Section: CME Category: Vascular

Results from a Multi-Center Randomized Controlled Trial Evaluating the Efficacy of Dehydrated Human Amnion/Chorion Membrane Allograft for the Treatment of Venous Leg Ulcers

Gregory Tovmassian, DPM

Gregory Tovmassian, DPM discusses venous leg ulcers, their etiology and treatment. Dr Tovmassian reviews the significant major trials involving the use of standard of care treatments with and without dHACM supplementation and the conclusions drawn with each study.

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Goals and Objectives
  1. Analyze etiology and epidemiology of venous leg ulcers
  2. Discuss standard of care (SOC) treatment
  3. Review available advanced treatment modalities
  4. Review available literature
  5. Describe biology/histology of placenta based products
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    Release Date: 03/16/2018 Expiration Date: 12/31/2020

  • Author
  • Gregory Tovmassian, DPM

    Sacramento Foot and Ankle Center
    Center for Clinical Research
    Sacramento, CA
    Adjunct Assistant Clinical Professor
    California School of Podiatric Medicine at Samuel Merritt University
    Oakland, CA

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  • Lecture Transcript
  • Male Speaker 1: Our final speaker and presentation at this juncture prior to the break. Speaking about venous leg ulcers, Matt had mentioned something about treating venous leg ulcers. And again this is a big problem that you've seen throughout the course of this morning's and today’s talks. So we're going to present results from multi-center randomized RCT evaluating the efficacy of dehydrated human chorionic and amniotic membrane for the treatment of venous leg ulcers. Our speaker is new to us. It's Dr. Gregory Tomassian. He comes to us from Sacramento, California. So let’s welcome Dr. Tomassian.


    If you're using that I hope you have your dongle. Okay, great. Okay, wonderful. Thank you.

    Male Speaker 2: Okay. Thank you. Hello everyone. I'm kind of fortunate to be the last speaker before the break, so leaves very little reason for you all to run away. Also, it's nice to see all the other information presented before me as it sets the stage for some of the slides that I have prepared for you. I understand that some of my slides will be a kind of brief and we'll address that. Before I get started, I want to figure out the time situation because it doesn't make sense over there. Alright. Let’s go ahead. As already mentioned, I come from Sacramento, California. That’s where my private practice is. That’s also where I have an opportunity to participate in clinical trials. This is one of the ones I have been fortunate enough to participate in and now I have an opportunity to present some of the results. But with that said, we're going to go forward. I have no financial relationship to report. The learning objectives for this talk are listed here. We're going to spend some time talking about etiology and epidemiology of venous leg ulcers. For completeness sake, we'll also go over some of the standard of care treatment that’s available for venous leg ulcers. We'll briefly talk about some of the advanced treatment modalities and placenta-based product. We'll overview the level one evidence for this particular topic that’s available and we'll conclude with the trial that was just published a few months ago. When talking about epidemiology, it's important to understand that in 2014, it has been estimated that 2 million people were affected by this disease and obviously leading to significant cost to society. VLUs as all of us understand have a significant chronicity that leads to them staying open for months and even years on in. This will subsequently lead to psychosocial and economic burdens. In 2014, it was estimated that 15 billion dollars were spent on addressing treatment of venous leg ulcers. These don't just start spontaneously. It's a long chain of complex events that precipitates these and usually including venous insufficiency and venous hypertension. These will lead to various inflammatory processes, which will include leukocyte migration, endothelial damage, platelet aggravation and intracellular edema. And as that occurs, we'll also see that over time small vessel damage, further edema, hemosiderin deposits as well as local inflammation will develop leading to ulcerations directly or from minor trauma. And all of these same factors will later contribute to delays in healing. This is a busy slide. It shows up actually relatively well. Hopefully most of you can see it, but I'll go through most of the information here as it's important for us to understand that all of the basic principles of wound care applied to venous leg ulcers, which consists of debridement as thoroughly discussed in some of the previous talks, exudate control, which for venous leg ulcers arguably even more important than diabetic foot ulcers and infection control.


