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Lawrence A Lavery, DPM, MPH discusses the clinical outcomes of amniotic membrane studies with diabetic foot ulcers and compares these results with other randomized clinical trials.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Professor and Director of Clinical Research
Department of Plastic Surgery
University of Texas
Southwestern Medical Center - Dallas, TX
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Lawrence Lavery has nothing to disclose.
Male Speaker: So I'm going to talk about the next generation of wound care and talk about placental membranes. I really appreciate the talks that address some of these issues because I'll take us a little bit different slant. So these are my conflicts, most of them are related to companies that our group does clinical research with. So the objectives for this session are to discuss clinical outcomes with amniotic mesenchymal stem cells, to discuss wound healing clinical trials with stem cells, and to discuss adverse events associated with clinical trials. And I think people have alluded to some of this earlier. So I really want to talk about the level of evidence and I think that this is an exciting area because there's a growing body of work and because of the time limitation, I'll just touch on animal studies and then maybe touch on one or two of the small prospective studies and then finish with the most largest randomized clinical study with the active stem-cell therapy. This is just one of the clinical studies and I know in podiatry, we don't have access often to a lot of animal wound models or even benchtop research. A lot of animal studies are done in rodents which is not a classical wound healing model for humans because like dogs or cats, their skin is mobile. They tend to – you have to put some kind of tissue, so the skin doesn't overlap the deep wound which is probably very convenient if you're a rat and you get injured because you'll heal very quickly. But that's not how we do it. So this is a study that used 24 Sprague Dawley rats and they created full circular, full thickness wounds on their back. So not necessarily an impaired wound model, I mean, we do a lot of studies with pigs and pigs live in dirt and excrement. And so we tried to do studies to infect them. It's like, "I laugh at your bacteria. I live in squalor and you can't infect me." It's hard to make their wounds in a young healthy animal, so they had delayed healing. A lot of these studies don't translate into human studies, so they looked at four conditions in this animal model. A control group using Tegaderm disc, an experimental group using a collagen disc, amniotic stem cells, and amniotic fluid. And so this is what this looks like on the back of a rat, but they don't show use the little material that you usually have to put around this, so it just doesn't close. You don't have to do that in pigs. The wounds were assessed through macroscopic histological examination, immunohistochemistry over a certain time period. I’ll show you that time periods. If you look at the mean or constant contraction rates for the two stem-cell therapies, they were significantly faster at days 14, 17, and 21 compared to the two control arms. Hard to interpret that from this graph with the bars representing variation. If you look at the same data and look at the mean percentage of would epithelization rate over time, it's the same thing. It's the two stem cell therapy groups that have a significant difference or faster healing compared that to the two control arms at day 14, 17, and 21. A number of animal models, I mean, I’ll probably finish this slide a dozen animal models with different stem cells and epithelial applications from bone, from placental tissue, and from adipose tissue. But all have shown accelerated healing or some accelerated cellular outcome in mostly rodent models. So what about the prospective studies? I think this is how we start, I mean, I'm going to try this in 20 people and see if it looks like it makes a difference. There's recent work, I think, more and more industry is going to have pressure to instead of coming to you and saying, "Look, I have a case report. I used my product and here they are. They're healed."
