Lawrence A Lavery, DPM, MPH discusses the basics of topical oxygen therapy, the current literature regarding its efficacy, and compares it to current standard treatments for diabetic foot ulcerations.
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Unidentified Male Speaker: Okay. So this kind of an interesting topic because it's a little bit controversial. I think the rationale for this contradicts convention, accepted wisdom, and kind of the foundations of the faith that you can deliver oxygen topically over the skin and it will all make a difference. I mean, it's one of those things that you learn during your training 25 years ago that everyone just scoffed at. There's some basic science work though. There's actually a nice body of basic science work that suggest topical oxygen therapy can increase growth factors in the wound bed up to 20-fold in some cases, increase oxygen in the wound bed from kind of a resting level of five to up to 40 millimeters of mercury.
There's some other basic science work in animal and in benchtop studies that provide a rationale for this that I guess we neglected when we passed this off as not having any merit 25, 30 years ago. So I want to talk about the evidence for really two studies today or two applications for topical oxygen therapy. One is the randomized clinical study to treat diabetic foot ulcers, and the second, a wound pain study, both of which I think are kind of interesting and perhaps surprising results. So this is really kind of the classic phase three, although this is a post-marketing study. This is kind of what the FDA looks for, for a classic 12-week diabetic foot ulcer study. Unlike most of the device studies, and by that, I mean cellular and tissue-based product studies, where neither the patient nor the investigator is blinded.
This is a product that lands itself really nicely to a double blinded placebo-controlled randomized clinical study. So it was a 12-week study like most of the work in this space. Patients received a really high quality of standard of care with at home dressing, occlusive layer, and a very high quality offloading boot. And so basically, you got an active device that deliver action to the wound bed and you get the same device that just was setup so it wouldn't deliver any oxygen to the wound bed. So this is a post-marketing surveillance study. It was designed and monitored with discussions and consultation with CMS because those are the folks that everyone is trying to get to understand their technology.
CMS had a couple concerns about the wound size and the degree of wound chronicity, and how that impacted wound healing. So it was really agreed upon that those outcomes would be evaluated as part of the analysis plan, and I can't remember another study that has done this. So I think it's some really novel interesting information. So they agreed to look at both of those parameters and then they also looked at percent wound area reduction, which many people are interested in. CMS still is not convinced that that is going to be a primary outcome. I think they're always happy to consider it as a secondary outcome. So this is the little randomization process. Patients were screened. They had a two-week run-in period.
Those who failed randomization were not eligible. The other people continued with the current 12-week – the other people who were randomized continued with the 12-week evaluation period. For the people that had finished, there was then a follow-up phase if inpatients whose wounds closed. So this is what the CONSORT diagram looks like. There were 386 people screened, 225 randomized, 146 were in the intent-to-treat analysis. You can see how this divides into active and sham treatment. Seventy-four people in the active group, 72 in the sham-controlled placebo group. In the protocol part of this one, there were 52 patients and 53 people in the sham group. And then, 24 people healed in the active group, 12 in the sham group. So there was more than 85% screening failure rate, which I think kind of goes to how rigid the criteria are for these type of studies and how difficult it is for a lot of people to get in.
The primary outcome fit the classic definition to FTE it looks for wound tearing. The definition was complete wound closure with real epithelialization with no wound drainage. So that's the definition of a healed wound. The secondary outcomes were what they almost always are in DFU studies, the time to healing, the effect of baseline wounds slice on wound closure as previously described, the affected wound chronicity on wound closure. There's no difference in the demographics in patients at baseline. The wound size was 3.7 centimeters. The average age was 56 and the study population was predominantly men, very similar to almost every other DFU study in this space over the last 10 years.
So in the active and placebo group, there was about twice the rate of wound healing in the 12-week study period, about 204% improvement in people that had active therapy compared to sham therapy. So as I said, the CDO treatment arm closed more than twice as many wounds as the placebo group. You didn't see any other – there were no other therapies that they could be included in either treatment arm during the study period. Not all studies have this limitation. Some people can add different treatments as part of standard of care. So this was a much cleaner design from that perspective.
This is a diagram that shows the days to wound closure and the active and sham treatment groups are based on 50%, 75% and 100% wound closure and you can see each time interval or percent wound area closure I guess you'd say. There is a significant improvement in people that received the active therapy compared to the sham therapy. Time to wound closure was significantly shorter and time to 50% wound closure was significantly shorter with the active treatment arm, 18 compared to about 29 days. This is a graph that shows the effect of the active treatment arm or continuous oxygen therapy on the mean quartile of wound size. So essentially, as the wound size increases the performance of the active therapy arm got better.