    Also systemic factors; we understand that chronic venous insufficiency often coincides with various systemic factors, congestive heart failure being one of them, so if the patient is not well compensated in that regard and is volume overloaded, this can play a huge role in treatment of venous leg ulcers, so it's worth addressing. With all of that being said though, compression is arguably one of the more important factors of standard of care treatment for venous leg ulcers. When I say compression, I'm typically implying multilayer compression dressings almost regardless of brand or whether your preference is two, three or four layer system. All of these are found acceptable in managing swelling. And for patients that cannot tolerate multilayer compression dressings, obviously the intermittent compression pumps are a worthy adjunct. I have used that even in patients who have multilayer compression dressings and that’s typically of value. As far as arterial insufficiency goes, as you see on left side of the screen, there are certain guidelines you want to look forward whatever your study of choice is to evaluate adequate arterial perfusion. It is of value, but I have found that it's not often a factor for venous leg ulcers. Not that it doesn't happen, but it doesn't happen as frequently as it does with diabetic ulcers in my opinion. Regardless of all of these even if all of that's being done appropriately, there is this four-week mark of greater than 40% healing that we should all be aware of and we'll see some of the trials where that comes from, but if the wound is not responding well and well being defined as more than 40% healing in four weeks, it is worth considering some alternative or advanced treatments as shown in this diagram from Cochrane Database Review and some of the trials I will be mentioning in a few seconds. This is another reminder of the fact that even in the best case scenario, we can expect only 45 degrees of venous leg ulcers to be healed at the 12-week mark. And more importantly, even that statistics stems off the fact that we have to see at least 40% reduction in size at the four-week mark to assume our treatment to be effective. So if it's not effective at reaching that clinical marker, something needs to be reassessed. Whether it's going through the same algorithm making sure you have checked off all of those factors we just discussed and if you have done that well, then you go on to consider other modalities. What do I mean alternate or advanced modalities? Well, this is not nearly all inclusive, but at the same time helps us get a general idea of what we could consider adding to our treatment whether it's some of the ointments available, some of the xenograft, which could be bovine or porcine based or combined. Even some of the grafts that have you know shark cartilage in them. More so for the sake of this discussion, we're going to be focusing on allografts that are placenta based and to fall in the same category as umbilical cord and also allografts in terms of living cells. In terms of split-thickness skin grafts, this is being used in a lot of places and it has its place. My experience has been the fact that when recurrence happens after a split-thickness skin graft, they are even harder to treat than native skin. So it's not something I employ in my practice frequently. Then surgical, mechanical, and enzymatic and autolytic, all the debridements that we've heard about just a few minutes ago including ultrasound technology whether that be debridement through ultrasound or non-contact ultrasound technologies. These again -- the slide is not all inclusive, but if you're practicing anything like mine, you probably have a rep coming from one or multiple of these companies to your office every week if not every day. We have not had any fights in the office with the reps, but at the same time occasionally they come in bunches. Now, the purpose of this talk is again to focus on placenta-based products, which will consist of various components of the placenta tissue, whether it be the entire spectrum as listed here in the picture or any components, amnion or chorion.


