being treated for study and what you can see here is that the only difference between these two devices are this device had the oxygen severed and so it's produced oxygen but it circulates inside the device. This was blocked inside the device and no oxygen went out. So as far as the patients and doctors were concerned, this device is still producing oxygen. It still ran the battery down. The alarm's still working and everything else.
The only difference was you have one arm, we refer to as placebo, which is moist wound therapy. The other arm is the active, which is moist wound therapy plus oxygen. So that's the only difference in this study. So for the design, again it's post market surveillance study designed with CMS. It takes about six months to work with CMS to come up all the inclusion-exclusion criteria and really focus on how we can create a fully blinded placebo trial. But also during that timeframe, it was apparent that several things very much concerned CMS about lot of current published literature were effects of wound size and also effects of how chronic wounds work. So they want us to look at both. We agreed to analyze wound size as the study progressed. And then for the wound chronicity, we had a two-week running period and we monitored actual closure rates using an independent analysis of planometric photographs so that we can see exactly how the wounds are progressing for closure and we limited closure to 30% per week or 50% in two weeks and the reason we did was based on the study by Lavery et. al., which shows 60% in four weeks if you have wound closure more than that for a diabetic foot ulcer, the wound will most likely closed with moist wound therapy alone. However, if you have wound closure less than that, the wound is very unlikely to close without advanced modality such as negative pressure, tissue grafting or oxygen therapies. And so this was our inclusion criteria. This was the other end that we analyzed and then we also did a midpoint and we will go over that as we go through the results. So you look at the study design, description overview, how we conducted the study. We have two screening periods. So the first two screening periods were basically coming in and they were during that timeframe only exposed to moist wound therapy. No devices applied. The third screening visit, we actually had a placement. So we call that randomization visit.
What happened here is during if either one of these, we saw the inclusion and exclusion criteria fail or the wound became too small or closed too rapidly, they are considered screening failed and because we had this planometric analysis where we took digital photograph and went to an independent tracer and then to a third party doctor that reviewed all these photographs to have consistency. If they rejected it, the patient was rejected after randomization because they found at randomization to be ineligible. So at that point in time, they are not eligible, they are allowed to be treated outside the study with an active device. So for those that entered the treatment phase, we did a follow-up phone call immediately during the week to follow up with the patient if they understood things or doing the diary correctly following with the use of device. And then they went to study for up to 12 weeks, so three-month trial and the primary outcome being full closure. So if they closed, they went to a follow-up durability phase of three months to see if the wound stayed closed for three months or they exited the study and again we give them the same option to receive an active device to be treated outside of the trial. So the CONSORT diagram as I was mentioning, we have lot of inclusion and exclusion criteria, but if you look at the patients that -- we screened 386 patients. We randomized 225, we ended up with 146 being treated. Over 80% of the loss in here was due to wound becoming too small or closing too quickly. So it directly addressed one of CMS's concerns that in a lot of stage, we're actually including patients or wounds that should have been excluded according to criteria they want to look at. So we ended up with 74 in active group, 72 in the sham and what I am going to talk about today is our intent to treat because this publication is on intent to treat; however, we are currently finalizing the paper for -- I'm sorry, this is for protocol. We're currently finalizing the intent to treat results, which you can see here today when I go through the results is we are seeing in the intent to treat.
It's almost identical to what representing today improved protocol and the reason for that delay is because we had that durability followup period and we want to try to get the results out sooner for the protocol and then follow with the intent to treat. So again, study overview, primary outcome, full wound closure. Secondary outcomes, time to wound closure affected based on wound size and wound closure and affected wound chronicity on wound closure. So if you look at the demographics, we saw no significant difference between the arms. The wound size were little over 3 cm squared, average is about 68 years old patients and most of patients were white or Hispanic and male. So if you look at the what's the effect on initial wound size and the outcomes or difference between the arms, we saw no differences. So if you look whether the wound is closed or open, there was really no difference in what the original sizes were. And what you do see is there is a slightly larger size in the active group and not significant. If you look at the primary outcomes, what we saw was that it was statistically significant for the wound closure and the active arm with CDO closed more than twice as many wounds as the placebo moist wound therapy by itself. One of the secondary outcomes was rate of wound closure. So how fast the wounds closed and when we looked at was the time to reach 50% wound closure, 75% wound closure and full closure. Then what we saw was that at each time point, the CDO closed significantly faster. If you look an overall grouping, the P value became better showing that overall it closed significantly faster. The next one we looked at was wound size. So this is again looking at what was the wound size looked at initially when being treated and we looked at quartiles. Since we had 100 patients, we divided into four quartiles of 25 patients. These were the average baseline wound sizes that are shown and what you can see here is that as the wound size increases, we actually have an increasing relative effect. So you go from here being slightly less than double to more than three-and-half times wound closure.