No one ever comes to you and says, "Look, I have a new product. Here's Mr. Smith, he's had this wound for two years. We put on 10 applications and he still didn't heal." No one shows you that case report. So prospective case series – so this is a recent paper. It's actually a really nice read. It was published in the Journal of Foot Ankle Surgery just recently. This was a prospective cohort study that involved 20 patients with 20 chronic foot wounds and these were really chronic foot wounds. So these are people that had failed to heal using the standard of care for more than a year. So these people are automatically eliminated from almost every phase-3 diabetic foot ulcer clinical trial. They're too hard to heal, so you just eliminate them. Their duration on the wound on average was about 37 months. Their mean wound size was 10 centimeters. It was a 12-week evaluation study. So this was a study that used placental tissue that was obtained from planned caesarean sections, it was a cryo-preserved product. The number of applications on average was about two. So two applications during the study period, 90% of the patient's healed, the average healing time was 10 and a half weeks, and no adverse events were reported. So something that if you were going to try a couple – it’s like phase-1 oncology study now we're going to try this on people that we don't think are going to do very well and see how, see if this accelerates their death or if they live for an additional two weeks. So really high-risk patient population and the results are pretty compelling. This was some data that was presented earlier, I think, this is going to be published after my new management this month. So this was data that was presented early this morning: 62 patients, 55 wounds, 21 DFUs, 33 VLUs not VSUs – I'm not sure what that is. In the States, it's ulcer, I guess – and 11 wounds of the category of other. 50% had failed previous surgery. The mean wound size was large, it was 9 centimeters. The medium time to closure was only six weeks and then the number of applications was three. Again, if you're going to start with a cohort's study, this makes you think, "There's a signal here. We need to go to the next level." This is the Kaplan-Meier without another treatment arm so this is just the wound healing time with the study group. They're suggesting there’s a 70% probability of wound closure at 20 weeks in this cohort. And then, this data that is a single center, 15-patient study, 60% had failed previous treatment. The average wound size was about 6 centimeters, up to about 19. 67% achieved wound closure at 12 weeks; 90% of patients that received either weekly or every other week application. Perhaps, a dosing response in the small study, average applications were about 4 and no adverse events. Some of the early relatively small prospective cohort studies certainly look promising; certainly look like it's something that needs to go to the next level. The next level is probably the highest level, the randomized clinical trial. The title of the study is "The evaluation, efficacy, and safety of graphics, human cellular repair matrix for the treatment of chronic diabetic foot ulcers – a multi-centered, controlled, randomized, single-blinded imaging verification, off-label crossover study." Say that 10 times fast. The application of the study product is unblinded because both the physician, the patient know what they’re getting after treatment because there's not a sham for this product. This is a multi-centered study, these are the 20 sites that participate in the study – 20 sites really a cross section in the United States. This is a very classical design; it's a one to one ratio, people that get the treatment compared to controls. This study enrollment is over. The primary end-points were 12-week wound closure and then verification with this unblinded or blinded imaging from an outside source.
In the control group received standard of care. I think they received a much higher standard of care that is generally available in the community. They had sharp debridement and lived by the investigators, so you can decide if the wound needed to be debrided. Offloading, so if people have a wound on the bottom of the foot, they got a removable cast to offload it. If it was on the dorsum of the foot or if it was on the ankle, they could be offloaded in a post-op shoe. And if you look at what the literature says about this, only about 16% of people get a removable cast for offloading. Often, insurance doesn't pay for this and the VA system access is different, so more people can get a higher level of offloading, and then a non-adherent dressing for the wound. The inclusion criteria for the study were also very classic, and a summary to almost every other phase-3 diabetic foot ulcer study. Patients were 18 to 80-years of age. They had really confirmed Type-1 or Type-2 diabetes based on the definition that the ADA uses. The ulcers were defined as chronic wounds and they could range from 4 to 52 weeks. They were wounds that were below the ankle and they could be on the bottom or the dorsum of the foot. The wound size range from 1 centimeter square to 15 centimeters square. And the exclusion criteria was also very classical, patients who had a one week running period and if their wound close by, – the wound area reduction was 30% or more, they were excluded. So if they responded well, they were excluded initially. Patients were excluded if their random blood glucose was greater than 450, if their ulcer had a non-diabetic ideology, if there was gangrene, if the patient was receiving dialysis, or if their glycated hemoglobin was greater than 12%, so very similar of what the FDA likes to see. This was a tissue-based wound product that provides extracellular matrix similar to what a lot of cell-based products, whether they're cellular or acellular offer. This provides a reservoir for growth factors and the mesenchymal stem cells, and you get this beautiful immuno-privilege that comes along with active stem-cells