    The biggest difference in the products is the way they are prepped and we heard one of the products mentioned earlier where the preparation process was thoroughly described. I will just simply show you guys the major categories whether it would be dehydrated, cryopreserved or hypothermic presentations. Each company will have their own preparatory technique with ample available literature. When talking about level one studies, this list, even though short, it's actually quite inclusive meaning with the exception of the wound VAC, VLU trial, randomized trial that was just mentioned, the only other one that's of value that's not listed here is the one that preceded the low frequency ultrasound trial in 2013. Other than that, this is more or less all we have for level one randomized clinical trials for this particular topic and we'll go over each of these for trials here in the second concluding with the one that was published this year. So the first one to discuss is the trial that was looking into non-contact low frequency ultrasound as an adjunct to standard of care. This was published in 2015. The premise for their study was that non-contact ultrasound would affect the microenvironment of the wound, which of course is the goal of various different products. They were able to have these patients come back for three times a week for dressing changes and of course the treatment arm would get ultrasound treatment at each of those visits. So they had 112 participants with documented venous stasis and venous leg ulcers of more than 30 days' duration within the measurements of 4 to 58 cm sq. Of those, only 81 subjects went on to get randomized simply because the rest of them healed too much and you saw that being the case with some of the diabetic foot ulcer trials that were presented. If the wound is healing faster than a certain rate and then in this trial the certain rate was 30% in the first two weeks, it's expected to heal well with standard of care and there is no purpose of trying to include this patient in a trial like this or ones similar to this one. And they kept track of percent of wound reduction, number of wounds healed, pain and quality of life. So their results were basically as seen here that after four weeks of treatment, an average wound size reduction was 61% in active treatment group and 45% in the standard of care group. They also noticed that the reductions in median as well as absolute wound area and pain score were clinically significant and you see the numbers there were 65% versus 44% and wound size reduction 9 cm sq. versus 4.1 cm sq. So based on that information, they were able to conclude that addition of low-frequency ultrasound therapy is a great consideration for wounds that are not progressing as expected with standard of care treatment. They also recognized the fact that more treatment is necessary to address the whole microenvironment factor that they were looking into. Another big and arguably a pivotal study in this particular arena was this 1999 study where they were looking a bi-layered living skin construct and it’s effect to accelerate healing specifically on hard-to-heal wounds. And what they define as hard-to-heal or one of the criteria was the wound that’s open more than for one-year duration. So they were able to identify 120 subjects that met that criteria and again separated them into the standard of care versus standard of care plus the graft groups and tracked frequency of healing, which was defined by 100% epithelization. So in their study, they found that this graft skin was indeed statistically more significant or significantly effective in achieving healing and so their comparison was 47% versus 19% at six months.


    And they went on to also conclude that you can achieve six-month closure with this product in over 60% more effectively than you can with standard of care alone. Now getting further into the placenta-based products, this is a trial from 2015 looking at dehydrated human amnion and chorion membrane allografts and its efficacy along with multilayer compression dressing versus multilayer compression dressing alone. They were also looking to see if one application versus two applications of the allograft was going to make a difference and as we'll see in a second, it really didn't. But what did make a difference is the presence of allograft itself. So their primary outcome was proportion of the patients achieving 40% wound size reduction at four weeks. And again some of the earlier slides we mentioned are, kind of, being supported by this type of data as well. So they were able to have 84 participants, 53 of which were randomized to receive allograft and 31 in the standard of care arm. After four weeks of treatment, greater than 40% wound reduction was seen in 62% of the allograft group and only 32% in the standard of care group. Other clinically significant differences were seen in terms of mean size reduction where it was 48% for the combined group and just 19% for the standard of care group. What also makes this particular trial unique is that they did a follow-up to the randomized control trial by doing a retrospective review of those same patients at the 24-week mark. And what they found was a 73% correct correlation of those wounds going on to heal or not. In other words, to make it more clear, they found that if at four weeks the 40% healing was achieved, then those wounds typically went on to heal by 24 weeks and the opposite was true for those that didn't achieve that marker. Now, we'll enter, kind of, the last phase of this presentation discussing the multilayer randomized control clinical trial evaluating the efficacy of dehydrated human amnion and chorion membrane allograft for treatment of venous leg ulcers. This trial was published earlier this year and I was fortunate enough to be one of the principal investigators on this trial and subsequently invited to talk about it. So the purpose of the trial was to evaluate the efficacy of using a commercially available allograft that's dehydrated amnion-chorion membrane along with or stay in adjunct to standard comprehensive wound therapy. The hypothesis was of course that such graft would make a statistically significant difference and give us an advantage in healing these wounds. Primary end points pretty standard. They were looking at complete wound closure at 12 weeks as well as secondary endpoints looking at proportion of subjects with complete wound healing at 12 weeks and then at 16 weeks to see how that compares. And of course they tracked all adverse events and serious adverse events as well as any major product-related complications, which fortunately there were none. Some of the inclusion and exclusion criteria I will go over here, the 18 years old or older with full-thickness venous leg ulcers that are present for more than 30 days were included in this trial as long as they had a greater than 0.75 ABI and wound itself was located above the medial malleolus, I should say, at least 50% of it located above the medial malleolus. Of course, there is typically a couple of dozen more inclusion criteria, but those I think are most pertinent. As far as exclusion, just as most wound care trails especially venous leg ulcer trials, they excluded anyone with exposed muscle, tendon or bone, anyone with active signs of infection or any suggestion that there could be a malignancy present. Anyone who was on negative pressure wound therapy or hyperbaric oxygen therapy was asked to wait at least seven days for a washout period and a 30-day washout period for any advanced wound care products.