The patient is showing as the wound gets larger, the active oxygen was actually having more of an impact in the wound relative to moist wound therapy. The next one we looked at was effective wound chronicity. So this is basically looking at -- again, look at the first two week period before they get treated with the device. How fast was that wound closing? And the reason for that and one of the things CMS talked us about was if you look at lot of studies, patient come in, they get enrolled in the study right away and then they go. They don't really know the history. This way, you have them coming in, is being treated by a physician in that facility for at least two weeks and they are seeing whether that change is the wound care. I am sure lot of you are seeing that too. You bring somebody in. They are not closed for long time. You could under good care and also no changes. So trying to eliminate that effect by doing this. Again, the main results are shown at the top line and as you go down, these are more chronic wounds. This again is similar to the Lavery [phonetic] publication of 30% in two weeks which he called 60% in four. We used it as equivalent. What's interesting, you should see here as we expect is wounds become more chronic, they are harder to close, but we saw the active not decreased by much. It went 46% down to 42% closure in the course of study. However, the placebo decreased by almost half. And you can see that in your relative performance, we went from being able to close for more than twice as many wounds to more than three times as many wounds in the same timeframe as wounds became more chronic. One thing is that this is actually coined by Armstrong by seeing these different results. His verbal response was that it appears that the more you need CDO, the better it appears to form.
Another way of looking at this is to graph it and this graph shows since these were even proportions of percentage, which did linearly and you could see here by plotting it, you see it's a very good correlation, very strong correlation coefficient that as the wounds become more chronic, the impact of options become more necessary for wound healing. In the last point I wanted to talk about is a comparison to other studies. So one thing you always see is your studies don't really see comparisons to what else is out there and I want to focus before I show the results on differences in the studies, so you can kind of see what we are talking about here. We call level of average. You hear lot of talk about level one studies. This study is actually first of its kind to be published, so it's a first published study in wound care, a fully blinded study where the patients, the doctors and the nurses nobody knew which arm what was being treated. So we remove that bias for the treatment. So that's one thing. Another is if you look at how oxygen is applied, it's basically applied like moist wound therapy. It's applied until the wound closes. Nothing else is being used. What surprising is looking at these other studies is you will see that not only that they resort to some point, the technology was removed, for example like pressure is one of those that does that but they also allow in their protocol, the published protocols, closure by other means including surgical means or amputation as successful outcome if it's deemed necessary about the site. So our study does not allow that. It only allows for full closure by either placebo or the active group. And we don't have any studies up here for the other two comparative oxygen therapies as we couldn't find any with larger sample sizes. So HBO and TOT are not included in this graph. So with that, let's move on to the actual outcomes and what you see here is this is the outcome we showed before. So this is the main outcome. It doesn't include any of the more chronic wounds or wound size effects like that.
So relative performance of 29%, equivalent or better than the other therapy shown and what we show here is a negative pressure in two different skin substitute sites that were published. And as I mentioned before, the intent to treat, you will see similar results coming up in our publication on that plus a lot more explanation on some of the patients that fell out, why they fell out, things like that, but you are going to see the same results that were presenting here in our intent-to-treat analysis. So in conclusion for this study, as far as we were the first of its kind to be published with the fully blinded study with the running period to allow for wound chronicity, we used highly accurate digital photographs that were independently analyzed and verified and all the subjects and physicians were blinded as were the observers and analysts. So it's first of its kind study. And for the results, we see the outcomes, it closed significantly better and faster, two to three times better than placebo and performing better in larger wounds and as wounds became more chronic. Thank you.
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