therapy, so you’d expect a decreased in formation and then acceleration or a protection of infection based on what we know from basic science for stem-cell therapy. As I said before, there's a one week running period in the study, there was a 12-week treatment period, and patients were randomized in a one-to-one ratio. Four patients that were in the control group, if they did not heal on 12 weeks, they can crossover and get active therapy with the mesenchymal stem-cell therapy for up to 12-weeks. So the primary endpoints were also classical. The first was a proportion of wounds that healed, the second is the time of healing, the number of treatments, wound closure patients that were healed in a crossover period, the proportion of patients that had, at least a 50% wound area reduction in 28 days and wound recurrence 12 weeks after their initial therapy. So this little comes of their baseline probably this is very similar to what I’ve seen in clinical practice, patient's were in their 50s, predominantly male. They were obese, mean body mass index was 32 to 33. Their wound sizes were relatively long for phase-3 DFU studies, 3.4 centimeter square and 3.9 in the control arm, and the wound duration or the median wound duration was 113 and a 123 days. No difference in any of the clinical characteristics or baseline data between the active therapy and the standard of care treatment group. This was discussed a little bit earlier in the day. This was the first DFU study where the interim analysis, the planned interim analysis was successful. It was successful not only for the primary endpoint but for all of the secondary endpoints as well. So this is not uncommon in oncology studies and other drug studies to have a planned interim analysis either stop the study because of superiority or because of inferiority. We’ve just finished a breast reconstruction study that the interim analysis stopped the study because of futility.
There was actually no difference when half the people are enrolled and active in the sham treatment group. So this is classic design. In this study, 62% of patients healed that had the stem-cell therapy, 21% of patients healed that had the standard of care or controlled therapy. This represents a 191% relative improvement or an odds ratio portion. It's about the two-fold odds ratio, so 97 people are included in the interim analysis. The primary endpoint P-value was extremely good. This is the Kaplan-Meier survival analysis, so you can see there's an early separation from the control arm and the treatment group in this model. So this is the data that really supports the Kaplan-Meier survival analysis. The median time for wound healing and an active treatment group is 42 days compared to 70 days and the standard of care or control arm or 4-week difference in wound healing. As you would expect, a lot of the other outcomes are going to roll off at this faster healing time, decrease infection, decrease number of treatments, and so that's exactly what we saw. So if you look at the 50% wound area reduction at 28 days, it’s 62% in the active treatment group, and only 36% in the standard of their care group or the control treatment arm. A lot of people, I think industry or insurers have tried to hang their hat on – you need to wait to wait for 4 weeks of standard care before you initiate advance wound therapy. I mean remember the study by [Peter Chan] [16:55] and the subsequent studies, usually did a post-talk analysis of phase-3 clinical studies. So they eliminate extremely high-risk patients. They eliminate people who have old wounds, people that have chronic kidney disease, and so there are a lot of high-risk people that you know that Mr. Smith, took 18 months to heal his last wound and he comes back 9 months later and has another wound. You know he is a high-risk patient. This I think, is the Peter Chan argument of 50% wound area reduction to trigger advanced wound therapy. I think it’s a very simplistic way to look at it with an idealized patient population. I think the high-risk people, we know, and those are probably people you need to pull trigger on earlier for an advanced wound therapies. As you would expect with faster wound healing, there were fewer treatments, the average number of treatments in the active treatment was 6, and 12 in the control arm and the durability of your response. So FDA has been asking about this for a long time and I used to think that this was just because the NBA does the NBA [Laugh] – FDA doesn't have a lot of insight into the ideology and recurrence of diabetic foot ulcers. I've always thought that this has a lot more to do with post-op care, and surveillance, and patient education and if you don't do that and people go back in the same environment. What the literature says is with no change in footwear and education and foot care 60% to 85% of people will re-ulcerate in the next year. And if they get good treatment, still a third of people will re-ulcerate in the next year. So if you look at this, the people that we're treating with this active therapy, the durability of their wound closure was 52% in the active group and only 15% in the controlled group. I think this is very compelling data that there were something happening on the cellular level that makes this perhaps a decrease scar formation or increase your subcutaneous tissue. We certainly need to understand this more and I think this is data that we need to peel the onion in the next two or three layers to understand why this is better, and if it's the things that we prescribed and do or if it's on the cellular level. But I think this is very compelling because this is where the money is. People having repeated that because every time they have an event, they're at risk for infection and amputation. Okay, so this is the data from the crossover study. The 20 patients in the control arm did not heal and they were allowed to get this active therapy weekly for 12 weeks. Of these patients who had failed therapy, 80% heal in the 12-week evaluation period.