    From screening to randomization, as is often the case, the patients go through a two-week screening process as they did here in this trial in order to make sure that their, a) qualifying based on all the other criteria, and b) to see if they're healing too fast, so to speak, to participate in a clinical trial. And for this particular trial, it was said to be anything greater than 25% healing within the first two weeks would be considered an exclusion because those wounds are expected to go on to heal without any further or I should say, anything beyond standard of care. The wound size ranges 1 cm to 25 cm sq. after debridement. And these are randomized via sealed envelope group to make sure. All these same numbers I would rather go over in the schematic here. So as you can see initially there was 189 patients considered for the trial and entering the screening phase. Of those, 61 subjects were excluded based on healing more than 25%. So again some of the easier arguably less chronic, less challenging wounds were excluded and only the ones that weren't healing at that rate were included. So 128 patients were randomized equally separated between the two groups, 64 patients each, which is a significant sample size for a randomized clinical trial. Of those, 109 patients completed. The rest were excluded either for protocol violation reasons or serious adverse events. Three withdrew consent as you can see there. So the analysis consisted of 52 in allograft group and 57 in the standard of care group. This shows you that they were pretty evenly matched through this randomization process as far as patient’s demographics go, including age, smoking status, body mass index, history of diabetes, etc. Same can be said about wound characteristics, so they are pretty evenly matched in that regard as well considering wound location, duration and the starting size. This is just a kind of technicality in the sense of, once principal investigator saw or considered the wound healed and submitted a photo of a healed wound, there were three independent wound care specialists that were blind to the treatment group confirming the healing. And also all adverse events and serious adverse events were tracked by an independent committee. So the treatment phase, as I mentioned earlier, consisted of 12 weeks. That meant 12 weeks of standard of care for the standard of care group, which had a primary and secondary dressing as mentioned here. And the second group got the exact same treatment plus the allograft placed weekly up to 12 weeks or until complete healing, which of course significant number of patients will heal before the 12-week mark. What was also nice about this particular trial taking into account the standard 12-week treatment phase and the results from that, they also had the patients come back at 16-week mark whether they healed initially or not and that was, a) to assess for recurrence if the patient had healed at the 12-week mark and b) it was to see if that additional four weeks was going to have any effect in terms of healing rate or achieving complete healing. And what was also unique about this particular trial of patients that were initially in the standard of care group, but did not heal 40% by the eight-week mark were allowed to cross over into the active treatment group and start to receive allograft that's to avoid holding out on effective treatment. This is what the results look like in a graft format. So there is statistically significant difference in healing rates with 60% in allograft group and 35% in the standard of care group at 12 weeks and there was a similar relationship when that was evaluated at the 16-week mark. This is just another way to represent the same information using a Kaplan-Meier Curve showing that the patients were 2.26 times more likely to heal in allograft group as they were in standard of care at 12 weeks and roughly around two times also more likely to do so at the 16-week mark.


    This is a list of all the adverse events, none of which were, a) related to the treatment itself and none of which really deferred from one group to the other. So key highlights takeaway points, this is a great representation of the patient population that most of you are probably seeing considering the fact that nine of the sites included in this trial were private office setting and six were hospital-based centers and everything else we just discussed in terms of its efficacy at the 12-week and 16-week mark. These are my references. Thank you.