So instead of most studies, larger wounds fail to heal more frequently in both the active and sham treatment arms. In this group, the larger wounds did better when they got continuous oxygen therapy. So something that you absolutely would not affect or expect. So this effect of run-in on closure rates with looking at the percent wound area reduction. So as wounds increase in chronicity, the CDO active treatment patients had increase in their relative performance. So overall, there was a two-fold increase with wounds that were worse were – or not worse, were older, their performance or effectiveness improved. So there was a significant increase in the P value as well. And chronic wounds or wounds that had markers for that were more chronic were less responsive to standard wound care.
So I think another surprising clinical outcome. The data also will set the effect of weight bearing, so usually, weight bearing wounds, you would expect are going to have a blunted healing response because there's been repetitive trauma. So the percent of weight bearing wounds was not different in the two treatment arms, 83% in active and 75.5% in the placebo group. So if you look at wound closure by treatment arm by weight bearing or non-weight bearing wounds in the placebo arm, the percentage of weight bearing wounds was first of all the percentage was similar between groups as I showed you in the first slide.
The majority of wounds in the placebo group that closed were non-weight bearing wounds. Only 10% of the weight bearing wounds closed. There was essentially no difference in wound closure based on weight bearing or non-weight bearing in patients that receive active therapy. So I think another surprising clinical outcome. So there is a significant benefit patients who received the active therapy in weight bearing wounds or a 465% or more than a four-fold improvement when people had the active therapy and had weight bearing wounds compared to standard of care.
Again, I don't think any other study has evaluated their data like this and compared treatment outcomes. I guess my cartoons were off. So this I think is where the money goes in wounds, its adversity band. So often, this patient population is sick. They have a lot of AEs and SAEs. There was no significance in the overall adversity bands in the two treatment arms. The overall adverse events were 14% and 18%. CDO had fewer adverse events related to infection. The infection rate in both of these studies is low though. So the infection rate overall was 11%.
The CDO infections were less severe, 75%, fewer hospitalizations, and there's no gangrene in people that received active therapy. So if you compare this to other randomized clinical studies, so Dermagraft, AlphaGRAFT, OSIRIS, GRAFTJACKET, I guess that's all that's out there. If you look at the third column on the right, let me see if my – no. I don't have a cartoon for that. If you look at the adverse events, the adverse events in this table are infections. On the far left side, 18% in the placental tissue, these people have received active therapy.
36% is control arm. There's obviously a significant difference in that group. In the AlphaGRAFT and Dermagraft studies, there was 19% in active therapy, 32% in the control arm, 22% and 30% in the control arm. So in really highly selected patients that are well-perfused who A1Cs are good if less than 12% is good, a third of people develop infections in a 12-week period. And you can see the odds ratio at the bottom for healing in these randomized clinical studies. So this is a slide again, probably two or three people have talked at least part of their presentation over the last few days about the importance of debridement and this is another part of this story to add to this.
So if you go back and look at the Regranex study that David Steed did a post hoc analysis and looked at people that were debrided and weren't debrided. So self-report of what debridement is, which probably may not necessarily reflect reality unless you measure it. But it was a small number of people like less than half a people in many studies had their wounds debrided on regular basis. So that was 25 years ago. I think our wound acuity has changed and so people are more likely to be debrided.
There was one site called site X on this slide, where only 41% of patients were debrided. And so the patients have had active therapy, having their wound debrided, allowed optimal access to action to penetrate the wound, and they had a significant improvement in their relative benefit compared to control pretty much across the board. So site X had remarkably lowered debridements. All the other sites were 98%. Site X did not show a significant difference between the two treatment arms, the other groups do.
And I mean, this makes sense for anything that you're going to apply to a wound. If you're going to put an [M9] [0:14:13] tissue product and you're going to not debride the wound, and you're going to have dead tissue, you're product isn't going to work. I mean, it doesn't have a good interface with the wound. So again, I think this adds another layer to the evidence and almost all of the evidence for our wound debridements are post hoc analysis from randomized clinical studies. Some are wound center claims data studies, but nothing has been prospected and probably won't be. Sites that debrided frequently closed 51% of the time in active arm and 21% of the time in the placebo arm, really, kind of the same thought process that Dave Steed talked about probably 20 years ago now.