I mean, this is also very noble for the study. Most companies don't do this because of the additional expense and time. So when I finished talking about adverse events which I think, I mean, this is where the money is in diabetic foot ulcers. What we spend on the outpatient is a fraction of the cost of what happens when people get into the hospital. And once you're admitted and you have surgery or you have an amputation, the recidivism for additional amputations goes up tremendously. There was a significant difference overall for adverse events and people who got active therapy. They had 42% adverse events and 66% in the control group. So these are sick high-risk patients and overall this was a pretty normal adverse event rate for DFU studies. The majority of the complications were related to infection which is what you would expect. But I think the data, I think, is really interesting and compelling and I think as this becomes evaluated, we understand this more, I mean, the insights about this therapy – well, perhaps will be even more exciting. So what you saw with infection was not only whether fewer infections but they were less severe infections. When you look at the number of infections, 14 people in the 12-week treatment phase were treated for an infection in the active therapy and 32% in the control arm. But I think this is where the money is. Only 2% of the patients had an active therapy required hospitalization for their infection, so 15% in the standard of therapy group. This is the serious adverse event group that starts the dominos for amputation and recidivism. Again, even with a relatively small number of patients for a randomized clinical study, this was significant. I think it's natural when you get a product like this to compare to what you know. If you look at this randomized clinical study, with the two bioengineered tissue products that we're familiar with fibroblast, product dermagraft, or a combination of fibroblast or keratinocyte, Apligraf product. The wound size is larger in the stem cell study. Looks like it's probably significantly smaller than the dermagraft randomized clinical study. The percent of patients that healed in weeks were 62%, 30%, and 56%. The control arms healing was 0.03, 21%, 18%, and 38%. I think the time to healing translates into a lot of reduction and adverse events, 42 days compared to 65 days and this number wasn't available in the dermagraft study. Faster healing time probably drives a lot of prevention aspects. If you look at adverse events, overall, it was 42 versus 66%, a significant difference. There wasn't a difference in the dermagraft study in adverse events. In the Apligraf study, they only reported infection and amputation adverse events combined, not total, so it was 29% versus 43. When you separate those out in the stem-cell therapy group, it was 14 versus 32%. Perhaps, this is related to the immune-privilege that other speakers have talked about this morning that's related to stem-cell therapy. This is a slide that compares the relative effect of using the advance therapy compared to their control arm, and this clinical study – fibroblast, bioengineered tissue, fibroblast keratinocyte, bioengineered tissue and PGF data studies, which are now more than a decade old. So 191% relative improvement in that study, about three times more than what has been previously been reported in the literature. To conclude, I think, this is exciting. It's the first randomized clinical study that's been successful in the DFU space in the last decade. I mean, for those of you who do clinical trials, there's a dozen clinical trials going on at all times. And the reason you don't hear about them is because they failed. I mean, no one’s going to spend money coming here and telling you about their fabulous failure. And investigators enroll 5, 10, 20 patients not enough to stand here and report. I think this is the first study with a successful interim analysis in the DFU space. I think that's exciting. It's the first clinical application of stem cells that is commercialized and you can use in clinical practice that has evidence to support its effectiveness. And I think it's exciting because it's the first interim analysis where the primary and all the secondary endpoints are successful. So with that, I will finish and thank you for your attention.