The relative efficacy improved 204% and 240% with wound debridement. So it's the foundation that they – you have to debride wounds, you have to offload them or your results just aren't going to be good. So this is a graph that compares a couple different studies. So Bloom did a study with negative pressure wound therapy in DFUs, kind of Wagner 1, UT1A diabetic foot ulcers, small wounds. Marston and Edmonds did the Dermagraft, AlphaGRAFT clinical trials. So if you look at those studies, the healing rates were 46% in this study, 34% or 30% and 52% in the other groups, all the control arms do poorly. I mean for all of the nice work about the effectiveness of offloading, all the head-to-head comparisons, people had offloaded in a good boot heal 50%, or 60%, or 70%, or 80%.
When you put them in an RCT study with amniotic tissue or some other product or topical oxygen therapy, it goes to hell and a third of your patients heal. It's interesting story, part of this story I think. This gives you some relative comparison to other things in the literature. My summaries are already messed up, huh? So this is a really nicely designed clinical study where the company visit CMS and tried to give them the design that they want that the classic running period, you digital photograph to measure the wound and to measure the size of the wound. It's a nice design because almost nothing in this space has double blinding. CMS sited the study design as the gold standard for studies going forward.
Probably the next best study in this space was the Integra DFU study that was done four or five years ago, which was a large really well-designed study. The CDO group closed significantly faster than standard of care, 204% more and also performed better when they're larger wounds, more chronic wounds and weight bearing wounds than the control arm. It also show that you really need to debride wounds to get the best outcomes for these clinical studies. I think this is really interesting data because I would never have believed this. I would never have thought that this kind of technology would be this effective. I mean it flies in the face of everything that I was taught.
Okay. So the next piece of this that I think is even more interesting is this pilot study that was done on pain and patients with wounds. So this was a pilot study with 20 patients, 23 wounds, 65% were female, the average age was 74, so really different than the DFU population, right? The baseline measurement was 15 centimeters squared so much bigger wounds, up to 117 centimeters squared. Oh man, that's not me. There were older wounds. The median baseline pain on the visual analog scale was eight out of 10.
So these people had large wounds they were more – they were ankle and they were primary venous and vascular wounds 80% of the time, 87% were about the ankle. So completely different patient population, the neuropathic diabetic wounds, kind of potpourri of different wound ideologies, but overall, all of the patients were more reported a significant pain relief from a median visual analog pain scale of eight to zero to one and only one patient reported that their pain was one. So during the study, people went from an average of eight to zero or one.
Pain relief was fairly rapid by four days, 39% were pain free, 52% ended up with less than two, 91% experienced noticeable pain relief greater than 25%. Several reported complete pain relief the day of the first application, so and for many patients, getting the active therapy, a lot of people to stop narcotic pain medication, especially if they're running around at 8%. So in addition, 83% of the patients who experience significant closure, 57% closed completely. So again, this is a pilot study with 20 patients.
The wounds with the median age of 135 days that closed in 51 days, the largest was 55 centimeters squared with a base pain of 10 out of 10 went down to zero. The remainder were out of trajectory to heal until noncompliance was noted, wounds closed 53% and 93%. The largest was 117 centimeters squared that started with a baseline pain of 10 out of 10 and went down to zero, so kind of a reoccurring story. If wounds that generally – if wounds generally did not close, pain relief was still dramatic. So your pain relief wasn't necessarily related to wound closure. 75% were pain free by the first follow-up visit, the median closure was only 5% and they still had complete, complete pain closure.
So there's something else going on and I think for a lot of patients, I mean this is a dramatic benefit for especially patients that are taking gabapentin and Lyrica and narcotics to try to control their pain. Wounds that didn't close initially had greater pain relief 44% pain free at the first visit compared with 39%. It's a pretty dramatic change. One patient had three different wounds that were treated and experienced pain relief every time. Initially, the slide is kind of out of place as she go back with the other wounds. So this data from a wound registry that shows that they had 76% success rate with kind of a variety of wounds with long duration – I meant that to put that at the end of the other study data.
So this is a pilot study that really shows some very impressive results. It's the RCT with wound healing is really novel because there aren't for many double blind placebo-controlled study, the highest level of data, especially for people that peak at level 1A and 1B because you can never or often, it's difficult to blind the investigator or evaluator. Performance improved with the continuous or with action therapy in larger wounds, and wounds that were chronic, and wounds that were weight bearing, which I think is also a really novel way to look at this data. Yeah. And so I guess with that, I will finish.
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